bluuebunny/crossref_metadata_2025 huggingface dataset:
The Endogeneity of Race: Black Racial Identification and Men’s Earnings in Mexico
Authors: Villarreal Andrés , Bailey Stanley R
Published: June 2019

A growing body of sociological research has shown that racial identification is not only fluid, but crucially depends on other individual- and societal-level factors. When such factors are also associated with socioeconomic outcomes such as earnings, estimates of the disadvantage experienced by individuals because of how they identify racially obtained from standard regression models may be biased. We illustrate this potential bias using data from a large-scale survey conducted by the Mexican census bureau. This survey is the first by the government agency since the country’s independence to include a question on black identification. We find evidence of a substantial bias in estimates of racial disadvantage. Results from our initial models treating racial self-identification as an exogenous predictor indicate that black men have higher earnings than non-black men. However, when we use an instrumental variables model that treats racial self-identification as endogenous, that is, as a function of the same unobserved characteristics as individuals’ earnings, we find a significant negative effect of black identification on earnings. While previous studies have acknowledged the endogeneity of race, ours is the first to explicitly model racial self-identification as an endogenous predictor to obtain an unbiased estimate of its effect on individuals’ socioeconomic conditions.
Phenotype of ventilatory control in children with moderate to severe persistent asthma and obstructive sleep apnea
Authors: He Zhihui , Armoni Domany Keren , Nava-Guerra Leonardo , Khoo Michael C K , Difrancesco Mark , Xu Yuanfang , Mcconnell Keith , Hossain Md Monir , Amin Raouf
Published: June 2019

Study Objectives

To examine the role of ventilatory control in asthmatic children with obstructive sleep apnea (OSA) and the relationships between measures of ventilatory control, OSA severity, and pulmonary function.

Methods

Five- to 18-year-old children with persistent asthma and nightly snoring were enrolled in the study. Children had physical examination, pulmonary function test, and polysomnography. Loop and controller gains were derived from 5 min segments which included a sigh during nonrapid eye movement sleep by applying a mathematical model that quantifies ventilatory control from the ensuing responses to the sighs. Plant gain was derived from 5 min segments of spontaneous breathing (i.e. without sighs). Nonparametric statistical tests were used for group comparisons. Cluster analysis was performed using Bayesian profile regression.

Results

One hundred thirty-four children were included in the study, 77 with and 57 without OSA. Plant gain was higher in children with OSA than in those without OSA (p = 0.002). A negative correlation was observed between plant gain and forced expiratory volume in 1 second (p = 0.048) and the ratio of f forced expiratory volume to forced vital capacity (p = 0.02). Plant gain correlated positively with severity of OSA. Cluster analysis demonstrated that children with more severe OSA and abnormal lung function had higher plant gain and a lower controller gain compared with the rest of the population.

Conclusions

Children with OSA and persistent asthma with abnormal lung function have phenotypic characteristics which consist of diminished capacity of the lungs to maintain blood gas homeostasis reflected by an increase in plant gain and decreased chemoreceptor sensitivity.
Repair of severe winter xylem embolism supports summer water transport and carbon gain in flagged crowns of the subalpine conifer Abies veitchii
Authors: Ogasa Mayumi Y , Taneda Haruhiko , Ooeda Hiroki , Ohtsuka Akihiro , Maruta Emiko
Published: June 2019

Xylem embolism induced by winter drought is a serious dysfunction in evergreen conifers growing at wind-exposed sites in the mountains. Some coniferous species can recover from winter embolism. The aim of this study was to determine whether wind direction influences embolism formation and/or repair dynamics on short windward and long leeward branches of asymmetrical `flagged' crowns. We analyzed the effect of branch orientation on percentage loss of xylem conductive area (PLC), leaf functional traits and the xylem:leaf area ratio for subalpine, wind-exposed flagged-crown Abies veitchii trees in the northern Yatsugatake Mountains of central Japan. In late winter, the shoot water potential was below −2.5 MPa, and the PLC exceeded 80% in 2-year-old branches, independent of branch orientation within a flagged crown. Both of these parameters almost fully recovered by summer. At branch internodes 4 years of age and older, seasonal changes in PLC were not found in either windward or leeward branches, but the PLC was higher in less leafy windward branches. The leaf nitrogen content and water-use efficiency of mature leaves were comparable between windward branches and leafy leeward branches. The ratio of xylem conductive area to total leaf area was the same for windward and leeward branches. These results indicate that the repair of winter xylem embolism allows leaf physiological functions to be maintained under sufficient leaf water supply, even on winter-wind-exposed branches. This permits substantial photosynthetic carbon gain during the following growing season on both windward and leeward branches. Thus, xylem recovery from winter embolism is a key trait for the survival of harsh winters and to support productivity on the individual level in flagged-crown A. veitchii trees.
Determinants of Lung Function at Age 8.5 Years in a Birth Cohort of Thai Children
Authors: Anuntaseree Wanaporn , Ruangnapa Kanokpan , Sangsupawanich Pasuree , Mo-suwan Ladda , Saelim Kantara , Pruphetkaew Nannapat
Published: June 2019

Background and aims

Early life factors have reported the associations with impaired lung function in later life. In the present study, the birth cohort was followed up longitudinally to investigate the determinants of lung function in Thai children.

Methods

Cohort subjects were recruited from children born in Songkhla Province in southern Thailand. Data collections were obtained starting from antenatal, at birth, and at 1, 5 and 8.5 years of age. Spirometry was assessed at age 8.5 years. The variables investigated included birth weight, smoke exposure, respiratory diseases during the newborn period and during the first year of life, and asthma diagnosed at age 5 or 8.5 years.

Results

Of 1056 subjects, 892 (84.5%) subjects completed the spirometric measurements. The presence of asthma was the only factor that was significantly associated with a lower forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio, forced expiratory flow at 25–75% vital capacity (FEF25–75%VC) and peak expiratory flow rate (PEFR). The regression analysis found that asthma was significantly associated with a lower FEV1/FVC ratio, FEF25–75%VC, and PEFR value with estimated coefficients ± standard error of –1.27 ± 0.55%, p = 0.02; –131.8 ± 48.2 ml/s, p = 0.006; and –166.2 ± 65.0 ml/s, p = 0.01, respectively. Asthma diagnosed at age 5 or 8.5 years was more likely among children who had lower respiratory tract illness during the first year of life. The odds ratio for the association was 4.81 (95% confidence interval 2.14–10.83, p < 0.001).

Conclusion

The main factor associated with lower lung function in Thai cohort subjects was the present of asthma by age 5 or 8.5 years and early respiratory illness was the risk factor for asthma in childhood period.
Clinical Outcomes Associated with Fluid Overload in Critically Ill Pediatric Patients
Authors: El-Nawawy Ahmed , Moustafa Azza A , Antonios Manal A M , Atta May M
Published: June 2019

Background

Fluid overload (FO) has been accused as being one of the ICU problems affecting morbidity and mortality. The aim of the study was to assess the effect and critical threshold of FO that is related to mortality.

Methods

This prospective observational study was conducted in a pediatric ICU. All patients admitted (n = 203) during 12 months with a length of stay more than 48 h were recruited.

Results

FO was found to be related to mortality (p = 0.025) but was not proved to be an independent risk factor of fatal outcome by the logistic regression model. This raises the suspicion about any cause—effect relationship between FO and mortality. Even though, FO was statistically a fair discriminator of death (AUC = 0.655, p = 0.0008) and a cutoff level of FO was set at 7%. Kaplan–Meier curve showed that cumulative of survival differed significantly between groups of patients with FO more and less than 7% (p = 0.002)

Conclusion

Frequent and accurate monitoring of FO is crucial among critically ill patients. The present study suggested a threshold of 7% FO beyond which a more conservative regimen of fluid administration might improve patients’ outcome.
Ultrastructure of the midgut epithelium in three species of Macrobiotidae (Tardigrada: Eutardigrada: Parachela)
Authors: Rost-Roszkowska M , Janelt K , Poprawa I
Published: June 2019

Three species of Macrobiotidae, Macrobiotus polonicus, Macrobiotus diversus and Macrobiotus pallarii, were selected for analysis of the fine structure of the midgut epithelium. They are gonochoric and carnivorous species that live in wet terrestrial and freshwater environments. The ultrastructure of the midgut epithelium of the investigated Macrobiotidae species was analysed in both males and females. Their digestive system is composed of fore- and hindguts that are covered by a cuticle, and the middle region, termed the midgut. It is lined with a simple epithelium that is formed by digestive cells that have a distinct brush border. Crescent-shaped cells that form an anterior ring in the border between the fore- and midgut were detected. The ultrastructure of the intestinal epithelium of the examined species differs slightly depending on sex. The digestive cells of the posterior segment of the intestine contain numerous lipid droplets, which are the reserve material. We concluded that the digestive cells of the Macrobiotidae midgut are responsible for its intracellular digestion owing to endocytosis. They also participate in the extracellular digestion owing to merocrine secretion (exocytosis). However, the midgut is not the main organ that accumulates reserve material. Additionally, the midgut epithelium does not participate in oogenesis.
A prospective analysis of circulating plasma metabolomics and ovarian cancer risk
Authors: Zeleznik Oana A. , Eliassen A. Heather , Kraft Peter , Poole Elizabeth M. , Rosner Bernard , Jeanfavre Sarah , Deik Amy , Bullock Kevin , Hitchcock Daniel , Avila-Pancheco Julian , Clish Clary B. , Tworoger Shelley S.
Published: June 2019

We assessed the association of pre-diagnostic plasma metabolites (N=420) with ovarian cancer risk. We included 252 cases and 252 matched controls from the Nurses’ Health Studies. Multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) comparing the 90th-10thpercentile in metabolite levels, using permutation tests to account for testing multiple correlated hypotheses. Weighted gene co-expression network analysis (WGCNA) modules (n=10) and metabolite set enrichment analysis (MSEA; n=23) were also evaluated. Pseudouridine had the strongest statistical association with ovarian cancer risk overall (OR=2.56, 95%CI=1.48-4.45; p=0.001/adjusted-p=0.15). C36:2 phosphatidylcholine (PC) plasmalogen had the strongest statistical association with lower risk (OR=0.11, 95%CI=0.03-0.35; p<0.001/adjusted-p=0.06) and pseudouridine with higher risk (OR=9.84, 95%CI=2.89-37.82; p<0.001/adjusted-p=0.07) of non-serous tumors. Seven WGCNA modules and 15 classes were associated with risk at FDR≤0.20. Triacylglycerols (TAGs) showed heterogeneity by tumor aggressiveness (case-only heterogeneity-p<0.0001). TAG association with risk overall and serous tumors differed by acyl carbon content and saturation. Pseudouridine may be a novel risk factor for ovarian cancer. TAGs may also be important, particularly for rapidly fatal tumors, with associations differing by structural features. Validation in independent prospective studies and complementary experimental work to understand biological mechanisms is needed.
Mendelian Randomization Analysis Dissects the Relationship between NAFLD, T2D, and Obesity and Provides Implications to Precision Medicine
Authors: Liu Zhipeng , Zhang Yang , Graham Sarah , Pique-Regi Roger , Dong Xiaocheng Charlie , Chen Y. Eugene , Willer Cristen , Liu Wanqing
Published: June 2019

Background

Non-alcoholic fatty liver disease (NAFLD) is epidemiologically correlated with both type 2 diabetes (T2D) and obesity. However, the causal inter-relationships among the three diseases have not been completely investigated.

Aim

We aim to explore the causal relationships among the three diseases.

Design and methods

We performed a genome-wide association study (GWAS) on fatty liver disease in ∼400,000 UK BioBank samples. Using this data as well as the largest-to-date publicly available summary-level GWAS data, we performed a two-sample bidirectional Mendelian Randomization (MR) analysis. This analysis tested the causal inter-relationship between NAFLD, T2D, and obesity, as well as the association between genetically driven NAFLD (with two well-established SNPs at the PNPLA3 and TM6SF2 loci) and glycemic and lipidemic traits, respectively. Transgenic mice expressing the human PNPLA3 I148I (TghPNPLA3-I148I) and PNPLA3 I148M (TghPNPLA3-I148M) isoforms were used to further validate the causal effects.

Results

We found that genetically instrumented hepatic steatosis significantly increased the risk for T2D (OR=1.3, 95% CI: [1.2, 1.4],p=8.3e-14) but not the intermediate glycemic phenotypes at the Bonferroni-adjusted level of significance (p<0.002). There was a moderate, but significant causal association between genetically driven hepatic steatosis and decreased risk for BMI (β=- 0.027 SD, 95%CI: [−0.043, −0.01],p=1.3e-4), but an increased risk for WHRadjBMI (Waist-Hip Ratio adjusted for BMI) (β=0.039 SD, 95%CI: [0.023, 0.054],p=8.2e-7), as well as a decreased level for total cholesterol (β=-0.084 SD, 95%CI [−0.13, −0.036],p=6.8e-4), but not triglycerides (β=0.02 SD, 95%CI [−0.023, 0.062],p=0.36). The reverse MR analyses suggested that genetically driven T2D (OR=1.1, 95% CI: [1.0, 1.2],p=1.7e-3), BMI (OR=2.3, 95% CI: [2.0, 2.7],p=1.4e-25) and WHRadjBMI (OR=1.5, 95% CI: [1.3, 1.8],p=1.1e-6) causally increase the NAFLD risk. In the animal study, as compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed higher fasting glucose level and reduced glucose clearance. Meanwhile, the TghPNPLA3-I148M mice demonstrated a reduced body weight, increased central to peripheral fat ratio, decreased circulating total cholesterol as compared to the TghPNPLA3-I148I controls.

Conclusion

This large-scale bidirectional MR study suggests that lifelong, genetically driven NAFLD is a causal risk factor for T2D (hence potentially a “NAFLD-driven T2D” subtype) and central obesity (or “NAFLD-driven obesity” subtype), but protects against overall obesity; while genetically driven T2D, obesity, and central obesity also causally increase the risk of NAFLD, hence a “metabolic NAFLD”. This causal relationship revealed new insights into disease subtypes and provided novel hypotheses for precision treatment or prevention for the three diseases.
A new colorectal cancer risk prediction model incorporating family history, personal and environmental factors
Authors: Zheng Yingye , Hua Xinwei , Win Aung K. , MacInnis Robert J. , Gallinger Steven , Marchand Loic Le , Lindor Noralane M. , Baron John A. , Hopper John L. , Dowty James G. , Antoniou Antonis C. , Zheng Jiayin , Jenkins Mark A. , Newcomb Polly A.
Published: June 2019

Purpose

Reducing colorectal cancer (CRC) incidence and mortality through early detection would improve efficacy if targeted. A CRC risk-prediction model incorporating personal, family, genetic and environmental risk factors could enhance prediction.

Methods

We developed risk-prediction models using population-based CRC cases (N=4,445) and controls (N=3,967) recruited by the Colon Cancer Family Registry Cohort (CCFRC). A familial risk profile (FRP) was calculated to summarize individuals’ risk based on their CRC family history, family structure, germline mutation probability in major susceptibility genes, and a polygenic component. Using logistic regression, we developed risk models including individuals’ FRP or a binary CRC family-history (FH), and risk factors collected at recruitment. Model validation used follow-up data for population-(N=12,052) and clinic-based (N=5,584) relatives with no cancer history at recruitment, assessing calibration (E/O) and discrimination (AUC).

Results

The E/O (95% confidence interval [CI]) for FRP models for population-based relatives were 1.04 (0.74-1.45) and 0.86 (0.64-1.20) for men and women, and for clinic-based relatives 1.15 (0.87-1.58) and 1.04 (0.76-1.45). The age-adjusted AUC (95% CI) for FRP models in population-based relatives were 0.69 (0.60-0.78) and 0.70 (0.62-0.77), and for clinic-based relatives 0.77 (0.69-0.84) and 0.68 (0.60-0.76). The incremental values of AUC (95% CI) for FRP over FH models for population-based relatives were 0.08 (0.01-0.15) and 0.10 (0.04-0.16), and for clinic-based relatives 0.11 (0.05-0.17) and 0.11 (0.06-0.17).

Conclusion

The FRP-based model and FH-based model calibrate well in both settings. The FRP-based model provided better risk-prediction and discrimination than the FH-based model. A detailed family history may be useful for targeted risk-based screening and clinical management.
Genomic and phenotypic comparison of environmental and patient-derived isolates ofPseudomonas aeruginosasuggest that antimicrobial resistance is rare within the environment
Authors: Ramsay Kay A , Wardell Samuel J T , Patrick Wayne M , Brockway Ben , Reid David W , Winstanley Craig , Bell Scott C , Lamont Iain L
Published: June 2019

Patient-derived isolates of the opportunistic pathogenPseudomonas aeruginosaare frequently resistant to antibiotics due to the presence of sequence variants in resistance-associated genes. However, the frequency of antibiotic resistance and of resistance-associated sequence variants in environmental isolates ofP. aeruginosahas not been well studied. Antimicrobial susceptibility testing (ciprofloxacin, ceftazidime, meropenem, tobramycin) of environmental (n=50) and cystic fibrosis (n=42)P. aeruginosaisolates was carried out. Following whole genome sequencing of all isolates, twenty-five resistance-associated genes were analysed for the presence of likely function-altering sequence variants. Environmental isolates were susceptible to all antibiotics with one exception, whereas patient-derived isolates had significant frequencies of resistance to each antibiotic and a greater number of likely resistance-associated genetic variants. These findings indicate that the natural environment does not act as a reservoir of antibiotic-resistantP. aeruginosa, supporting a model in which antibiotic susceptible environmental bacteria infect patients and develop resistance during infection.

Author Contributions
NoRCE: Non-coding RNA Sets Cis Enrichment Tool
Authors: Olgun Gulden , Nabi Afshan , Tastan Oznur
Published: June 2019

While some non-coding RNAs (ncRNAs) are assigned to critical regulatory roles, most remain functionally uncharacterized. This presents a challenge whenever an interesting set of ncRNAs needs to be analyzed in a functional context. Transcripts located close-by on the genome are often regulated together. This genomic spatial proximity can lead to a functional association. Based on this idea, we present a tool, NoRCE, that performs cis enrichment analysis for a given set of ncRNAs. Enrichment is carried out using the functional annotations of the coding genes located proximal to the input ncRNAs. NoRCE allows incorporating other biologically relevant information such as topologically associating domain (TAD) boundaries, co-expression patterns, and miRNA target prediction information. NoRCE repository provides several data, such as cell-line specific TAD boundaries, functional gene sets, and expression data for coding and ncRNAs specific to cancer for the analysis. Additionally, users can utilize their custom data files in their investigation. Enrichment results can be retrieved in a tabular format or visualized in several different ways. NoRCE is currently available for the following species: human, mouse, rat, zebrafish, fruit fly, worm, and yeast. NoRCE is a platform-independent, user-friendly, comprehensive R package that could be used to gain insight into the functional importance of a list of any type of interesting ncRNAs. Users can run the pipeline in a single function; also, the tool offers flexibility to conduct the users’ preferred analysis in a single base and design their pipeline. It is available in Bioconductor and https://github.com/guldenolgun/NoRCE.
Plasticity in auditory categorization is supported by differential engagement of the auditory-linguistic network
Authors: Bidelman Gavin M. , Walker Breya
Published: June 2019

To construct our perceptual world, the brain categorizes variable sensory cues into behaviorally-relevant groupings. Categorical representations are apparent within a distributed fronto-temporo-parietal brain network but how this neural circuitry is shaped by experience remains undefined. Here, we asked whether speech (and music) categories might be formed within different auditory-linguistic brain regions depending on listeners’ auditory expertise. We recorded EEG in highly skilled (musicians) vs. novice (nonmusicians) perceivers as they rapidly categorized speech and musical sounds. Musicians showed perceptual enhancements across domains, yet source EEG data revealed a double dissociation in the neurobiological mechanisms supporting categorization between groups. Whereas musicians coded categories in primary auditory cortex (PAC), nonmusicians recruited non-auditory regions (e.g., inferior frontal gyrus, IFG) to generate category-level information. Functional connectivity confirmed nonmusicians’ increased left IFG involvement reflects stronger routing of signal from PAC directed to IFG, presumably because sensory coding is insufficient to construct categories in less experienced listeners. Our findings establish auditory experience modulates specific engagement and inter-regional communication in the auditory-linguistic network supporting CP. Whereas early canonical PAC representations are sufficient to generate categories in highly trained ears, less experienced perceivers broadcast information downstream to higher-order linguistic brain areas (IFG) to construct abstract sound labels.
Nowcasting by Bayesian Smoothing: A flexible, generalizable model for real-time epidemic tracking
Authors: McGough Sarah F. , Johansson Michael A. , Lipsitch Marc , Menzies Nicolas A.
Published: June 2019

Delays in case reporting are common to disease surveillance systems, making it difficult to track diseases in real-time. “Nowcast” approaches attempt to estimate the complete case counts for a given reporting date, using a time series of case reports that is known to be incomplete due to reporting delays. Modeling the reporting delay distribution is a common feature of nowcast approaches. However, many nowcast approaches ignore a crucial feature of infectious disease transmission—that future cases are intrinsically linked to past reported cases—and are optimized to a single application, which may limit generalizability. Here, we present a Bayesian approach, NobBS (Nowcasting by Bayesian Smoothing) capable of producing smooth and accurate nowcasts in multiple disease settings. We test NobBS on dengue in Puerto Rico and influenza-like illness (ILI) in the United States to examine performance and robustness across settings exhibiting a range of common reporting delay characteristics (from stable to time-varying), and compare this approach with a published nowcasting package. We show that introducing a temporal relationship between cases considerably improves performance when the reporting delay distribution is time-varying, and we identify trade-offs in the role of moving windows to accurately capture changes in the delay. We present software implementing this new approach (R package “NobBS”) for widespread application.

Significance

Achieving accurate, real-time estimates of disease activity is challenged by delays in case reporting. However, approaches that seek to estimate cases in spite of reporting delays often do not consider the temporal relationship between cases during an outbreak, nor do they identify characteristics of robust approaches that generalize to a wide range of surveillance contexts with very different reporting delays. Here, we present a smooth Bayesian nowcasting approach that produces accurate estimates that capture the time evolution of the epidemic curve and outperform a previous approach in the literature. We assess the performance for two diseases to identify important features of the reporting delay distribution that contribute to the model’s performance and robustness across surveillance settings.
De novoβ-alanine synthesis in α-proteobacteria involves a β-alanine synthase from the uracil degradation pathway
Authors: López-Sámano Mariana , Lozano-Aguirre Beltrán Luis Fernando , Sánchez-Thomas Rosina , Dávalos Araceli , Villaseñor Tomás , García-García Jorge Donato , García-de los Santos Alejandro
Published: June 2019

β-alanine synthesis in bacteria occurs by the decarboxylation of L-aspartate as part of the pantothenate synthesis pathway. In the other two domains of life we find different pathways for β-alanine formation, such as sources from spermine in plants, uracil in yeast and by transamination reactions in insects and mammals. There are also promiscuous decarboxylases that can decarboxylate aspartate. Several bioinformatics studies about the conservation of pantothenate synthesis pathway performed on bacteria, archaea and eukaryotes, have shown a partial conservation of the pathway. As a part of our work, we performed an analysis of the prevalence of reported β-alanine synthesis pathways in 204 genomes of alpha-proteobacteria, with a focus on theRhizobialesorder. The aim of this work was to determine the enzyme or pathway used to synthetize β-alanine inRhizobium etliCFN42. Our bioinformatics analysis showed that this strain encodes the pyrimidine degradation pathway in its genome. We obtained a β-alanine synthase (amaB)mutant that was a β-alanine auxotroph. Complementation with the cloned gene restored the wild type phenotype. Biochemical analysis confirmed that the recombinant AmaB catalyzed the formation of β-alanine from 3-Ureidopropionic acidin vitro. Here we show a different way in bacteria to produce this essential metabolite.

Importance

Since the pioneer studies of Cronan (1980) on β-alanine synthesis inE. coli, it has been assumed that the decarboxilation of aspartate by the L-aspartate-α-decarboxylase it’s the main enzymatic reaction for β-alanine synthesis in bacteria. Forty years later, while we were studying the pantothenic acid synthesis in rhizobia, we demonstrate that a numerous and diverse group of bacteria classified as α-proteobacteria synthesize β-alaninede novousing β-alanine synthase, the last enzyme from the reductive pathway for uracil degradation.

Additionally, there is a growing interest in β-amino acid due to its remarkable pharmaceuticals properties as hypoglycemic, antiketogenic and anti-fungal agents.
SINEUP long non-coding RNA acts via PTBP1 and HNRNPK to promote translational initiation assemblies
Authors: Toki Naoko , Takahashi Hazuki , Zucchelli Silvia , Gustincich Stefano , Carninci Piero
Published: June 2019

SINEUPs are long non-coding RNAs (lncRNAs) that contain a SINE element, which up-regulate the translation of target mRNA and have been studied in a wide range of applications for biological and therapeutic tools, although the molecular mechanism is unclear. Here, we focused on the kinetic distribution of target mRNAs and SINEUP RNAs by performing co-transfection of expression vectors for these transcripts into human embryonic normal kidney cells (HEK293T/17) to investigate the network of translational regulation. The results showed that co-localization of target mRNAs and SINEUP RNAs in the cytoplasm was one of the key phenomena. We identified PTBP1 and HNRNPK as essential RNA binding proteins. These proteins contributed to SINEUP RNA sub-cellular distribution and to assembly of translational initiation complexes, leading to enhanced target mRNA translation. These findings will promote a better understanding of the mechanisms on the fate of regulatory RNAs implicated in efficient protein translation.
Identification of nutrient deficiency in bean plants by prompt chlorophyll fluorescence measurements and Artificial Neural Networks
Authors: Aleksandrov Vladimir
Published: June 2019

The deficiency of macro (N, P, S, Ca, Mg and K) and micro (Zn, Cu, B, Mo, Cl, Mn and Fe) minerals has a major effect on plant development. The lack of some nutrient minerals especially of nitrogen, potassium, calcium, phosphorus and iron is a huge problem for agriculture and early warning and prevention of the problem will be very useful for agro-industry. Methods currently used to determine nutritional deficiency in plants are soil analysis, plant tissue analysis, or combined methods. But these methods are slow and expensive. In this study, a new method for determining nutrient deficiency in plants based on the prompt fluorescence of chlorophyll a is proposed. In this paper bean plants are grown on a complete nutrient solution (control) were compared with those grown in a medium, which lacked one of these elements - N, P, K, Ca and Fe. In this article the mineral deficiency in nutrient solution was evaluated by the stress response of the plants estimated by leaves photosynthetic activity. The photosynthetic activity was estimated by analysis of the chlorophyll fluorescence using JIP-test approach that reflects functional activity of Photosystems I and II and of electron transfer chain between them, as well as the physiological state of the photosynthetic apparatus as whole. Next the fluorescence transient recorded from plants grown in nutrient solution with deficiency of N, P, K, Ca and Iron, as an input data in Artificial Neural Network was used. This ANN was train to recognise deficiency of N, P, K, Ca and Iron in bean plants. The results obtained were of high recognition accuracy. The ANN of fluorescence transient was presented as a possible approach to identify/predict the nutrient deficiency using the fast chlorophyll fluorescence records.
Kinetic mechanisms of fast glutamate sensing by fluorescent protein probes
Authors: Coates C. , Kerruth S. , Helassa N. , Török K.
Published: June 2019

Protein-based fluorescent glutamate sensors have the potential for real-time monitoring of synaptic and cellular glutamate concentration changes, however even the fastest currently available sensors’ response times of 2-3 ms are too slow for accurate reporting of the post-synaptic AMPA receptor function in physiological conditions. We have developed probes based on the bacterial periplasmic glutamate/aspartate binding protein with either an endogenously fluorescent protein or a synthetic fluorophore as the indicator of glutamate binding: affinity variants of iGluSnFR termed iGluh, iGlumand iGlulcovering a range ofKd−s (5.8 μM, 2.1 mM and 50 mM, respectively) and a novel fluorescently labelled indicator, Fl-GluBP with aKdof 9.7 μM are presented. The fluorescence response kinetics of all the probes are consistent with two-step mechanisms involving ligand binding and rate limiting isomerisation, however the contribution in each step to the total fluorescence enhancement and kinetic paths to the final state are diverse. In contrast to the previously characterised ultrafast indicators iGluuand iGluf, for which fluorescence enhancement occurred only in the rate limiting isomerisation step, the sensors described here all have biphasic binding kinetics with a significant fraction of the fluorescence increase evoked by glutamate binding which, in the case of iGluhand Fl-GluBP, occurs with a diffusion limited rate constant. The above genetically encoded and chemically labelled fluorescent glutamate sensor variants demonstrate how single amino acid changes around the binding site introduce structural heterogeneity affecting the kinetic mechanism of interactions with glutamate. Through their broad affinity range and mechanistic variety, the probes contribute to a novel toolkit for monitoring processes of glutamate neurotransmission and cellular homeostasis.

STATEMENT OF SIGNIFICANCE

Glutamate is a major excitatory neurotransmitter, important in synaptic plasticity e.g. memory formation. Although predicted to clear rapidly from the synaptic cleft following presynaptic release, optical monitoring of glutamate neurotransmission has only become possible with the advent of fluorescent, protein-based indicators. Understanding their biophysical properties is important for quantification of the observed processes. Here we report the biophysical characterisation of a number of glutamate indicator variants based on the bacterial periplasmic glutamate/aspartate binding protein, revealing the subtle differences in their kinetic pathway caused by structural alteration of the glutamate binding protein by point mutations. Diffusion limited glutamate binding indicated by a novel chemically labelled probe hints at the mechanism that underlies the rapid response of the AMPA receptor.
The p38MAPK-MK2-HSP27 Pathway Regulates the mRNA Stability of the Senescence-Associated Secretory Phenotype
Authors: Moore Hayley R. , Alspach Elise , Hirsch Jeffrey L. , Monahan Joseph , Stewart Sheila A.
Published: June 2019

Age is a significant risk factor for the development of cancer. Both age-dependent accumulation of cell autonomous mutations within preneoplastic cells and increases in senescent stromal cells within the tumor microenvironment are thought to collaborate to drive tumorigenesis. Senescent cells express pro-tumorigenic factors termed the senescence-associated secretory phenotype (SASP), subject to a variety of regulatory mechanisms that are not fully elucidated. Previous work demonstrated that p38 mitogen-activated protein kinase (p38MAPK)-dependent regulation of AUF1 occupancy on SASP factor mRNAs post-transcriptionally stabilizes many SASP mRNAs and contributes to their increased expression. Here, we address the mechanism by which p38MAPK regulates AUF1’s occupancy and activity on SASP factor mRNAs. We found that the p38MAPK-MK2-HSP27 pathway regulates both mRNA stability and AUF1 occupancy in cells induced to senesce. Furthermore, the tumor-promoting abilities of senescent stromal cells were lost upon inhibition of MK2, suggesting that this pathway is a viable therapeutic target within the tumor microenvironment.
RanGTP induces an effector gradient of XCTK2 and importin α/β for spindle microtubule cross-linking
Authors: Ems-McClung Stephanie C. , Emch Mackenzie , Zhang Stephanie , Mahnoor Serena , Weaver Lesley N. , Walczak Claire E.
Published: June 2019

High RanGTP around chromatin is important for governing spindle assembly during meiosis and mitosis by releasing the inhibitory effects of importin α/β. Here we examine how the Ran gradient regulates Kinesin-14 function to control spindle organization. We show thatXenopusKinesin-14, XCTK2, and importin α/β form an effector gradient, which is highest at the poles that diminishes toward the chromatin and is inverse of the RanGTP gradient. Importin α/β preferentially inhibit XCTK2 anti-parallel microtubule cross-linking and sliding by decreasing the microtubule affinity of the XCTK2 tail domain. This change in microtubule affinity enables RanGTP to target endogenous XCTK2 to the spindle. We propose that these combined actions of the Ran pathway are critical to promote Kinesin-14 parallel microtubule cross-linking at the spindle poles to cluster centrosomes in cancer cells. Furthermore, our work illustrates that RanGTP regulation in the spindle is not simply a switch, but rather generates effector gradients where RanGTP gradually tunes the activities of spindle assembly factors.

Ems-McClung et al. visualize a RanGTP effector gradient of association between XCTK2 and importin α/β in the spindle. The importins preferentially inhibit XCTK2-mediate anti-parallel microtubule cross-linking and sliding, which allows XCTK2 to cross-link parallel microtubules and help focus spindle poles.
Gastruloid development competence discriminates different states of pluripotency between naïve and primed
Authors: Cermola Federica , D’Aniello Cristina , Tatè Rosarita , De Cesare Dario , Martinez-Arias Alfonso , Minchiotti Gabriella , Patriarca Eduardo Jorge
Published: June 2019

Floating spheroidal aggregates (aggregomes) of mouse embryonic stem cells (mESCs) can develop into polarized/elongated organoids, namely gastruloids. Here we report a high-performing assay to measure gastruloids formation efficiency (GFE), i.e. the fraction of gastruloid-developing aggregomes. By exploiting this procedure, we provide morphological and molecular evidence that gastruloid development relies on Cripto. We also demonstrate that GFE decreases as pluripotency progresses from naïve to primed state. Indeed, naïve ESC-derived aggregomes efficiently elongate (GFE≥95%), while primed EpiSCs fail to aggregate and consequently to generate gastruloids (GFE=0%). Conversely, while early-primed EpiLCs properly aggregate, EpiLC-derived aggregomes are mostly abortive (GFE=0%). Unlike EpiLCs, L-Proline-treated ESCs (PiCs) generate productive aggregomes (GFE≥50%), which however begin to elongate earlier and generate smaller gastruloids that appear more differentiated. Like EpiLCs, PiCs are competent to differentiate into primordial germ cell-like cells (PGCLCs), suggesting that PiCs capture an EpiLC-like state with unique competence for both gastruloid formation and differentiation into PGCLCs. Thus we propose GFE assay as a simple and robust in vitro method to discriminate different phenotypic/functional states of the pluripotency continuum.
Genomic architecture of Shh dependent cochlear morphogenesis
Authors: Muthu Victor , Rohacek Alex. M. , Yao Yao , Rakowiecki Staci M. , Brown Alexander S. , Zhao Ying-Tao , Meyers James , Won Kyoung-Jae , Ramdas Shweta , Brown Christopher D. , Peterson Kevin A. , Epstein Douglas J.
Published: June 2019

The mammalian cochlea develops from a ventral outgrowth of the otic vesicle in response to Shh signaling. Mouse embryos lacking Shh or its essential signal transduction components display cochlear agenesis, however, a detailed understanding of the transcriptional network mediating this process is unclear. Here, we describe an integrated genomic approach to identify Shh dependent genes and associated regulatory sequences that promote cochlear duct morphogenesis. A comparative transcriptome analysis of otic vesicles from mouse mutants exhibiting loss (Smoecko) and gain (Shh-P1) of Shh signaling revealed a set of Shh responsive genes partitioned into four expression categories in the ventral half of the otic vesicle. This target gene classification scheme provided novel insights into several unanticipated roles for Shh, including priming the cochlear epithelium for subsequent sensory development. We also mapped regions of open chromatin in the inner ear by ATAC-seq that, in combination with Gli2 ChIP-seq, identified inner ear enhancers in the vicinity of Shh responsive genes. These datasets are useful entry points for deciphering Shh dependent regulatory mechanisms involved in cochlear duct morphogenesis and establishment of its constituent cell types.

SUMMARY STATEMENT

An integrated genomic approach identifies Shh responsive genes and associated regulatory sequences with known and previously uncharacterized roles in cochlear morphogenesis, including genes that prime the cochlea for sensory development.
Socioeconomic status and the structure of the self‐concept
Authors: Easterbrook Matthew J. , Kuppens Toon , Manstead Antony S. R.
Published: June 2019

Individuals have a myriad of potential identities that they can use to define who they are, yet little research has investigated which types of identities people tend to prioritize within their self‐concepts, and how this may vary across individuals. We analyse data from two large UK social surveys (Ns = 16,966 and 44,903) that assessed the importance respondents attached to various identities within their self‐concepts, and find that social class plays a crucial role. Our results show that respondents attached high importance to identities that are indicative of their social class (income, education, and professional), and at least as much importance as they gave to identities more commonly studied by psychologists (such as ethnicity, nationality, or gender). Furthermore, respondents’ objective social class was one of the strongest predictors of the importance they attached to different types of identities: Higher class respondents placed greater importance on identities that are indicative of their social class, but less importance on identities based on basic demographics, chosen communities, or their sociocultural orientation. Our results suggest that social class plays an important role in structuring the self‐concept, and that researchers should pay more attention to the importance of social class to self and identity processes.
Clinicopathological significance of heterogeneic ezrin expression in poorly differentiated clusters of colorectal cancers
Authors: Aikawa Akane , Fujita Hideto , Kosaka Takeo , Minato Hiroshi , Kiyokawa Etsuko
Published: June 2019

Multicellular structures, such as tumor buddings and poorly differentiated clusters (PDC), exist at the invasive front of colorectal cancers (CRC). Although it has been reported that CRC with PDC showed frequent lymph node metastases with a worse prognosis, the molecular markers of PDC that are responsible for prognosis have not been identified. We here noticed for the first time that Ezrin, a regulator of the actin cytoskeleton, is expressed in the corner cells of PDC. We then aimed to verify whether heterogeneous Ezrin expression in PDC predicts the prognosis of CRC patients. We immunohistochemically analyzed Ezrin expression in PDC of 184 patients with completely resected stages I‐III CRC. We established the Ezrin corner score (ECS), which quantifies the tendency of Ezrin‐positive cells to accumulate at the corners of PDC. On the basis of ECS values, 2 indices, the mean ECS and the number of PDC with high ECS, were obtained. Both indices were significantly higher in CRC with lymphatic invasion, higher PDC grade, and presence of micropapillary (MP) PDC. The mean ECS‐high group showed shorter recurrence‐free survival than the mean ECS‐low group but without significance. The other index, the number of ECS‐high PDC, was significantly associated with recurrence‐free survival. These results suggest that Ezrin is involved in PDC progression and lymphatic invasion, and that ECS may be a marker for aggressive PDC.
When Stronger Knowledge Slows You Down: Semantic Relatedness Predicts Children's Co‐Activation of Related Items in a Visual Search Paradigm
Authors: Vales Catarina , Fisher Anna V.
Published: June 2019

A large literature suggests that the organization of words in semantic memory, reflecting meaningful relations among words and the concepts to which they refer, supports many cognitive processes, including memory encoding and retrieval, word learning, and inferential reasoning. The co‐activation of related items has been proposed as a mechanism by which semantic knowledge influences cognition, and contemporary accounts of semantic knowledge propose that this co‐activation is graded—that it depends on how strongly related the items are in semantic memory. Prior research with adults yielded evidence supporting this prediction; however, there is currently no evidence of graded co‐activation early in development. This study provides the first evidence that in children the co‐activation of related items depends on their relational strength in semantic memory. Participants (N = 84, age range: 3–9 years) were asked to identify a target (e.g., bone) amid distractors. Children's responses were slowed down by the presence of a related distractor (e.g., puppy) relative to unrelated distractors (e.g., flower)—suggesting that children co‐activated related items upon hearing the name of the target. Importantly, the degree of this co‐activation was predicted by the strength of the target–distractor relation, such that distractors more strongly related to the targets slowed down children to a larger extent. These findings have important implications for understanding how organized semantic knowledge affects other cognitive processes across development.
Relapse risk factors in anti‐N‐methyl‐D‐aspartate receptor encephalitis
Authors: Nosadini Margherita , Granata Tiziana , Matricardi Sara , Freri Elena , Ragona Francesca , Papetti Laura , Suppiej Agnese , Valeriani Massimiliano , Sartori Stefano ,   Italian Working Group on Paediatric Anti‐N‐methyl‐D‐aspartate Receptor Encephalitis
Published: June 2019

Aim

To identify factors that may predict and affect the risk of relapse in anti‐N‐methyl‐D‐aspartate receptor (NMDAR) encephalitis.

Method

This was a retrospective study of an Italian cohort of patients with paediatric (≤18y) onset anti‐NMDAR encephalitis.

Results

Of the 62 children included (39 females; median age at onset 9y 10mo, range 1y 2mo–18y; onset between 2005 and 2018), 21 per cent relapsed (median two total events per relapsing patient, range 2–4). Time to first relapse was median 31.5 months (range 7–89mo). Severity at first relapse was lower than onset (median modified Rankin Scale [mRS] 3, range 2–4, vs median mRS 5, range 3–5; admission to intensive care unit: 0/10 vs 3/10). At the survival analysis, the risk of relapsing was significantly lower in patients who received three or more different immune therapies at first disease event (hazard ratio 0.208, 95% confidence interval 0.046–0.941; p=0.042). Neurological outcome at follow‐up did not differ significantly between patients with relapsing and monophasic disease (mRS 0–1 in 39/49 vs 12/13; p=0.431), although follow‐up duration was significantly longer in relapsing (median 84mo, range 14–137mo) than in monophasic patients (median 32mo, range 4–108mo; p=0.002).

Interpretation

Relapses may occur in about one‐fifth of children with anti‐NMDAR encephalitis, are generally milder than at onset, and may span over a long period, although they do not seem to be associated with severity in the acute phase or with outcome at follow‐up. Aggressive immune therapy at onset may reduce risk of relapse.

What this paper adds

Relapses of anti‐N‐methyl‐D‐aspartate receptor encephalitis may span over a long period.

Relapses were not associated with severity in the acute phase or outcome at follow‐up.

Aggressive immune therapy at onset appears to decrease risk of relapse.
Treatments in Aicardi–Goutières syndrome
Authors: Crow Yanick J , Shetty Jayakara , Livingston John H
Published: June 2019

Comprehensive reviews of the clinical characteristics and pathogenesis of Aicardi–Goutières syndrome (AGS), particularly its contextualization within a putative type I interferonopathy framework, already exist. However, recent reports of attempts at treatment suggest that an assessment of the field from a therapeutic perspective is warranted at this time. Here, we briefly summarize the neurological phenotypes associated with mutations in the seven genes so far associated with AGS, rehearse current knowledge of the pathology as it relates to possible treatment approaches, critically appraise the potential utility of therapies, and discuss the challenges in assessing clinical efficacy.

What this paper adds

Progress in understanding AGS disease pathogenesis has led to the first attempts at targeted treatment.

Further rational therapies are expected to become available in the short‐ to medium‐term.