bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying longevity associated genes by integrating gene expression and curated annotations
Authors: Townes F. William , Carr Kareem , Miller Jeffrey W.
Published: November 2020

Aging is a complex process with poorly understood genetic mechanisms. Recent studies have sought to classify genes as pro-longevity or anti-longevity using a variety of machine learning algorithms. However, it is not clear which types of features are best for optimizing classification performance and which algorithms are best suited to this task. Further, performance assessments based on held-out test data are lacking. We systematically compare five popular classification algorithms using gene ontology and gene expression datasets as features to predict the pro-longevity versus anti-longevity status of genes for two model organisms (C. elegans and S. cerevisiae) using the GenAge database as ground truth. We find that elastic net penalized logistic regression performs particularly well at this task. Using elastic net, we make novel predictions of pro- and anti-longevity genes that are not currently in the GenAge database.
Hantavirus pulmonary syndrome outbreaks associated with climate variability in Northwestern Argentina, 1997–2017
Authors: Ferro Ignacio , Bellomo Carla M. , López Walter , Coelho Rocío , Alonso Daniel , Bruno Agostina , Córdoba Francisco E. , Martinez Valeria P.
Published: November 2020

Background

Rodent-borne hantaviruses (genus Orthohantavirus) are the etiologic agents causing two human diseases: hemorrhagic fever with renal syndrome (HFRS) in Euroasia; and hantavirus pulmonary syndrome (HPS) in North and South America. In South America fatality rates of HPS can reach up to 35%–50%. The transmission of pathogenic hantaviruses to humans occurs mainly via inhalation of aerosolized excreta from infected rodents. Thus, the epidemiology of HPS is necessarily linked to the ecology of their rodent hosts and the contact with a human, which in turn may be influenced by climatic variability. Here we examined the relationship between climatic variables and hantavirus transmission aim to develop an early warning system of potential hantavirus outbreaks based on ecologically relevant climatic factors.

Methodology and main findings

We compiled reported HPS cases in northwestern Argentina during the 1997–2017 period and divided our data into biannual, quarterly, and bimestrial time periods to allow annual and shorter time delays to be observed. To evaluate the relationship of hantavirus transmission with mean temperature and precipitation we used dynamic regression analysis. We found a significant association between HPS incidence and lagged rainfall and temperature with a delay of 2 to 6 months. For the biannual and quarterly models, hantavirus transmission was positively associated with lagged rainfall and temperature; whereas the bimestrial models indicate a direct relationship with the rainfall but inverse for temperature in the second lagged period.

Conclusions/Significance

This work demonstrates that climate variability plays a significant role in the transmission of hantavirus in northwestern Argentina. The model developed in this study provides a basis for the forecast of potential HPS outbreaks based on climatic parameters. Our findings are valuable for the development of public health policies and prevention strategies to mitigate possible outbreaks. Nonetheless, a surveillance program on rodent population dynamics would lead to a more accurate forecast of HPS outbreaks.
Analyses of the performance of the Ebola virus disease alert management system in South Sudan: August 2018 to November 2019
Authors: Olu Olushayo Oluseun , Lako Richard , Bunga Sudhir , Berta Kibebu , Kol Matthew , Ramadan Patrick Otim , Ryan Caroline , Udenweze Ifeanyi , Guyo Argata Guracha , Conteh Ishata , Huda Qudsia , Gai Malick , Saulo Dina , Papowitz Heather , Gray Henry John , Chimbaru Alex , Wangdi Kencho , Grube Steven M. , Barr Beth Tippett , Wamala Joseph Francis
Published: November 2020

South Sudan implemented Ebola virus disease preparedness interventions aiming at preventing and rapidly containing any importation of the virus from the Democratic Republic of Congo starting from August 2018. One of these interventions was a surveillance system which included an Ebola alert management system. This study analyzed the performance of this system. A descriptive cross-sectional study of the Ebola virus disease alerts which were reported in South Sudan from August 2018 to November 2019 was conducted using both quantitative and qualitative methods. As of 30 November 2019, a total of 107 alerts had been detected in the country out of which 51 (47.7%) met the case definition and were investigated with blood samples collected for laboratory confirmation. Most (81%) of the investigated alerts were South Sudanese nationals. The alerts were identified by health workers (53.1%) at health facilities, at the community (20.4%) and by screeners at the points of entry (12.2%). Most of the investigated alerts were detected from the high-risk states of Gbudwe (46.9%), Jubek (16.3%) and Torit (10.2%). The investigated alerts commonly presented with fever, bleeding, headache and vomiting. The median timeliness for deployment of Rapid Response Team was less than one day and significantly different between the 6-month time periods (K-W = 7.7567; df = 2; p = 0.0024) from 2018 to 2019. Strengths of the alert management system included existence of a dedicated national alert hotline, case definition for alerts and rapid response teams while the weaknesses were occasional inability to access the alert toll-free hotline and lack of transport for deployment of the rapid response teams which often constrain quick response. This study demonstrates that the Ebola virus disease alert management system in South Sudan was fully functional despite the associated challenges and provides evidence to further improve Ebola preparedness in the country.
Extracellular non-coding RNA signatures of the metacestode stage of Echinococcus multilocularis
Authors: Ancarola María Eugenia , Lichtenstein Gabriel , Herbig Johannes , Holroyd Nancy , Mariconti Mara , Brunetti Enrico , Berriman Matthew , Albrecht Krystyna , Marcilla Antonio , Rosenzvit Mara Cecilia , Kamenetzky Laura , Brehm Klaus , Cucher Marcela
Published: November 2020

Extracellular RNAs (ex-RNAs) are secreted by cells through different means that may involve association with proteins, lipoproteins or extracellular vesicles (EV). In the context of parasitism, ex-RNAs represent new and exciting communication intermediaries with promising potential as novel biomarkers. In the last years, it was shown that helminth parasites secrete ex-RNAs, however, most work mainly focused on RNA secretion mediated by EV. Ex-RNA study is of special interest in those helminth infections that still lack biomarkers for early and/or follow-up diagnosis, such as echinococcosis, a neglected zoonotic disease caused by cestodes of the genus Echinococcus. In this work, we have characterised the ex-RNA profile secreted by in vitro grown metacestodes of Echinococcus multilocularis, the casuative agent of alveolar echinococcosis.

We have used high throughput RNA-sequencing together with RT-qPCR to characterise the ex-RNA profile secreted towards the extra- and intra-parasite milieus in EV-enriched and EV-depleted fractions. We show that a polarized secretion of small RNAs takes place, with microRNAs mainly secreted to the extra-parasite milieu and rRNA- and tRNA-derived sequences mostly secreted to the intra-parasite milieu. In addition, we show by nanoparticle tracking analyses that viable metacestodes secrete EV mainly into the metacestode inner vesicular fluid (MVF); however, the number of nanoparticles in culture medium and MVF increases > 10-fold when metacestodes show signs of tegument impairment. Interestingly, we confirm the presence of host miRNAs in the intra-parasite milieu, implying their internalization and transport through the tegument towards the MVF. Finally, our assessment of the detection of Echinococcus miRNAs in patient samples by RT-qPCR yielded negative results suggesting the tested miRNAs may not be good biomarkers for this disease.

A comprehensive study of the secretion mechanisms throughout the life cycle of these parasites will help to understand parasite interaction with the host and also, improve current diagnostic tools.
Replication stress and FOXM1 drive radiation induced genomic instability and cell transformation
Authors: Li Zhentian , Yu David S. , Doetsch Paul W. , Werner Erica
Published: November 2020

In contrast to the vast majority of research that has focused on the immediate effects of ionizing radiation, this work concentrates on the molecular mechanism driving delayed effects that emerge in the progeny of the exposed cells. We employed functional protein arrays to identify molecular changes induced in a human bronchial epithelial cell line (HBEC3-KT) and osteosarcoma cell line (U2OS) and evaluated their impact on outcomes associated with radiation induced genomic instability (RIGI) at day 5 and 7 post-exposure to a 2Gy X-ray dose, which revealed replication stress in the context of increased FOXM1b expression. Irradiated cells had reduced DNA replication rate detected by the DNA fiber assay and increased DNA resection detected by RPA foci and phosphorylation. Irradiated cells increased utilization of homologous recombination-dependent repair detected by a gene conversion assay and DNA damage at mitosis reflected by RPA positive chromosomal bridges, micronuclei formation and 53BP1 positive bodies in G1, all known outcomes of replication stress. Interference with the function of FOXM1, a transcription factor widely expressed in cancer, employing an aptamer, decreased radiation-induced micronuclei formation and cell transformation while plasmid-driven overexpression of FOXM1b was sufficient to induce replication stress, micronuclei formation and cell transformation.
Pain burden, sensory profile and inflammatory cytokines of dogs with naturally-occurring neuropathic pain treated with gabapentin alone or with meloxicam
Authors: Ruel Hélène L. M. , Watanabe Ryota , Evangelista Marina C. , Beauchamp Guy , Auger Jean-Philippe , Segura Mariela , Steagall Paulo V.
Published: November 2020

Canine neuropathic pain (NeuP) has been poorly investigated. This study aimed to evaluate the pain burden, sensory profile and inflammatory cytokines in dogs with naturally-occurring NeuP. Twenty-nine client-owned dogs with NeuP were included in a prospective, partially masked, randomized crossover clinical trial, and treated with gabapentin/placebo/gabapentin-meloxicam or gabapentin-meloxicam/placebo/gabapentin (each treatment block of 7 days; total 21 days). Pain scores, mechanical (MNT) and electrical (ENT) nociceptive thresholds and descending noxious inhibitory controls (DNIC) were assessed at baseline, days 7, 14, and 21. DNIC was evaluated using ΔMNT (after-before conditioning stimulus). Positive or negative ΔMNT corresponded to inhibitory or facilitatory pain profiles, respectively. Pain scores were recorded using the Client Specific Outcome Measures (CSOM), Canine Brief Pain Inventory (CBPI), and short-form Glasgow Composite Measure Pain Scale (CMPS-SF). Data from baseline were compared to those of sixteen healthy controls. ΔMNT, but not MNT and ENT, was significantly larger in controls (2.3 ± 0.9 N) than in NeuP (-0.2 ± 0.7 N). The percentage of dogs with facilitatory sensory profile was similar at baseline and after placebo (61.5–63%), and between controls and after gabapentin (33.3–34.6%). The CBPI scores were significantly different between gabapentin (CBPIpainand CBPIoverall impression) and/or gabapentin-meloxicam (CBPIpainandinterference) when compared with baseline, but not placebo. The CBPI scores were not significantly different between placebo and baseline. The concentration of cytokines was not different between groups or treatments. Dogs with NeuP have deficient inhibitory pain mechanisms. Pain burden was reduced after gabapentin and/or gabapentin-meloxicam when compared with baseline using CBPI and CMPS-SF scores. However, these scores were not superior than placebo, nor placebo was superior to baseline evaluations. A caregiver placebo effect may have biased the results.
A compelling symmetry: The extended fetuses-at-risk perspective on modal, optimal and relative birthweight and gestational age
Authors: Joseph K. S.
Published: November 2020

Background

The relationship between several intriguing perinatal phenomena, namely, modal, optimal, and relative birthweight and gestational age, remains poorly understood, especially the mechanism by which relative birthweight and gestational age resolve the paradox of intersecting perinatal mortality curves.

Methods

Birthweight and gestational age distributions and birthweight- and gestational age-specific perinatal death rates of low- and high-risk cohorts in the United States, 2004–2015, were estimated using births-based and extended fetuses-at-risk formulations. The relationships between these births-based distributions and rates, and the first derivatives of fetuses-at-risk birth and perinatal death rates were examined in order to assess how the rate of change in fetuses-at-risk rates affects gestational age distributions and births-based perinatal death rate patterns.

Results

Modal gestational age typically exceeded optimal gestational age because both were influenced by the peak in the first derivative of the birth rate, while optimal gestational age was additionally influenced by the point at which the first derivative of the fetuses-at-risk perinatal death rate showed a sharp increase in late gestation. The clustering and correlation between modal and optimal gestational age within cohorts, the higher perinatal death rate at optimal gestational age among higher-risk cohorts, and the symmetric left-shift in births-based gestational age-specific perinatal death rates in higher-risk cohorts explained how relative gestational age resolved the paradox of intersecting perinatal mortality curves.

Conclusions

Changes in the first derivative of the fetuses-at-risk birth and perinatal death rates underlie several births-based perinatal phenomena and this explanation further unifies the fetuses-at-risk and births-based models of perinatal death.
Mining GWAS and eQTL data for CF lung disease modifiers by gene expression imputation
Authors: Dang Hong , Polineni Deepika , Pace Rhonda G. , Stonebraker Jaclyn R. , Corvol Harriet , Cutting Garry R. , Drumm Mitchell L. , Strug Lisa J. , O’Neal Wanda K. , Knowles Michael R.
Published: November 2020

Genome wide association studies (GWAS) have identified several genomic loci with candidate modifiers of cystic fibrosis (CF) lung disease, but only a small proportion of the expected genetic contribution is accounted for at these loci. We leveraged expression data from CF cohorts, and Genotype-Tissue Expression (GTEx) reference data sets from multiple human tissues to generate predictive models, which were used to impute transcriptional regulation from genetic variance in our GWAS population. The imputed gene expression was tested for association with CF lung disease severity. By comparing and combining results from alternative approaches, we identified 379 candidate modifier genes. We delved into 52 modifier candidates that showed consensus between approaches, and 28 of them were near known GWAS loci. A number of these genes are implicated in the pathophysiology of CF lung disease (e.g., immunity, infection, inflammation, HLA pathways, glycosylation, and mucociliary clearance) and the CFTR protein biology (e.g., cytoskeleton, microtubule, mitochondrial function, lipid metabolism, endoplasmic reticulum/Golgi, and ubiquitination). Gene set enrichment results are consistent with current knowledge of CF lung disease pathogenesis. HLA Class II genes on chr6, andCEP72,EXOC3, andTPPPnear the GWAS peak on chr5 are most consistently associated with CF lung disease severity across the tissues tested. The results help to prioritize genes in the GWAS regions, predict direction of gene expression regulation, and identify new candidate modifiers throughout the genome for potential therapeutic development.
The effect of autophagy and mitochondrial fission on Harderian gland is greater than apoptosis in male hamsters during different photoperiods
Authors: Xu Jin-Hui , Wang Zhe , Mou Jun-Jie , Zhao Xiang-Yu , Geng Xiao-Cui , Wu Ming , Xue Hui-Liang , Chen Lei , Xu Lai-Xiang
Published: November 2020

Photoperiod is an important factor of mammalian seasonal rhythm. Here, we studied morphological differences in the Harderian gland (HG), a vital photosensitive organ, in male striped dwarf hamsters (Cricetulus barabensis) under different photoperiods (short photoperiod, SP; moderate photoperiod, MP; long photoperiod, LP), and investigated the underlying molecular mechanisms related to these morphological differences. Results showed that carcass weight and HG weight were lower under SP and LP conditions. There was an inverse correlation between blood melatonin levels and photoperiod in the order SP > MP > LP. Protein expression of hydroxyindole-O-methyltransferase (HIOMT), a MT synthesis-related enzyme, was highest in the SP group. Protein expression of bax/bcl2 showed no significant differences, indicating that the level of apoptosis remained stable. Protein expression of LC3II/LC3I was higher in the SP group than that in the MP group. Furthermore, comparison of changes in the HG ultrastructure demonstrated autolysosome formation in the LP, suggesting the lowest autophagy level in under MP. Furthermore, the protein expression levels of ATP synthase and mitochondrial fission factor were highest in the MP group, whereas citrate synthase, dynamin-related protein1, and fission1 remained unchanged in the three groups. The change trends of ATP synthase and citrate synthase activity were similar to that of protein expression among the three groups. In summary, the up-regulation of autophagy under SP and LP may be a primary factor leading to loss of HG weight and reduced mitochondrial energy supply capacity.
Biochar and compost effects on soil microbial communities and nitrogen induced respiration in turfgrass soils
Authors: Azeem Muhammad , Hale Lauren , Montgomery Jonathan , Crowley David , McGiffen Milton E.
Published: November 2020

We examined the effect of a labile soil amendment, compost, and recalcitrant biochar on soil microbial community structure, diversity, and activity during turfgrass establishment. Two application rates of biochar (B1 at 12.5 t ha-1and B2 at 25 t ha-1), a 5 centimeter (cm) green waste compost treatment (CM) in top soil, a treatment with 12.5 t ha-1biochar and 5 cm compost (B1+CM), and an unamended control (CK) treatment were prepared and seeded with tall fescue. Overall, results of phospholipid fatty acid analysis (PLFA) profiling and Illumina high-throughput sequencing of 16S rRNA genes amplified from soil DNA revealed significant shifts in microbial community structures in the compost amended soils whereas in biochar amended soils communities were more similar to the control, unamended soil. Similarly, increases in enzymatic rates (6–56%) and nitrogen-induced respiration (94%) were all largest in compost amended soils, with biochar amended soils exhibiting similar patterns to the control soils. Both biochar and compost amendments impacted microbial community structures and functions, but compost amendment, whether applied alone or co-applied with biochar, exhibited the strongest shifts in the microbial community metrics examined. Our results suggest application of compost to soils in need of microbiome change (reclamation projects) or biochar when the microbiome is functioning and long-term goals such as carbon sequestration are more desirable.
High resolution microscopy to evaluate the efficiency of surface sterilization of Zea Mays seeds
Authors: Davoudpour Yalda , Schmidt Matthias , Calabrese Federica , Richnow Hans Hermann , Musat Niculina
Published: November 2020

Surface sterilization of seeds is a key step in providing microorganisms-free seeds for numerous applications like understanding the role of seed-borne microorganisms in plant development, studying microbial cells-plant interactions by inoculating model microorganisms in a simplified system or selective cultivation of seed endobionts. However applying efficient treatment for surface sterilization of seeds without affecting the plant growth is not an easy task. In this study we aimed to provide an efficient surface sterilization treatment for maize seeds using i) hydrogen peroxide (HP), ii) sodium hypochlorite (SH) and iii) ethanol-sodium hypochlorite (EtOH-SH) under stirring (st) and vacuum-stirring (va-st) conditions. We used fluorescence microscopy and ultra-high resolution Helium Ion Microscopy (HIM) as powerful imaging approaches in combination with macroscopic techniques to visualize, quantify and evaluate the efficiency of seed sterilization, quality of root germination, seedlings and root hair development as well as the presence or absence of microorganisms on the root surface. Our results showed a strong reduction in microbial cell numbers of 4 orders of magnitude after the EtOH-SH treatments. Moreover, seeds exposed to EtOH-SH treatments displayed the lowest percentage of microbial growth (50%) and the highest percentage of germinated seeds (100%) compared to other sterilization treatments. HIM imaging proved the absence of microbial cells on the roots grown from seeds exposed to EtOH-SH treatments. Moreover, root hair development seemed not to be affected by any of the sterilization treatments. Our findings demonstrated that EtOH-SH treatments are significantly reducing the abundance of microbial cells from the surface of maize seeds and can be used with high confidence in future studies.
Component of nicotine-induced intracellular calcium elevation mediated through α3- and α5-containing nicotinic acetylcholine receptors are regulated by cyclic AMP in SH-SY 5Y cells
Authors: Takahashi Tamayo , Yoshida Takayuki , Harada Kana , Miyagi Tatsuhiko , Hashimoto Kouichi , Hide Izumi , Tanaka Shigeru , Irifune Masahiro , Sakai Norio
Published: November 2020

The pathway from the medial habenular nucleus to the interpeduncular nucleus, in which nicotinic acetylcholine receptor (nAChR) including the α3 and α5 subunits (α3 * and α5 * nAChRs) are expressed, is implicated in nicotine dependence. We investigated whether α3 * and α5 * nAChRs are regulated by cAMP using SH-SY5Y cells to clarify the significance of these receptors in nicotine dependence. We analyzed the nicotine-induced elevation of intracellular Ca2+ ([Ca2+]i). Nicotine induces a concentration-dependent increase in [Ca2+]i. The elimination of Ca2+ from extracellular fluid or intracellular stores demonstrated that the nicotine-induced [Ca2+]i elevation was due to extracellular influx and intracellular mobilization. The effects of tubocurarine on nicotine-induced [Ca2+]i elevation and current suggest that intracellular mobilization is caused by plasma membrane-permeating nicotine. The inhibition of α3 *, α5 *, α7 nAChR and voltage-gated Ca2+ channels by using siRNAs and selective antagonists revealed the involvement of these nAChR subunits and channels in nicotine-induced [Ca2+]i elevation. To distinguish and characterize the α3 * and α5 * nAChR-mediated Ca2+ influx, we measured the [Ca2+]i elevation induced by nonmembrane-permeating acetylcholine when muscarinic receptors, α7nAChR and Ca2+ channels were blocked. Under this condition, the [Ca2+]i elevation was significantly inhibited with a 48-h treatment of dibutyryl cAMP, which was accompanied by the downregulation of α3 and β4 mRNA. These findings suggest that α3 * and α5 * nAChR-mediated Ca2+ influx is possibly regulated by cAMP at the transcriptional level.
On the coherence of model-based dose-finding designs for drug combination trials
Authors: Park Yeonhee , Liu Suyu
Published: November 2020

The concept of coherence was proposed for single-agent phase I clinical trials to describe the property that a design never escalates the dose when the most recently treated patient has toxicity and never de-escalates the dose when the most recently treated patient has no toxicity. It provides a useful theoretical tool for investigating the properties of phase I trial designs. In this paper, we generalize the concept of coherence to drug combination trials, which are substantially different and more challenging than single-agent trials. For example, in the dose-combination matrix, each dose has up to 8 neighboring doses as candidates for dose escalation and de-escalation, and the toxicity orders of these doses are only partially known. We derive sufficient conditions for a model-based drug combination trial design to be coherent. Our results are more general and relaxed than the existing results and are applicable to both single-agent and drug combination trials. We illustrate the application of our theoretical results with a number of drug combination dose-finding designs in the literature.
Desmin and CD31 immunolabeling for detecting venous invasion of the pancreatobiliary tract cancers
Authors: Shin Junyoung , Wood Laura D. , Hruban Ralph H. , Hong Seung-Mo
Published: November 2020

Although venous invasion (VI) is a poor prognostic factor for patients with pancreatobiliary tract cancers, its histopathologic characteristics have not been well described. We evaluated the patterns of VI and the added benefit provided by CD31, desmin, and dual CD31‒desmin immunolabeling for identification of VI. We included 120 surgically resected pancreatobiliary tract cancer cases—59 cases as a test set with known VI and 61 cases as a validation set without information of VI. VI was classified into three patterns: intraepithelial neoplasia-like (IN-like), conventional, and destructive. Hematoxylin and eosin (H&E) staining and CD31, desmin, and dual CD31‒desmin immunolabeling were performed. Foci number and patterns of VI were compared with the test and validation sets. More foci of VI were detected by single CD31 (P = 0.022) than H&E staining in the test set. CD31 immunolabeling detected more foci of the conventional pattern of VI, and desmin immunolabeling detected more foci of the destructive pattern (all, P < 0.001). Dual CD31‒desmin immunolabeling identified more foci of VI (P = 0.012) and specifically detected more foci of IN-like (P = 0.045) and destructive patterns (P < 0.001) than H&E staining in the validation set. However, dual CD31‒desmin immunolabeling was not helpful for detecting the conventional pattern of VI in the validation set. Patients with VI detected by dual CD31‒desmin immunolabeling had shorter disease-free survival (P <0.001) than those without VI. VI detected by dual CD31‒desmin immunolabeling was a worse prognostic indicator (P = 0.009). More foci of VI could be detected with additional single CD31 or dual CD31‒desmin immunolabeling. The precise evaluation of VI with dual CD31‒desmin immunolabeling can provide additional prognostic information for patients with surgically resected pancreatobiliary tract cancers.
Identification of the enzymes responsible for m2,2G and acp3U formation on cytosolic tRNA from insects and plants
Authors: Funk Holly M. , Zhao Ruoxia , Thomas Maggie , Spigelmyer Sarah M. , Sebree Nichlas J. , Bales Regan O. , Burchett Jamison B. , Mamaril Justen B. , Limbach Patrick A. , Guy Michael P.
Published: November 2020

Posttranscriptional modification of tRNA is critical for efficient protein translation and proper cell growth, and defects in tRNA modifications are often associated with human disease. Although most of the enzymes required for eukaryotic tRNA modifications are known, many of these enzymes have not been identified and characterized in several model multicellular eukaryotes. Here, we present two related approaches to identify the genes required for tRNA modifications in multicellular organisms using primer extension assays with fluorescent oligonucleotides. To demonstrate the utility of these approaches we first use expression of exogenous genes in yeast to experimentally identify twoTRM1orthologs capable of formingN2,N2-dimethylguanosine (m2,2G) on residue 26 of cytosolic tRNA in the model plantArabidopsis thaliana. We also show that a predicted catalytic aspartate residue is required for function in each of the proteins. We next use RNA interference in culturedDrosophila melanogastercells to identify the gene required for m2,2G26formation on cytosolic tRNA. Additionally, using these approaches we experimentally identifyD.melanogastergeneCG10050as the corresponding ortholog of humanDTWD2, which encodes the protein required for formation of 3-amino-3-propylcarboxyuridine (acp3U) on residue 20a of cytosolic tRNA. We further show thatA.thalianageneAT2G41750can form acp3U20bon anA.thalianatRNA expressed in yeast cells, and that the aspartate and tryptophan residues in the DXTW motif of this protein are required for modification activity. These results demonstrate that these approaches can be used to study tRNA modification enzymes.
Weighing the waitlist: Weight changes and access to kidney transplantation among obese candidates
Authors: Ku Elaine , Whelan Adrian M. , McCulloch Charles E. , Lee Brian , Niemann Claus U. , Roll Garrett R. , Grimes Barbara A. , Johansen Kirsten L.
Published: November 2020

High body mass index is a known barrier to access to kidney transplantation in patients with end-stage kidney disease. The extent to which weight and weight changes affect access to transplantation among obese candidates differentially by race/ethnicity has received little attention. We included 10 221 obese patients waitlisted for kidney transplantation prior to end-stage kidney disease onset between 1995–2015. We used multinomial logistic regression models to examine the association between race/ethnicity and annualized change in body mass index (defined as stable [-2 to 2 kg/m2/year], loss [>2 kg/m2/year] or gain [>2 kg/m2/year]). We then used Fine-Gray models to examine the association between weight changes and access to living or deceased donor transplantation by race/ethnicity, accounting for the competing risk of death. Overall, 29% of the cohort lost weight and 7% gained weight; 46% received a transplant. Non-Hispanic blacks had a 24% (95% CI 1.12–1.38) higher odds of weight loss and 22% lower odds of weight gain (95% CI 0.64–0.95) compared with non-Hispanic whites. Hispanics did not differ from whites in their odds of weight loss or weight gain. Overall, weight gain was associated with lower access to transplantation (HR 0.88 [95% CI 0.79–0.99]) compared with maintenance of stable weight, but weight loss was not associated with better access to transplantation (HR 0.96 [95% CI 0.90–1.02]), although this relation differed by baseline body mass index and for recipients of living versus deceased donor organs. For example, weight loss was associated with improved access to living donor transplantation (HR 1.24 [95% CI 1.07–1.44]) in whites but not in blacks or Hispanics. In a cohort of obese patients waitlisted before dialysis, blacks were more likely to lose weight and less likely to gain weight compared with whites. Weight loss was only associated with improved access to living donor transplantation among whites. Further studies are needed to understand the reasons for the observed associations.
Clinicopathological significance of core 3 O-glycan synthetic enzyme, β1,3-N-acetylglucosaminyltransferase 6 in pancreatic ductal adenocarcinoma
Authors: Doi Noriteru , Ino Yoshinori , Angata Kiyohiko , Shimada Kazuaki , Narimatsu Hisashi , Hiraoka Nobuyoshi
Published: November 2020

Mucin-typeO-glycans are involved in cancer initiation and progression, although details of their biological and clinicopathological roles remain unclear. The aim of this study was to investigate the clinicopathological significance of β1,3-N-acetylglucosaminyltransferase 6 (β3Gn-T6), an essential enzyme for the synthesis of core 3O-glycan and several otherO-glycans in pancreatic ductal adenocarcinoma (PDAC). We performed immunohistochemical and lectin-histochemical analyses to detect the expression of β3Gn-T6 and severalO-glycans in 156 cases of PDAC with pancreatic intraepithelial neoplasias (PanINs) and corresponding normal tissue samples. The T antigen, Tn antigen, sialyl Lewis X (sLeX) antigen, and sLeX on core 2O-glycan were more highly expressed in PDAC cells than in normal pancreatic duct epithelial cells (NPDEs). Conversely, the expression of 6-sulfoN-acetyllactosamine on extended core 1O-glycan was found in NPDEs and was low in PDAC cells. These glycan expression levels were not associated with patient outcomes. β3Gn-T6 was expressed in ~20% of PDAC cases and 30–40% of PanINs but not in NPDEs. Higher expression of β3Gn-T6 was found in PDAC cells in more differentiated adenocarcinoma cases showing significantly longer disease-free survival in both univariate and multivariate analyses. In addition, the expression of β3Gn-T6 in PDAC cells and PanINs significantly correlated with the expression of MUC5AC in these cells, suggesting that β3Gn-T6 expression is related to cellular differentiation status of the gastric foveolar phenotype. Thus, it is likely that β3Gn-T6 expression in PDAC cells is a favorable prognostic factor in PDAC patients, and that the expression of β3Gn-T6 correlates with the gastric foveolar phenotype in pancreatic carcinogenesis.
Is active sitting on a dynamic office chair controlled by the trunk muscles?
Authors: Kuster Roman Peter , Bauer Christoph Michael , Baumgartner Daniel
Published: November 2020

Today’s office chairs are not known to promote active sitting or to activate the lumbar trunk muscles, both of which functions are ergonomically recommended. This study investigated a newly developed dynamic office chair with a moveable seat, specifically designed to promote trunk muscle controlled active sitting. The study aimed to determine the means by which the seat movement was controlled during active sitting. This was accomplished by quantifying trunk and thigh muscular activity and body kinematics. Additionally, the effect of increased spinal motion on muscular activity and body kinematics was analysed. Ten subjects were equipped with reflective body markers and surface electromyography on three lumbar back muscles (multifidus, iliocostalis, longissimus) and two thigh muscles (vastus lateralis and medialis). Subjects performed a reading task during static and active sitting in spontaneous and maximum ranges of motion in a simulated office laboratory setting. The temporal muscle activation pattern, average muscle activity and body segment kinematics were analysed and compared using Friedman and post-hoc Wilcoxon tests (p≤0.05). Active sitting on the new chair significantly affected the lumbar trunk muscles, with characteristic cyclic unloading/loading in response to the seat movement. Neither thigh muscle activity nor lateral body weight shift were substantially affected by active sitting. When participants increased their range of motion, the lumbar back muscles were activated for longer and relaxation times were shorter. The characteristic activity pattern of the lumbar trunk muscles was shown to be the most likely dominant factor in controlling seat movement during active sitting. Consequently, the new chair may have a potential positive impact on back health during prolonged sitting. Further studies are necessary to analyse the frequency and intensity of active sitting during daily office work.
The paradox does not fit all: Racial disparities in asthma among Mexican Americans in the U.S.
Authors: Marquez-Velarde Guadalupe
Published: November 2020

Mexican Americans have a lower prevalence of asthma than White Americans, Black Americans, and Other Hispanics. This is concordant with the Hispanic Paradox, which posits that Hispanics have good health and lower mortality than White Americans despite their relative socioeconomic disadvantages. However, the research is limited in relation to the effects of race on health, independent of ethnicity, among this population. In this study, the author disaggregated Mexican Americans, foreign-born and U.S.-born into two categories, White and Black Mexicans, in order to assess their likelihood of having an asthma diagnosis, compared to White Americans and to each other. This study used harmonized data from the National Health Interview Survey from 2000–2018 with a final analytic sample of N = 1,094,516. The analysis was conducted using binary logistic regression, controlling for acculturation and health behavior-related variables, as well as sociodemographic characteristics. In the results, Black Mexicans had a significant disadvantage in relation to their White counterparts and White Americans. The findings suggest there is an intra-ethnic racial disparity in asthma and the Hispanic paradox is not applicable across racial lines for Mexican Americans. These findings also suggest Black Mexicans’ poor asthma outcomes are the byproduct of various mechanisms of racial inequality.
Validation of models using basic parameters to differentiate intestinal tuberculosis from Crohn’s disease: A multicenter study from Asia
Authors: Limsrivilai Julajak , Lee Choon Kin , Prueksapanich Piyapan , Harinwan Kamin , Sudcharoen Asawin , Cheewasereechon Natcha , Aniwan Satimai , Sripongpan Pimsiri , Wetwittayakhlang Panu , Pongpaibul Ananya , Sanpavat Anapat , Pausawasdi Nonthalee , Charatcharoenwitthaya Phunchai , Higgins Peter D. R. , Ng Siew Chien
Published: November 2020

Background

Data on external validation of models developed to distinguish Crohn’s disease (CD) from intestinal tuberculosis (ITB) are limited. This study aimed to validate and compare models using clinical, endoscopic, and/or pathology findings to differentiate CD from ITB.

Methods

Data from newly diagnosed ITB and CD patients were retrospectively collected from 5 centers located in Thailand or Hong Kong. The data was applied to Lee, et al., Makharia, et al., Jung, et al., and Limsrivilai, et al. model.

Results

Five hundred and thirty patients (383 CD, 147 ITB) with clinical and endoscopic data were included. The area under the receiver operating characteristic curve (AUROC) of Limsrivilai’s clinical-endoscopy (CE) model was 0.853, which was comparable to the value of 0.862 in Jung’s model (p = 0.52). Both models performed significantly better than Lee’s endoscopy model (AUROC: 0.713, p<0.01). Pathology was available for review in 199 patients (116 CD, 83 ITB). When 3 modalities were combined, Limsrivilai’s clinical-endoscopy-pathology (CEP) model performed significantly better (AUROC: 0.887) than Limsrivilai’s CE model (AUROC: 0.824, p = 0.01), Jung’s model (AUROC: 0.798, p = 0.005) and Makharia’s model (AUROC: 0.637, p<0.01). In 83 ITB patients, the rate of misdiagnosis with CD when used the proposed cutoff values in each original study was 9.6% for Limsrivilai’s CEP, 15.7% for Jung’s, and 66.3% for Makharia’s model.

Conclusions

Scoring systems with more parameters and diagnostic modalities performed better; however, application to clinical practice is still limited owing to high rate of misdiagnosis of ITB as CD. Models integrating more modalities such as imaging and serological tests are needed.
Antimicrobial peptide activity is anticorrelated with lipid a leaflet affinity
Authors: Nelson Nathaniel , Opene Belita , Ernst Robert K. , Schwartz Daniel K.
Published: November 2020

The activity of antimicrobial peptides (AMPs) has significant bacterial species bias, the mechanisms of which are not fully understood. We employed single-molecule tracking to measure the affinity of three different AMPs to hybrid supported bilayers composed of lipid A extracted from four different Gram negative bacteria and observed a strong empirical anticorrelation between the affinity of a particular AMP to a given lipid A layer and the activity of that AMP towards the bacterium from which that lipid A was extracted. This suggested that the species bias of AMP activity is directly related to AMP interactions with bacterial outer membranes, despite the fact that the mechanism of antimicrobial activity occurs at the inner membrane. The trend also suggested that the interactions between AMPs and the outer membrane lipid A (even in the absence of other components, such as lipopolysaccharides) capture effects that are relevant to the minimum inhibitory concentration.
Protein fractional synthesis rates within tissues of high- and low-active mice
Authors: Cross Kristina M. , Granados Jorge Z. , Ten Have Gabriella A. M. , Thaden John J. , Engelen Marielle P. K. J. , Lightfoot J. Timothy , Deutz Nicolaas E. P.
Published: November 2020

With the rise in physical inactivity and its related diseases, it is necessary to understand the mechanisms involved in physical activity regulation. Biological factors regulating physical activity are studied to establish a possible target for improving the physical activity level. However, little is known about the role metabolism plays in physical activity regulation. Therefore, we studied protein fractional synthesis rate (FSR) of multiple organ tissues of 12-week-old male mice that were previously established as inherently low-active (n = 15, C3H/HeJ strain) and high-active (n = 15, C57L/J strain). Total body water of each mouse was enriched to 5% deuterium oxide (D2O)viaintraperitoneal injection and maintained with D2O enriched drinking water for about 24 h. Blood samples from the jugular vein and tissues (kidney, heart, lung, muscle, fat, jejunum, ileum, liver, brain, skin, and bone) were collected for enrichment analysis of alanine by LC-MS/MS. Protein FSR was calculated as -ln(1-enrichment). Data are mean±SE as fraction/day (unpaired t-test). Kidney protein FSR in the low-active mice was 7.82% higher than in high-active mice (low-active: 0.1863±0.0018, high-active: 0.1754±0.0028, p = 0.0030). No differences were found in any of the other measured organ tissues. However, all tissues resulted in a generally higher protein FSR in the low-activity mice compared to the high-activity mice (e.g. lung LA: 0.0711±0.0015, HA: 0.0643±0.0020, heart LA: 0.0649± 0.0013 HA: 0.0712±0.0073). Our observations suggest that high-active mice in most organ tissues are no more inherently equipped for metabolic adaptation than low-active mice, but there may be a connection between protein metabolism of kidney tissue and physical activity level. In addition, low-active mice have higher organ-specific baseline protein FSR possibly contributing to the inability to achieve higher physical activity levels.
Executive functions form a single construct and are associated with schooling: Evidence from three low- and middle- income countries
Authors: Wray Charlotte , Kowalski Alysse , Mpondo Feziwe , Ochaeta Laura , Belleza Delia , DiGirolamo Ann , Waford Rachel , Richter Linda , Lee Nanette , Scerif Gaia , Stein Aryeh D. , Stein Alan ,   COHORTS
Published: November 2020

Measuring executive function (EF) among adults is important, as the cognitive processes involved in EF are critical to academic achievement, job success and mental health. Current evidence on measurement and structure of EF largely come from Western, Educated, Industrialized, Rich and Democratic (WEIRD) countries. However, measuring EF in low-and-middle-income countries (LMICs) is challenging, because of the dearth of EF measures validated across LMICs, particularly measures that do not require extensive training, expensive equipment, or professional administration. This paper uses data from three LMIC cohorts to test the feasibility, validity and reliability of EF assessment in adults using three sub-tests (representing key components of EF) of the NIH Toolbox Cognitive battery. For each cohort, all three EF measures (inhibition, flexibility and working memory) loaded well onto a unidimensional latent factor of EF. Factor scores related well to measures of fluid intelligence, processing speed and schooling. All measures showed good test-retest reliability across countries. This study provides evidence for a set of sound measures of EF that could be used across different cultural, language and socio-economic backgrounds in future LMIC research. Furthermore, our findings extend conclusions on the structure of EF beyond those drawn from WEIRD countries.
Development of a minimal KASP marker panel for distinguishing genotypes in apple collections
Authors: Winfield Mark , Burridge Amanda , Ordidge Matthew , Harper Helen , Wilkinson Paul , Thorogood Danny , Copas Liz , Edwards Keith , Barker Gary
Published: November 2020

Accurate identification of named accessions in germplasm collections is extremely important, especially for vegetatively propagated crops which are expensive to maintain. Thus, an inexpensive, reliable, and rapid genotyping method is essential because it avoids the need for laborious and time-consuming morphological comparisons. Single Nucleotide Polymorphism (SNP) marker panels containing large numbers of SNPs have been developed for many crop species, but such panels are much too large for basic cultivar identification. Here, we have identified a minimum set of SNP markers sufficient to distinguish apple cultivars held in the English and Welsh national collections providing a cheaper and automatable alternative to the markers currently used by the community. We show that SNP genotyping with a small set of well selected markers is equally efficient as microsatellites for the identification of apple cultivars and has the added advantage of automation and reduced cost when screening large numbers of samples.
Essential gene prediction using limited gene essentiality information–An integrative semi-supervised machine learning strategy
Authors: Nandi Sutanu , Ganguli Piyali , Sarkar Ram Rup
Published: November 2020

Essential gene prediction helps to find minimal genes indispensable for the survival of any organism. Machine learning (ML) algorithms have been useful for the prediction of gene essentiality. However, currently available ML pipelines perform poorly for organisms with limited experimental data. The objective is the development of a new ML pipeline to help in the annotation of essential genes of less explored disease-causing organisms for which minimal experimental data is available. The proposed strategy combines unsupervised feature selection technique, dimension reduction using the Kamada-Kawai algorithm, and semi-supervised ML algorithm employing Laplacian Support Vector Machine (LapSVM) for prediction of essential and non-essential genes from genome-scale metabolic networks using very limited labeled dataset. A novel scoring technique, Semi-Supervised Model Selection Score, equivalent to area under the ROC curve (auROC), has been proposed for the selection of the best model when supervised performance metrics calculation is difficult due to lack of data. The unsupervised feature selection followed by dimension reduction helped to observe a distinct circular pattern in the clustering of essential and non-essential genes. LapSVM then created a curve that dissected this circle for the classification and prediction of essential genes with high accuracy (auROC > 0.85) even with 1% labeled data for model training. After successful validation of this ML pipeline on both Eukaryotes and Prokaryotes that show high accuracy even when the labeled dataset is very limited, this strategy is used for the prediction of essential genes of organisms with inadequate experimentally known data, such asLeishmania sp. Using a graph-based semi-supervised machine learning scheme, a novel integrative approach has been proposed for essential gene prediction that shows universality in application to both Prokaryotes and Eukaryotes with limited labeled data. The essential genes predicted using the pipeline provide an important lead for the prediction of gene essentiality and identification of novel therapeutic targets for antibiotic and vaccine development against disease-causing parasites.