bluuebunny/crossref_metadata_2025 huggingface dataset:
Gradual decrease in the inter-population diversity of HIV-1 Env among group M lineages worldwide
Authors: Han Changze , Johnson Jacklyn , Dong Rentian , Kandula Raghavendranath , Kort Alexa J. , Wong Maria , Yang Tianbao , Breheny Patrick J. , Brown Grant D. , Haim Hillel
Published: September 2019

HIV-1 group M was transmitted to humans nearly one century ago. The virus has since diversified to form distinct clades, which spread to multiple regions worldwide. Of the different proteins encoded by HIV-1, the envelope glycoproteins (Envs) have diversified most rapidly in all infected populations. We compared the range of variants that emerged during the AIDS pandemic in diverse HIV-1 clades and distinct geographic regions. Our analyses focused on two components of Env that contain multiple epitopes of broadly-neutralizing antibodies: the glycan shield and apex domain. Interestingly, at each Env position, the amino acid in the inferred clade ancestor was replaced by a unique combination of emerging variants. Key antigenic sites and genetic signatures of vaccine protection have gradually evolved toward conserved frequency distributions (FDs) of all amino acids. FDs are specific for position and clade and are highly conserved in populations from different regions. Remarkably, founder effects of Env mutations in distinct clades and recently-infected regions were significantly reduced during the epidemic by evolution of each site toward the position-specific FD. These findings suggest that the selective pressures that guide evolution of Env are conserved in different populations. They are sufficiently strong to reduce founder effects at the clade and regional levels and have significantly altered the distribution of Env forms that circulate worldwide. Consequently, the intra-population diversity of the Env protein continues to increase whereas the inter-population diversity is gradually decreasing.

Importance

The Env protein of HIV-1 is the primary target in AIDS vaccine design. Due to frequent mutations, new Env variants continuously emerge in the population. The increasing number of Env forms and apparent randomness of the changes limit our ability to design broadly-effective vaccines. We examined the populations-level changes that occurred in Env during the AIDS epidemic. Each position of the molecule has evolved toward a specific combination of amino acids. Similar changes occurred in different HIV-1 subtypes and geographic regions toward the same sets of forms, often from distinct ancestral sequences. Such conserved patterns of evolution define a new framework for designing vaccines that are tailored to the unique combination of Env variants expected to circulate in each population.
Visualizing in vitro-in vivo correlation of miktoarm copolymer nanomicelles in cancer cellular uptake and trafficking
Authors: Cui Zheng , Zhang Xiaofei , Zhang Xiaojin , He Suna , Gao Wei , He Bing , Wang Xueqing , Zhang Hua , Zhong Zhenlin , Zhang Qiang
Published: September 2019

In this study, a clear correlation between the in vitro and in vivo cellular uptake and trafficking was discovered by delivering miktoarm copolymer nanomicelles (MCNs) to cancer cells and tumor tissues. To monitor this process, two different FRET pairs, DiO and DiI, DiD and DiR, were loaded into MCNs to monitor the Förster resonance energy transfer (FRET) efficiency. The change in FRET efficiency in vitro and in vivo demonstrated a similar sequence of events for the transport of MCNs: hyperbranched block PCL inserted into cytomembrane, while the loaded hydrophobic fluorescence probes were released and followed by time-dependent intracellular clustering within endocytic vesicles. Additionally, uptake of loaded fluorescence probes with successively increasing ratios of copolymers suggested that with the increase of mass ratio of copolymer to fluorescence probes, cellular uptake of probes significantly decreased. This result was also consistent with the uptake behavior in cancer tissues. Collectively, the interaction between MCNs and cellular membrane dictated the uptake and trafficking of core-loaded hydrophobic probes. This concept paves a new way to analyze in vitro-in vivo correlation of other nanocarriers for endocytosis mechanism studies as well as further novel copolymers design in biomedical applications.
Dynamic oligopeptide acquisition by the RagAB transporter fromPorphyromonas gingivalis
Authors: Madej Mariusz , White Joshua B. R. , Nowakowska Zuzanna , Rawson Shaun , Scavenius Carsten , Enghild Jan J. , Bereta Grzegorz P. , Pothula Karunakar , Kleinekathoefer Ulrich , Baslé Arnaud , Ranson Neil , Potempa Jan , van den Berg Bert
Published: September 2019

Porphyromonas gingivalis, an asaccharolyticBacteroidetes, is a keystone pathogen in human periodontitis that may also contribute to the development of other chronic inflammatory diseases, such as rheumatoid arthritis, cardiovascular disease and Alzheimer’s disease.P. gingivalisutilizes protease-generated peptides derived from extracellular proteins for growth, but how those peptides enter the cell is not clear. Here we identify RagAB as the outer membrane importer for peptides. X-ray crystal structures show that the transporter forms a dimeric RagA2B2complex with the RagB substrate binding surface-anchored lipoprotein forming a closed lid on the TonB-dependent transporter RagA. Cryo-electron microscopy structures reveal the opening of the RagB lid and thus provide direct evidence for a “pedal bin” nutrient uptake mechanism. Together with mutagenesis, peptide binding studies and RagAB peptidomics, our work identifies RagAB as a dynamic OM oligopeptide acquisition machine with considerable substrate selectivity that is essential for the efficient utilisation of proteinaceous nutrients byP. gingivalis.
Large-scale Phenomic and Genomic Analysis of Brain Asymmetrical Skew
Authors: Kong Xiang-Zhen , Postema Merel , Carrión Castillo Amaia , Pepe Antonietta , Crivello Fabrice , Joliot Marc , Mazoyer Bernard , Fisher Simon E. , Francks Clyde
Published: September 2019

The human cerebral hemispheres show a left-right asymmetrical torque pattern, which has been claimed to be absent in chimpanzees. The functional significance and developmental mechanisms are unknown. Here we carried out the largest-ever analysis of global brain shape asymmetry in magnetic resonance imaging data. Three population datasets were used, the UK Biobank (N = 39,678), Human Connectome Project (N = 1,113) and BIL&GIN (N = 453). At the population level, there was an anterior and dorsal skew of the right hemisphere, relative to the left. Both skews were associated independently with handedness, and various regional grey and white matter metrics oppositely in the two hemispheres, as well as other variables related to cognitive functions, sociodemographic factors, and physical and mental health. The two skews showed SNP-based heritabilities of 4-13%, but also substantial polygenicity in causal mixture model analysis, and no individually significant loci were found in GWAS for either skew. There was evidence for a significant genetic correlation (rg=−0.40, p=0.0075) between horizontal brain skew and Autism Spectrum Disorder. These results provide the first large-scale description of population-average brain skews and their inter-individual variations, their replicable associations with handedness, and insights into biological and other factors which associate with human brain asymmetry.
The genetic landscape of Ethiopia: diversity, intermixing and the association with culture
Authors: López Saioa , Tarekegn Ayele , Band Gavin , van Dorp Lucy , Bird Nancy , Morris Sam , Oljira Tamiru , Mekonnen Ephrem , Bekele Endashaw , Blench Roger , Thomas Mark G. , Bradman Neil , Hellenthal Garrett
Published: September 2019

The rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with -- and shape -- genetic structure in human populations. Using primarily novel genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals’ birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors upon shaping the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and increased genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic classifications, but indicate pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting how shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, these results identify the most important cultural and geographic proxies for genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.
The key miRNAs for metastasis and survival of colon adenocarcinoma
Authors: Yu Mengxi , Li Wei , Zhang Chuang , Xie Feng , He Chengyan
Published: September 2019

WGCNA (weighted gene co-expression network analysis) can provide a system-level insight into molecular interaction. To understand the co-expression pattern of miRNA in the progress of colon cancer development, this study constructed the WGCNA co-expression network to find the key microRNA of clinical significance and therefor provide possible personalized treatment targets. The miRNA expression data and clinical follow-up information of 442 valid colon cancer samples were obtained from TCGA. After the co-expression network was constructed, we found the turquoise module has the strongest correlation with stage IV. The miRNAs of the key module are enriched by GO and analyzed by KEGG, and the HUB-miRNAs are screened out through the network node degree. For clinical significance validation, data of 65 cases of colon cancer in GES29623 were analyzed by Cox regression and Kaplan-Meier, in 9 HUB-miRNAs, 2 miRNAs associated with overall survival rate were screened out. They can divide patients into high-risk group and low-risk group. Conclusion: has-miR-126-3p and has-miR-137 are the key miRNAs of COAD metastasis, they are of prognostic value in COAD.
Single-cell transcriptomic landscape of cardiac neural crest cell derivatives during embryonic and neonatal development
Authors: Liu Xuanyu , Chen Wen , Li Wenke , Zeng Ziyi , Priest James R. , Zhou Zhou
Published: September 2019

Rationale

Cardiac neural crest cells (CNCCs) contribute greatly to cardiovascular development. A thorough understanding of the cell lineages, transcriptomic states and regulatory networks of CNCC derivatives during normal development is essential for deciphering the pathogenesis of CNCC-associated congenital anomalies. However, the transcriptomic landscape of CNCC derivatives during development has not yet been examined at a single-cell resolution.

Objective

We sought to systematically characterize the cell lineages, define the developmental chronology and elucidate the transcriptomic dynamics of CNCC derivatives during embryonic and neonatal development.

Methods and Results

We performed single-cell transcriptomic sequencing of 34,131 CNCC-derived cells in mouse hearts from eight developmental stages between E10.5 and P7. Through single-cell analyses and single-molecule fluorescencein situhybridization, we confirmed the presence of CNCC-derived mural cells. Furthermore, we found the transition from CNCC-derived pericytes to microvascular smooth muscle cells, and identified the genes that were significantly regulated during this transition through pseudo-temporal analysis. CNCC-derived neurons first appeared at E10.5, which was earlier than previously recognized. In addition, the CNCC derivatives switched from a proliferative to a quiescent state with the progression of development. Gradual loss of the neural crest molecular signature with development was also observed in the CNCC derivatives. Our data suggested that many CNCC-derivatives had already committed or differentiated to a specific lineage when migrating to the heart. Finally, we characterized some previously unknown subpopulations of CNCC derivatives during development. For example, we found thatPenk+ cells, which were mainly localized in outflow tract cushions, were all derived from CNCCs.

Conclusions

Our study provides novel insights into the cell lineages, molecular signatures, developmental chronology and state change dynamics of CNCC derivatives during embryonic and neonatal development. Our dataset constitutes a valuable resource that will facilitate future efforts in exploring the role of CNCC derivatives in development and disease.
miR-26 suppresses adipocyte progenitor differentiation and fat production by targeting Fbxl19
Authors: Acharya Asha , Berry Daniel C. , Zhang He , Jiang Yuwei , Jones Benjamin T. , Hammer Robert E. , Graff Jonathan M. , Mendell Joshua T.
Published: September 2019

Fat storage in adult mammals is a highly regulated process that involves the mobilization of adipocyte progenitor cells (APCs) that differentiate to produce new adipocytes. Here we report a role for the broadly conserved miR-26 family of microRNAs (miR-26a-1, miR-26a-2, and miR-26b) as major regulators of APC differentiation and adipose tissue mass. Deletion of all miR-26-encoding loci in mice resulted in a dramatic expansion of adipose tissue in adult animals fed normal chow. Conversely, transgenic overexpression of miR-26a protected mice from high-fat diet-induced obesity. These effects were attributable to a cell-autonomous function of miR-26 as a potent inhibitor of APC differentiation. miR-26 blocks adipogenesis, at least in part, by repressing expression of Fbxl19, a conserved miR-26 target without a previously known role in adipocyte biology that encodes a component of SCF-type E3 ubiquitin ligase complexes. These findings have therefore revealed a novel pathway that plays a critical role in regulating adipose tissue formation in vivo and suggest new potential therapeutic targets for obesity and related disorders.
Who predicts dollar-rupee volatility better? A tale of two options markets
Authors: Bhat Aparna Prasad
Published: September 2019

Purpose

The purpose of this paper is to examine whether volatility implied from dollar-rupee options is an unbiased and efficient predictor ofex postvolatility, and to determine which options market is a better predictor of future realized volatility and to ascertain whether the model-free measure of implied volatility outperforms the traditional measure derived from the Black–Scholes–Merton model.

Design/methodology/approach

The information content of exchange-traded implied volatility and that of quoted implied volatility for OTC options is compared with that of historical volatility and a GARCH(1, 1)-based volatility. Ordinary least squares regression is used to examine the unbiasedness and informational efficiency of implied volatility. Robustness of the results is tested by using two specifications of implied volatility and realized volatility and comparison across two markets.

Findings

Implied volatility from both OTC and exchange-traded options is found to contain significant information for predictingex postvolatility, but is neither unbiased nor informationally efficient. The implied volatility of at-the-money options derived using the Black–Scholes–Merton model is found to outperform the model-free implied volatility (MFIV) across both markets. MFIV from OTC options is found to be a better predictor of realized volatility than MFIV from exchange-traded options.

Practical implications

This study throws light on the predictive power of currency options in India and has strong practical implications for market practitioners. Efficient currency option markets can serve as effective vehicles both for hedging and speculation and can convey useful information to the regulators regarding the market participants’ expectations of future volatility.

Originality/value

This study is a comprehensive study of the informational efficiency of options on an emerging currency such as the Indian rupee. To the author’s knowledge, this is one of the first studies to compare the predictive ability of the exchange-traded and OTC markets and also to compare traditional model-dependent volatility with MFIV.
Effects of mummy consumption on fitness and oviposition site selection on Harmonia axyridis
Authors: Yu Xing‐Lin , Feng Yi , Feng Zhu‐Jun , Chana Phongsakorn , Zhu Guan‐Xiong , Xia Peng‐Liang , Liu Tong‐Xian
Published: September 2019

Intraguild predation (IGP) has been commonly reported between predators and parasitoids used as biological control agents as predators consuming parasitoids within their hosts. However, the effect of parasitoid–mummy consumption on the fitness of the predator and subsequent oviposition site selection have not been well studied. In our study, we conducted two laboratory experiments to examine the influence of Aphidius gifuensis Ashmead (Hymenoptera: Braconidae) mummies as prey on fitness and subsequently oviposition site selection of Harmonia axyridis (Pallas) (Coleoptera: Coccinellidae). Results indicate that when H. axyridis was reared on A. gifuensis mummies only, its larval development was prolonged, and body weight of the 4th instar larvae and newly emerged adults, and fecundity decreased. Moreover, H. axyridis did not exhibit oviposition preference on plants infested with unparasitized aphids or aphids parasitized for shorter than 9 days. However, compared with plants with mummies (parasitized ≥9 days), H. axyridis laid more eggs on plants with unparasitized aphids. In contrast, H. axyridis previously fed with A. gifuensis mummies did not show a significant oviposition preference between plants with unparasitized aphids and those with mummies (parasitized ≥9 days). Overall, our results suggest that mummy consumption reduced the fitness of H. axyridis. Although H. axyridis avoided laying eggs on plants with A. gifuensis mummies, prior feeding experience on A. gifuensis mummies could alter the oviposition site preference. Thus, in biological control practice, prior feeding experience of H. axyridis should be carefully considered for reduction of IGP and increase of fitness of H. axyridis on A. gifuensis.
Preliminary report of knockdown resistance in Culex pipiens pallens and Aedes koreicus from Korea
Authors: Ryu Jihun , Hwang Do Un , Bae Yeon Jae , Lee Si Hyeock , Kim Young Ho , Lee Seung‐Yeol , Jung Hee‐Young , Choi Kwang Shik
Published: September 2019

Pyrethroid insecticides have been effective and powerful for controlling mosquitoes. However, abuse of these insecticides increases the number of resistant mosquitoes. In this study, Culex pipiens pallens and Aedes koreicus were collected from an artificial reservoir in the vicinity of a populated area in Korea, which is also a migratory bird catchment area. To monitor resistance to pyrethroid insecticides in mosquitoes, genomic DNA from the collected mosquitoes was sequenced for the kdr mutation in the voltage‐gated sodium channel (VGSC) gene. As a result, three samples with homozygous resistance (17.6%) and one with heterozygous resistance (5.9%) were found among 17 Cx. pipiens pallens specimens. One of the samples had a unique sequence at the amplified VGSC region. Of the 15 Ae. koreicus, no insecticide resistant individuals were found. In Korea, this is the first report of kdr genetic traits in Ae. koreicus and Cx. pipiens pallens and of a unique VGSC allele in Cx. pipiens pallens. Further investigation is needed to monitor the kdr resistance of these species in Korea and to determine how the unique sequence found in Cx. pipiens pallens is related to insecticide resistance.
The effect of apatinib combined with chemotherapy or targeted therapy on non‐small cell lung cancer in vitro and vivo
Authors: Liu Mingtao , Wang Xiuxiu , Li Hui , Xu Lisheng , Jing Lijun , Jiang Peng , Liu Baoyi , Li Yu
Published: September 2019

Background

The aim of this study was to investigate the feasibility of using a combination of apatinib in the treatment of non‐small cell lung cancer. Apatinib is a tyrosine kinase inhibitor which selectivelyacts on vascular endothelial growth factor receptor 2 (VEGFR‐2) and has shown good efficacy in a variety of malignancies, but the drug resistance is fast in single drug therapy.

Methods

The inhibitory effect of apatinib and other drugs on lung cancer cells was determined by CCK‐8 test in vitro, and the IC50 value was determined. To establish a nude mouse xenograft model, observe the inhibitory effect of apatinib combined with other drugs on lung cancer xenografts in nude mice; immunohistochemical staining of tumor microvessel density and Ki67 expression in transplanted tumor tissues; Western blot analysis of related signaling pathways expression; immunohistochemistry was used to detect tumor microvessel density in other organs and to observe its safety.

Results

In this study, we found apatinib combined with pemetrexed, the first and third generation of epidermal growth factor receptor tyrosine kinase inhibitor, could synergistically inhibit the proliferation of non‐small cell lung cancer cell (NSCLC) lines, reduce the microvessel density and Ki67 protein levels of three non‐small cell lung cancer xenografts, and enhance anti‐tumor activity by synergistically inhibiting the MAPK‐ERK and PI3K‐AKT‐mTOR signaling pathway. Furthermore, there were no pathological abnormalities in the heart, brain, liver and kidney of each group.

Conclusions

The efficacy of apatinib combination is better than that of monotherapy, and there is no significant difference in toxicity of important organs, which suggests the feasibility of a combination of apatinib in the treatment of non‐small cell lung cancer.
Incidence of suicidal behaviour and violent crime following antidepressant medication: a Danish cohort study
Authors: Osler M. , Wium‐Andersen M. K. , Wium‐Andersen I. K. , Gronemann F. H. , Jørgensen M. B. , Rozing M. P.
Published: September 2019

Objective

To examine the incidence of suicidal and violent behaviour following initiation of antidepressant medication.

Method

Cohorts of 997 911 conscripts and 95 794 patients with a first‐time affective disorder were followed for purchase of antidepressant medication, suicide, suicide attempts and conviction for violent crime in Danish registries between 1997 through 2015. Incidence of outcomes was estimated for the first 28 days, 28–365 days or later after initiation of antidepressants or study entry.

Results

Of 16.5% of conscripts and 73.7% of patients with affective disorders initiated antidepressant medication. Incidence of suicide was 3–4 times higher during the first 28 days after initiation compared to the rates in the following year in both cohorts. A similar trend was seen among the untreated patients with affective disorders, whereas suicide incidence was stable at a low level among conscripts not treated with antidepressants. Incidence of attempted suicide was highest during the 28 days before and after initiation of antidepressants, while rates of violent crime were similar before and after initiation. These trends in incidence were independent of class of antidepressant.

Conclusion

Higher rates of suicidal behaviour in the weeks following initiation of antidepressant medication probably reflect disease severity and a delay in mood response.
Fathers’ alcohol use and suicidal behaviour in offspring during youth and young adulthood
Authors: Landberg J. , Danielsson A.‐K. , Hemmingsson T.
Published: September 2019

Objective

To examine the association between various indicators of father's alcohol use and suicidal behaviour in offspring during youth and young adulthood.

Methods

The study is based on a cohort of 68 910 Swedish citizens who were born between 1970 and 1985 and have fathers who participated in conscription for compulsory military training in 1969/70. Information on fathers’ alcohol use was collected during conscription. Offspring was followed for suicide attempts or completed suicides (through linkage with national registers) from age 12 to end of follow‐up in 2008.

Results

After adjustment for confounders, the hazard ratio (HR) for offspring to fathers who were heavy drinkers was 1.4 (95% CI 1.02, 1.93) while the associations turned non‐significant for offspring to fathers who often drank into intoxication, HR 1.14 (0.68, 1.90). The highest risk for suicidal behaviour was found for offspring to fathers who had been apprehended for drunkenness two times or more, or with an alcohol‐related hospitalization, with adjusted HRs of 2.1 (1.4, 3,14) and 1.9 (1.27, 2,85) respectively.

Conclusion

Fathers’ alcohol use is associated with increased risk of suicidal behaviour among offspring in youth and young adulthood.
Three‐dimensional computed tomographic examination of pelvic cavity in Van Cats and its morphometric investigation
Authors: Yilmaz Osman , Soyguder Zafer , Yavuz Alpaslan , Dundar Ilyas
Published: September 2019

This study was carried out to determine the morphometric values of the pelvic cavity, the cranial and caudal pelvic aperture by three‐dimensional (3D) reconstruction of the images obtained by computed tomography in adult Van Cats and to show the differences between these indicators in both genders. A total of 16 adult Van Cats, eight male and eight female, were used in the study. Animals were anesthetized with ketamine–xylazine combination and were scanned by computerized tomography. Images of the pelvic cavity were obtained. Three‐dimensional reconstruction of the pelvis was performed with three‐dimensional modelling program. Measurements of the diameters of the pelvic cavity, the cranial and caudal pelvic aperture were calculated from these images, and statistical analyzes were performed. Three‐dimensional modelling of the pelvic cavity of Van Cats were examined between males and females. The results showed that there were significant (p < .05) differences between measurement of the pelvic inclination, the medial transverse diameter, the caudal transverse diameter and the angle between ischiatic arch. In addition, the correlations between age and weight were found statistically significant (p < .05) with the dorsal transverse diameter, the intermediate transverse diameter and the caudal transverse diameter in males. On the other hand, the correlations of age were statistically significant (p < .01) with the cranial pelvic aperture and the caudal pelvic aperture in females. In conclusion, some biometric values of pelvic cavity were observed to be statistically different in Van Cats.
Trophoblasts promote induction of a regulatory phenotype in B cells that can protect against detrimental T cell–mediated inflammation
Authors: Guzman‐Genuino Ruth Marian , Dimova Tanya , You Yuan , Aldo Paulomi , Hayball John D. , Mor Gil , Diener Kerrilyn R.
Published: September 2019

Problem

A successful outcome to pregnancy is critically dependent on the initiation of maternal immune tolerance before embryo implantation. Cells of embryonic origin that come in contact with the uterine microenvironment can exert influence over the phenotype and function of immune cells to facilitate robust implantation; however, what influence they may have on B cells remains unknown. In this study, we investigate the effect of human trophoblast cells on B‐cell phenotype and the subsequent effect on peri‐implantation events.

Method of study

We cultured purified human B cells with the first‐trimester human trophoblast cell line Swan 71 to investigate trophoblast‐B‐cell interactions and utilized trophoblast spheroids in an in vitro implantation model of migration and invasion.

Results

Trophoblast‐educated B cells or TE‐B cells were found to consist of B cells in committed lineages such as plasmablasts and memory B cells, as well as increased proportions in subsets of CD24hiCD27+ regulatory B cells and CD19+IL‐10+ B cells. Conditioned media from the TE‐B cells showed reduced production of pro‐inflammatory cytokines that influenced the T‐cell proliferation and cytokine production. Using trophoblast spheroids, we assessed the role of TE‐B cells in trophoblast invasion and migration. Our results demonstrate a protective effect of TE‐B‐conditioned media against deleterious inflammation as evidenced by survival of the trophoblast spheroid in the presence of an immune assault and promotion of a migratory phenotype.

Conclusion

We posit that trophoblast‐mediated education of B cells leads to their acquisition of properties capable of modulating inflammation in the uterine environment during the peri‐implantation period.
Evaluation of IL8 pathway on the ocular surface: new insights in patients with ocular mucous membrane pemphigoid
Authors: Bruscolini Alice , Lambiase Alessandro , Segatto Marco , La Cava Maurizio , Nebbioso Marcella , Sacchetti Marta
Published: September 2019

Purpose

To evaluate the expression of IL8/CXCL8 cytokine and its receptor CXCR1 in tear film and ocular surface of patients with ocular mucous membrane pemphigoid (oMMP).

Methods

Ten patients with oMMP in the quiescent phase, 20 patients with primary Sjogren syndrome (pSS) and 13 age‐ and sex‐matched healthy controls (HCs) were included in this study. All patients undergone complete eye examination including lacrimal function tests and ocular surface staining assessed by ocular staining score. Ocular mucous membrane pemphigoid (oMMP) staging according to Mondino classification and dry eye severity grade according to Dry Eye Workshop 2007 classification were recorded. Tear samples and conjunctival epithelium were collected. IL‐8 tear concentration was measured by enzyme‐linked immunosorbent assay, and conjunctival IL8 was analysed by Western blot; conjunctival expression of CXCR1 was evaluated by immunohistochemistry. Il‐8 and CXCR1 expression in oMMP patients were compared with HCand pSS patients and correlated with ocular clinical findings.

Results

Tear levels of IL‐8 were significantly increased in patients with oMMP (260.1 ± 70 pg/ml) when compared to both HCs (98.5 ± 71.35 pg/ml; p = 0.001) and patients with pSS (96.3 ± 87.5 pg/ml; p = 0.001). Conjunctival expression of IL8 and CXCR1 was significantly increased in oMMP patients when compared to both healthy subjects and pSS patients.

Conclusion

The significant increase of tear and conjunctival IL8 and CXCR1 levels in patients with oMMP when compared to healthy subjects and patients with Sjogren syndrome suggests that changes of IL8 pathway are specific of oMMP and may represent a potential biomarker of the disease and/or therapeutic target.
In situ ruminal degradation and in vitro fermentation characteristics, and antioxidative activities of the lotus rhizome
Authors: Asano Sanae , Aoki Kohei , Kaizuka Yuna , Kobayashi Yuhi , Watanabe Kenta , Kato Chizuko , Saito Chihiro , Nishimura Syuichi , Kato Toshiaki , Takagi Motonori , Kajikawa Hiroshi
Published: September 2019

We evaluated the lotus rhizome as a potential ruminant feed by investigating its compositional properties, in situ degradation profile and in vitro fermentation characteristics with ruminal microbes, in comparison with cereal grains (corn, barley and wheat). The antioxidative activities in the lotus rhizome were also estimated. The soluble fraction of dry matter in lotus tuber was >70%, which was higher than those in the grains. The insoluble fraction in lotus tuber was not degraded by ruminal microbes in accord with a first‐order reaction. In an in vitro experiment, lotus tuber showed lower fermentation at 8 hr compared to the grains, but exhibited higher productions of gas and VFA at 48 hr along with a lower lactate and higher pH. The lower value of final lactate production in lotus tuber, indicating the metabolic capacity for lactate utilization retained, suggests a lower risk of ruminal acidosis compared to grains. Lotus rhizome had high antioxidant activities, with the foliar bud showing the strongest ferric reducing antioxidant power, followed in order by the apical bud, node, residual tuber, edible tuber, and nodal root. For ruminants, the lotus rhizome could thus be not only an energy feed but also the source of natural antioxidants.
Pneumonia: host susceptibility and shared genetics with pulmonary function and other traits
Authors: Khadzhieva M B , Kuzovlev A N , Salnikova L E
Published: September 2019

Pneumonia is a common and severe infectious lung disease. Host genetics, together with underlying medical and lifestyle conditions, determine pneumonia susceptibility. We performed a secondary analysis of the results of two genome-wide studies for pneumonia in 23andMe participants (40 600 cases/90 039 controls) (Tian et al., 2017) and UK Biobank (BB) participants (12 614 cases/324 585 controls) (via the Global Biobank Engine) and used the GTEx database to correlate the results with expression quantitative trait loci (eQTLs) data in lung and whole blood. In the 23andMe pneumonia single nucleotide polymorphism (SNP) set, 177 genotyped SNPs in the human leukocyte antigen (HLA) region satisfied the genome-wide significance level, P ≤ 5·0E-08. Several target genes (e.g. C4A, VARS2, SFTA2, HLA-C, HLA-DQA2) were unidirectionally regulated by many HLA eSNPs associated with a higher risk of pneumonia. In lung, C4A transcript was up-regulated by 291 pneumonia risk alleles spanning the half the HLA region. Among SNPs correlated with the expression levels of SFTA2 and VARS2, approximately 75% overlapped: all risk alleles were associated with VARS2 up-regulation and SFTA2 down-regulation. To find shared gene loci between pneumonia and pulmonary function (PF), we used data from the Global Biobank Engine and literature on genome-wide association studies (GWAS) of PF in general populations. Numerous gene loci overlapped between pneumonia and PF: 28·8% in the BB data set and 49·2% in the 23andMe data set. Enrichment analysis within the database of Genotypes and Phenotypes (dbGaP) and National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Catalog of pneumonia and pneumonia/PF gene sets identified significant overlap between these gene sets and genes related to inflammatory, developmental, neuropsychiatric and cardiovascular and obesity-related traits.
Multi-component meningococcal serogroup B (MenB)-4C vaccine induces effective opsonophagocytic killing in children with a complement deficiency
Authors: van den Broek B , van Els C A C M , Kuipers B , van Aerde K , Henriet S S , de Groot R , de Jonge M I , Langereis J D , van der Flier M
Published: September 2019

Vaccination against meningococcal serogroup B is recommended for patients with a complement deficiency; however, although immunogenicity in this patient group has been shown, efficacy has not yet been established. In this study, we collected serum from children with a complement deficiency in the alternative pathway or in late terminal pathway before and after vaccination with multi-component meningococcal serogroup B (MenB)-4C. MenB-4C is a multi-component, protein-based vaccine against MenB consisting of factor H-binding protein, Neisserial heparin-binding protein, Neisserial adhesion A and outer membrane vesicles containing Porin A. We assessed the vaccine immunogenicity and vaccine-mediated protection by a whole cell enzyme-linked immunosorbent assay with Neisseria meningitidis serogroup B strains H44/76, 5/99 and NZ98/254, which shows that vaccination induced antibody titers against meningococcus. We show that the classical serum bactericidal activity assay with exogenous serum indicates the presence of vaccine-induced antibodies and capacity to activate complement-mediated pathogen lysis. However, in children with a late terminal pathway deficiency, no complement-mediated pathogen lysis was observed when autologous serum was applied in the serum bactericidal activity assay, demonstrating a lack of serum bactericidal activity in children with complement deficiencies. However, MenB-4C vaccination still induced effective complement-dependent opsonophagocytic killing against N. meningitidis serogroup B in reconstituted whole blood with autologous serum from children with an alternative pathway or late terminal pathway deficiency. These findings support the recommendation to vaccinate all complement-deficient children against MenB.
Decision‐support tools for dynamic management
Authors: Welch Heather , Brodie Stephanie , Jacox Michael G. , Bograd Steven J. , Hazen Elliott L.
Published: September 2019

Spatial management is a valuable strategy to advance regional goals for nature conservation, economic development, and human health. One challenge of spatial management is navigating the prioritization of multiple features. This challenge becomes more pronounced in dynamic management scenarios, in which boundaries are flexible in space and time in response to changing biological, environmental, or socioeconomic conditions. To implement dynamic management, decision‐support tools are needed to guide spatial prioritization as feature distributions shift under changing conditions. Marxan is a widely applied decision‐support tool designed for static management scenarios, but its utility in dynamic management has not been evaluated. EcoCast is a new decision‐support tool developed explicitly for the dynamic management of multiple features, but it lacks some of Marxan's functionality. We used a hindcast analysis to compare the capacity of these 2 tools to prioritize 4 marine species in a dynamic management scenario for fisheries sustainability. We successfully configured Marxan to operate dynamically on a daily time scale to resemble EcoCast. The relationship between EcoCast solutions and the underlying species distributions was more linear and less noisy, whereas Marxan solutions had more contrast between waters that were good and poor to fish. Neither decision‐support tool clearly outperformed the other; the appropriateness of each depends on management purpose, resource‐manager preference, and technological capacity of tool developers.

Article impact statement: Marxan can function as a decision‐support tool for dynamic management scenarios in which boundaries are flexible in space and time.
Topographic ruggedness and rainfall mediate geographic range contraction of a threatened marsupial predator
Authors: Moore Harry A. , Dunlop Judy A. , Valentine Leonie E. , Woinarski John C. Z. , Ritchie Euan G. , Watson David M. , Nimmo Dale G.
Published: September 2019

Aim

Species range contractions are increasingly common globally. The niche reduction hypothesis posits that geographic range contractions are often patterned across space owing to heterogeneity in threat impacts and tolerance. We applied the niche reduction hypothesis to the decline of a threatened marsupial predator across northern Australia, the northern quoll (Dasyurus hallucatus).

Location

Northern Australia.

Methods

We assembled a database containing 3,178 historic and contemporary records for northern quolls across the extent of their distribution dating between 1778 and 2019. Based on these records, we estimated changes in the geographic range of the northern quoll using α‐hulls across four main populations. We then examined how range contractions related to factors likely to mediate the exposure, susceptibility, or tolerance of northern quolls to threats.

Result

The extent of range contractions showed an east–west gradient, most likely reflecting the timing of spread of introduced cane toads (Rhinella marina). There were clear changes in environmental characteristics within the contemporary compared to the historic geographic range, with the most substantial occurring in populations that have suffered the greatest range contractions. The contemporary range is comprised of higher quality habitats (measured using environmental niche models), characterized by higher topographical ruggedness and annual rainfall, and reduced distance to water, compared to the historic range.

Main conclusions

Changes to range and niche likely reflect the capacity of complex habitats to ameliorate threats (namely predation and altered fire regimes), and access to resources that increase threat tolerance. This study highlights the multivariate nature of ecological refuges and the importance of high‐quality habitats for the persistence of species exposed to multiple threats. Our methods provide a useful framework which can be applied across taxa in providing valuable insight to management.
Effects of sodium‐glucose co‐transporter‐2 inhibitors in type 2 diabetes in women versus men
Authors: Rådholm Karin , Zhou Zien , Clemens Kristin , Neal Bruce , Woodward Mark
Published: September 2019

Sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors prevent cardiovascular complications in type 2 diabetes. We aimed to study whether they have similar effects in women and men by summarizing the effects of SGLT2 inhibitors compared to placebo on vascular and safety outcomes stratified by sex. We included patients with type 2 diabetes enrolled in the EMPA‐REG OUTCOME, CANVAS Program, DECLARE TIMI‐58 and CREDENCE trials. There were no differences in the risk ratios between men and women, SGLT2 versus control (placebo), for vascular efficacy outcomes or death (all P for interaction ≥.12), with clear protection shown against major adverse cardiovascular events, heart failure, vascular death and total mortality. SGLT2 inhibitor treatment was also associated with similar relative risks in women and men for the safety outcomes of amputation, fracture, genital infection and urinary tract infection (all P for interaction ≥.17). SGLT2 inhibition provided similar protection against vascular risks and death, and similar risks of serious adverse events, for women and men.
Translocation (11;14) in newly diagnosed multiple myeloma, time to reclassify this standard risk chromosomal aberration?
Authors: Gran Charlotte , Uttervall Katarina , Borg Bruchfeld Johanna , Wallblom Ann , Alici Evren , Gahrton Gösta , Nahi Hareth
Published: September 2019

Objectives

The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), and its importance as prognostic factor has been controversial. The aim was to analyze its prognostic value.

Method

In this retrospective study of 469 newly diagnosed myeloma patients, outcomes in patients with (11;14) and standard risk (t(11;14)SR) or high risk (t(11;14)HR) cytogenetics were compared to outcomes of patients without t(11;14) and SR (non‐t(11;14)SR) or HR (non‐t(11;14)HR), respectively.

Results

Overall progression‐free survival (PFS) was shorter in t(11;14)SR than non‐t(11;14)SR (median 28.9 vs 35.3 months); however, the difference was not significant (P = .2). Overall survival (OS) did not differ significantly between the groups. In the subgroup of patients that did not receive high‐dose treatment, PFS was shorter for t(11;14)SR compared to non‐t(11;14)SR, 10.6 vs 24.6 months (P = .01). Although OS were shorter for t(11,14)SR compared to non‐t(11;14)SR (5‐year OS 41.7% vs 63.8%), the difference was not significant (P = .1). In HDT patients, no significant difference was observed for OS or PFS between those with or without t(11;14).

Conclusion

This study shows that t(11;14) is associated with poorer outcome in MM, particularly in non‐high‐dose‐treated SR patients. It should be considered an intermediate or high‐risk marker in these patients.
Mechanism of discrimination of isoleucyl‐tRNA synthetase against nonproteinogenic α‐aminobutyrate and its fluorinated analogues
Authors: Zivkovic Igor , Moschner Johann , Koksch Beate , Gruic‐Sovulj Ita
Published: September 2019

Isoleucyl‐tRNA synthetase (IleRS) is a paradigm for understanding how specificity against smaller hydrophobic substrates evolved in both the synthetic and editing reactions. IleRS misactivates nonproteinogenic norvaline (Nva) and proteinogenic valine (Val), with a 200‐fold lower efficiency than the cognate isoleucine (Ile). Translational errors are, however, prevented by IleRS hydrolytic editing. Nva and Val are both smaller than Ile by a single methylene group. How does the removal of one additional methylene group affects IleRS specificity? We found that the nonproteinogenic α‐aminobutyrate (Abu) is activated 30‐fold less efficiently than Nva and Val, indicating that the removal of the second methylene group comes with a lower penalty. As with Nva and Val, discrimination against Abu predominantly originated from a higher KM. To examine whether increased hydrophobicity could compensate for the loss of van der Waals interactions, we tested fluorinated Abu analogues. We found that fluorination further hampered activation by IleRS, and even more so by the evolutionary‐related ValRS. This suggests that hydrophobicity is not a main driving force of substrate binding in these enzymes. Finally, a discrimination factor of 7100 suggests that IleRS is not expected to edit Abu. However, we found that the IleRS editing domain hydrolyzes Abu‐tRNAIle with a rate of 40 s−1 and the introduction of fluorine did not slow down the hydrolysis. This raises interesting questions regarding the mechanism of specificity of the editing domain and its evolution. Understanding what shapes IleRS specificity is also of importance for reengineering translation to accommodate artificial substrates including fluorinated amino acids.

Enzymes

Isoleucyl‐tRNA synthetase (EC 6.1.1.5), leucyl‐tRNA synthetase (EC 6.1.1.4), valyl‐tRNA synthetase (EC 6.1.1.9).
Review: Epidemiology of Helicobacter pylori infection
Authors: Leja Mārcis , Grinberga‐Derica Ieva , Bilgilier Ceren , Steininger Christoph
Published: September 2019

This review summarizes recent publications on the epidemiology of Helicobacter pylori. Two major systemic analyses, from Malaysia and Ethiopia, were published. The Brazilian Consensus Conference has stated that H pylori infection is an infectious disease with an indication for antimicrobial therapy. A continuous decrease in H pylori prevalence was reported from many regions worldwide, including Korea, China, Iran, and Austria. A cross‐sectional H pylori prevalence study conducted in the United Arab Emirates found 41% prevalence in a group of healthy children and adults. Several studies from Asia addressed H pylori prevalence in adults undergoing regular checkup. The largest of such studies, performed in Korea, involved 24 471 subjects and reported 41.5% seroprevalence. A relatively smaller study from East China on 3252 subjects reported 27.5% prevalence. In contrast, a study from Spain reported 87.2% seroprevalence. A report on the association between smoking and H pylori seropositivity was published on behalf of the Stomach Cancer Pooling (StoP) Project—a consortium of epidemiological studies of gastric cancer. Also, other potential risk factors, including occupational risk factors, water supply, and food were analyzed. Gastroesophageal reflux and sexual partners has been associated with a higher risk for H pylori acquisition, and gut microbiota was suggested to play a role in intrafamilial transmission of H pylori. Finally, in a few studies (from Mexico and Japan), the catalytic model for predicting the potential risk of acquiring H pylori infection in the future was used. As anticipated, a further decline in H pylori‐related disease was demonstrated by applying the modeling.