bluuebunny/crossref_metadata_2025 huggingface dataset:
Pathologic T-cell response in ischaemic failing hearts elucidated by T-cell receptor sequencing and phenotypic characterization
Authors: Tang Ting-Ting , Zhu Yi-Cheng , Dong Nian-Guo , Zhang Si , Cai Jie , Zhang Ling-Xue , Han Yue , Xia Ni , Nie Shao-Fang , Zhang Min , Lv Bing-Jie , Jiao Jiao , Yang Xiang-Ping , Hu Yu , Liao Yu-Hua , Cheng Xiang
Published: July 2019

Aims

A persistent cardiac T-cell response initiated by myocardial infarction is linked to subsequent adverse ventricular remodelling and progression of heart failure. No data exist on T-cell receptor (TCR) repertoire changes in combination with phenotypic characterization of T cells in ischaemic failing human hearts.

Methods and results

Analysis of TCR repertoire with high-throughput sequencing revealed that compared with T cells in control hearts, those in ischaemic failing hearts showed a clonally expanded TCR repertoire but similar usage patterns of TRBV-J rearrangements and V gene segments; compared with T cells in peripheral blood, those in ischaemic failing hearts exhibited a restricted and clonally expanded TCR repertoire and different usage patterns of TRBV-J rearrangements and V gene segments, suggesting the occurrence of tissue-specific T-cell expansion in ischaemic failing hearts. Consistently, TCR clonotype sharing was prominent in ischaemic failing hearts, especially in hearts of patients who shared human leucocyte antigen (HLA) alleles. Furthermore, ischaemia heart failure (IHF) heart-associated clonotypes were more frequent in peripheral blood of IHF patients than in that of controls. Heart-infiltrating T cells displayed memory- and effector-like characteristics. Th1 cells were the predominant phenotype among CD4  + T cells; CD8  + T cells were equally as abundant as CD4  + T cells and produced high levels of interferon-γ, granzyme B, and perforin.

Conclusion

We provide novel evidence for a tissue-specific T-cell response predominated by Th1 cells and cytotoxic CD8  + T cells in ischaemic failing human hearts that may contribute to the progression of heart failure.
Rhizospheric life of Salmonella requires flagella-driven motility and EPS-mediated attachment to organic matter and enables cross-kingdom invasion
Authors: Karmakar Kapudeep , Nair Abhilash Vijay , Chandrasekharan Giridhar , Garai Preeti , Nath Utpal , Nataraj Karaba N , N.B Prakash , Chakravortty Dipshikha
Published: July 2019

Salmonella is an established pathogen of the members of the kingdom Animalia. Reports indicate that the association of Salmonella with fresh, edible plant products occurs at the pre-harvest state, i.e. in the field. In this study, we follow the interaction of Salmonella Typhimurium with the model plant Arabidopsis thaliana to understand the process of migration in soil. Plant factors like root exudates serve as chemo-attractants. Our ex situ experiments allowed us to track Salmonella from its free-living state to the endophytic state. We found that genes encoding two-component systems and proteins producing extracellular polymeric substances are essential for Salmonella to adhere to the soil and roots. To understand the trans-kingdom flow of Salmonella, we fed the contaminated plants to mice and observed that it invades and colonizes liver and spleen. To complete the disease cycle, we re-established the infection in plant by mixing the potting mixture with the fecal matter collected from the diseased animals. Our experiments revealed a cross-kingdom invasion by the pathogen via passage through a murine intermediate, a mechanism for its persistence in the soil and invasion in a non-canonical host. These results form a basis to break the life-cycle of Salmonella before it reaches its animal host and thus reduce Salmonella contamination of food products.
Not all saponins have a greater antiprotozoal activity than their related sapogenins
Authors: Ramos-Morales E , Lyons L , de la Fuente G , Braganca R , Newbold C J
Published: July 2019

The antiprotozoal effect of saponins varies according to both the structure of the sapogenin and the composition and linkage of the sugar moieties to the sapogenin. The effect of saponins on protozoa has been considered to be transient as it was thought that when saponins were deglycosilated to sapogenins in the rumen they became inactive; however, no studies have yet evaluated the antiprotozoal effect of sapogenins compared to their related saponins. The aims of this study were to evaluate the antiprotozoal effect of eighteen commercially available triterpenoid and steroid saponins and sapogenins in vitro, to investigate the effect of variations in the sugar moiety of related saponins and to compare different sapogenins bearing identical sugar moieties. Our results show that antiprotozoal activity is not an inherent feature of all saponins and that small variations in the structure of a compound can have a significant influence on their biological activity. Some sapogenins (20(S)-protopanaxatriol, asiatic acid and madecassic acid) inhibited protozoa activity to a greater extent than their corresponding saponins (Re and Rh1 and asiaticoside and madecassoside), thus the original hypothesis that the transient nature of the antiprotozoal action of saponins is due to the deglycosilation of saponins needs to be revisited.
The role of exploitation in the establishment of mutualistic microbial symbioses
Authors: Sørensen Megan E S , Lowe Chris D , Minter Ewan J A , Wood A Jamie , Cameron Duncan D , Brockhurst Michael A
Published: July 2019

Evolutionary theory suggests that the conditions required for the establishment of mutualistic symbioses through mutualism alone are highly restrictive, often requiring the evolution of complex stabilising mechanisms. Exploitation, whereby initially the host benefits at the expense of its symbiotic partner and mutual benefits evolve subsequently through trade-offs, offers an arguably simpler route to the establishment of mutualistic symbiosis. In this review, we discuss the theoretical and experimental evidence supporting a role for host exploitation in the establishment and evolution of mutualistic microbial symbioses, including data from both extant and experimentally evolved symbioses. We conclude that exploitation rather than mutualism may often explain the origin of mutualistic microbial symbioses.
Many plant pathogenic Pseudomonas savastanoi pv glycinea isolates possess an inactive quorum sensing ahlR gene via a point mutation
Authors: Degrassi Giuliano , Mortato Valentina , Devescovi Giulia , Hoshino Rodrigo , Chatnaparat Tiyakhon , Kojic Milan , Carpentieri-Pipolo Valeria , Zhao Youfu , Venturi Vittorio
Published: July 2019

Many plant bacterial pathogens monitor their group behaviour and their population density via production of N-acyl homoserine lactone signals which regulate the expression of several genes via the LuxI/R homologs. This regulatory network, termed quorum sensing (QS), is present in the soybean bacterial pathogen Pseudomonas savastanoi pv glycinea (Psg). The sequenced genomes of two strains of Psg, race 4 and B076, contain an N-acyl homoserine lactone (AHL) based LuxI/R QS system named AhlI/R. While studying the QS system of Psg strains race 4 and B076 isolated in USA, LMG5066 in New Zealand and IBSBF355 in Brazil, we found that B076, LMG5066 and IBSBF355 possess a point mutation in the ahlR gene that causes a frameshift resulting in a truncated AhlR protein. Psg race 4 does not possess the mutation in ahlR and the QS system is functional. The same mutation in the ahlR gene was found to be also present in 9 of 19 Psg strains isolated from diseased soybean in Illinois. Phenotypic analysis of strains showed that swarming motility is repressed whereas phosphate solubilisation was activated by QS in Psg. Analysing the secretome, we also found that four proteins were under QS regulation.
Far-field tsunami data assimilation for the 2015 Illapel earthquake
Authors: Wang Y , Satake K , Cienfuegos R , Quiroz M , Navarrete P
Published: July 2019

The 2015 Illapel earthquake (Mw 8.3) occurred off central Chile on September 16, and generated a tsunami that propagated across the Pacific Ocean. The tsunami was recorded on tide gauges and Deep-ocean Assessment and Reporting of Tsunami (DART) tsunameters in east Pacific. Near-field and far-field tsunami forecasts were issued based on the estimation of seismic source parameters. In this study, we retroactively evaluate the potentiality of forecasting this tsunami in the far field based solely on tsunami data assimilation from DART tsunameters. Since there are limited number of DART buoys, virtual stations are assumed by interpolation to construct a more complete tsunami wavefront for data assimilation. The comparison between forecasted and observed tsunami waveforms suggests that our method accurately forecasts the tsunami amplitudes and arrival time in the east Pacific. This approach could be a complementary method of current tsunami warning systems based on seismic observations.
The Relationship Between Viewing Environment, Narrative Environment, and Involvement With Narratives: The Case of Temperature
Authors: Tal-Or Nurit
Published: July 2019

Three studies explored the mutual effects of the physical environment of watching a narrative text and involvement with that text, using temperature. In Study 1, the temperatures in the room and the film were manipulated. As expected, a match between the temperatures enhanced the enjoyment of the film through the mediation of the perceived match and either transportation into the narrative, identification with the narrative’s protagonist, or engagement with the narrative. In Studies 2 and 3, the temperature in the film and transportation or identification were manipulated. As hypothesized, the temperature depicted in the movie indirectly affected the viewer’s feelings of warmth or coldness, especially when the viewer was transported into the narrative or identified with its protagonist. Moreover, this effect led to the viewers’ desire to consume certain food products. I discuss these findings using theories of transportation and identification.
A single-port video-assisted thoracoscopic surgery with CO2 insufflation for traumatic diaphragmatic hernia
Authors: Lee Jun Hee , Han Kook Nam , Hong Jeong In , Kim Hyun Koo
Published: July 2019

In this article, we present 2 cases with successful reduction of herniated organs and repair of a ruptured diaphragm through a single-port video-assisted thoracoscopic surgery (VATS) approach using CO2 gas insufflation in haemodynamically stable patients. A CO2 insufflation was useful to push the diaphragm down and aided in reducing the size of the herniated organ. This approach did not cause damage to the herniated organs and no additional instrument or assistant was required. Thus, CO2 insufflation makes the single-port VATS procedure easier even in haemodynamically stable trauma patients.
Association between coffee consumption and overall risk of being diagnosed with or dying from cancer among >300 000 UK Biobank participants in a large-scale Mendelian randomization study
Authors: Ong Jue-Sheng , Law Matthew H , An Jiyuan , Han Xikun , Gharahkhani Puya , Whiteman David C , Neale Rachel E , MacGregor Stuart
Published: July 2019

Background

Previous observational studies have suggested that coffee intake may be associated with a reduction in cancer risk. Mendelian randomization (MR) studies can help clarify whether the observed associations are likely to be causal. Here we evaluated whether coffee intake is associated with: (i) overall risk of being diagnosed with/dying from any cancer; and (ii) risk of individual cancers.

Methods

We identified 46 155 cases (of which 6998 were fatal) and 270 342 controls of White British ancestry from the UK Biobank cohort (UKB), based on ICD10 diagnoses. Individuals with benign tumours were excluded. Coffee intake was self-reported and recorded based on cup/day consumption. We conducted both observational and summary data MR analyses.

Results

There was no observational association between coffee intake and overall cancer risk [odds ratio (OR) per one cup/day increase = 0.99, 95% confidence interval (CI) 0.98, 1.00] or cancer death (OR = 1.01, 0.99, 1.03); the estimated OR from MR is 1.01 (0.94, 1.08) for overall cancer risk and 1.11 (0.95, 1.31) for cancer death. The relationship between coffee intake and individual cancer risks were consistent with a null effect, with most cancers showing little or no associations with coffee. Meta-analysis of our MR findings with publicly available summary data on various cancers do not support a strong causal relationship between coffee and risk of breast, ovarian, lung or prostate cancer, upon correction for multiple testing.

Conclusions

Taken together, coffee intake is not associated with overall risk of being diagnosed with or dying from cancer in UKB. For individual cancers, our findings were not statistically inconsistent with earlier observational studies, although for these we were unable to rule out a small effect on specific types of cancer.
Repurposing antihypertensive drugs for the prevention of Alzheimer’s disease: a Mendelian randomization study
Authors: Walker Venexia M , Kehoe Patrick G , Martin Richard M , Davies Neil M
Published: July 2019

Background

Evidence concerning the potential repurposing of antihypertensives for Alzheimer’s disease prevention is inconclusive. We used Mendelian randomization, which can be more robust to confounding by indication and patient characteristics, to investigate the effects of lowering systolic blood pressure, via the protein targets of different antihypertensive drug classes, on Alzheimer’s disease.

Methods

We used summary statistics from genome-wide association studies of systolic blood pressure and Alzheimer’s disease in a two-sample Mendelian randomization analysis. We identified single-nucleotide polymorphisms (SNPs) that mimic the action of antihypertensive protein targets and estimated the effect of lowering systolic blood pressure on Alzheimer’s disease in three ways: (i) combining the protein targets of antihypertensive drug classes, (ii) combining all protein targets and (iii) without consideration of the protein targets.

Results

There was limited evidence that lowering systolic blood pressure, via the protein targets of antihypertensive drug classes, affected Alzheimer’s disease risk. For example, the protein targets of calcium channel blockers had an odds ratio (OR) per 10 mmHg lower systolic blood pressure of 1.53 [95% confidence interval (CI): 0.94 to 2.49; p = 0.09; SNPs = 17]. We also found limited evidence for an effect when combining all protein targets (OR per 10 mmHg lower systolic blood pressure: 1.14; 95% CI: 0.83 to 1.56; p = 0.41; SNPs = 59) and without consideration of the protein targets (OR per 10 mmHg lower systolic blood pressure: 1.04; 95% CI: 0.95 to 1.13; p = 0.45; SNPs = 153).

Conclusions

Mendelian randomization suggests that lowering systolic blood pressure via the protein targets of antihypertensive drugs is unlikely to affect the risk of developing Alzheimer’s disease. Consequently, if specific antihypertensive drug classes do affect the risk of Alzheimer’s disease, they may not do so via systolic blood pressure.
Birthweight in offspring and cardiovascular mortality in their parents, aunts and uncles: a family-based cohort study of 1.35 million births
Authors: Shaikh Fareeha , Kjølllesdal Marte Karoline , Carslake David , Stoltenberg Camilla , Davey Smith George , Næss Øyvind
Published: July 2019

Background

A link between suboptimal fetal growth and higher risk of cardiovascular disease (CVD) is well documented. It has been difficult to assess the contribution of environmental versus genetic factors to the association, as these factors are closely connected in nuclear families. We investigated the association between offspring birthweight and CVD mortality in parents, aunts and uncles, and examined whether these associations are explained by CVD risk factors.

Methods

We linked Norwegian data from the Medical Birth Registry, the Cause of Death Registry and cardiovascular surveys. A total of 1 353 956 births (1967–2012) were linked to parents and one maternal and one paternal aunt/uncle. Offspring birthweight and CVD mortality association among all relationships was assessed by hazard ratios (HR) from Cox regressions. The influence of CVD risk factors on the associations was examined in a subgroup.

Results

Offspring birthweight was inversely associated with CVD mortality among parents and aunts/uncles. HR of CVD mortality for one standard deviation (SD) increase in offspring birthweight was 0.72 (0.69–0.75) in mothers and 0.89 (0.86–0.92) in fathers. In aunts/uncles, the HRs were between 0.90 (0.86–0.95) and 0.93 (0.91–0.95). Adjustment for CVD risk factors in a subgroup attenuated all the associations.

Conclusions

Birthweight was associated with increased risk of CVD in parents and in aunts/uncles. These associations were largely explained by CVD risk factors. Our findings suggest that associations between offspring birthweight and CVD in adult relatives involve both behavioural variables (especially smoking) and shared genetics relating to established CVD risk factors.
Assessing longer-term effectiveness of a combined household-level piped water and sanitation intervention on child diarrhoea, acute respiratory infection, soil-transmitted helminth infection and nutritional status: a matched cohort study in rural Odisha, India
Authors: Reese Heather , Routray Parimita , Torondel Belen , Sinharoy Sheela S , Mishra Samir , Freeman Matthew C , Chang Howard H , Clasen Thomas
Published: July 2019

Background

Open defecation is widespread in rural India, and few households have piped water connections. While government and other efforts have increased toilet coverage in India, and evaluations found limited immediate impacts on health, longer-term effects have not been rigorously assessed.

Methods

We conducted a matched cohort study to assess the longer-term effectiveness of a combined household-level piped water and sanitation intervention implemented by Gram Vikas (an Indian NGO) in rural Odisha, India. Forty-five intervention villages were randomly selected from a list of those where implementation was previously completed at least 5 years before, and matched to 45 control villages. We conducted surveys and collected stool samples between June 2015 and October 2016 in households with a child <5 years of age (n = 2398). Health surveillance included diarrhoea (primary outcome), acute respiratory infection (ARI), soil-transmitted helminth infection, and anthropometry.

Results

Intervention villages had higher improved toilet coverage (85% vs 18%), and increased toilet use by adults (74% vs 13%) and child faeces disposal (35% vs 6%) compared with control villages. There was no intervention association with diarrhoea [adjusted OR (aOR): 0.94, 95% confidence interval (CI): 0.74–1.20] or ARI. Compared with controls, children in intervention villages had lower helminth infection (aOR: 0.44, 95% CI: 0.18, 1.00) and improved height-for-age z scores (HAZ) (+0.17, 95% CI: 0.03–0.31).

Conclusions

This combined intervention, where household water connections were contingent on community-wide household toilet construction, was associated with improved HAZ, and reduced soil-transmitted helminth (STH) infection, though not reduced diarrhoea or ARI. Further research should explore the mechanism through which these heterogenous effects on health may occur.
A Randomized, Placebo-Controlled, Pilot Clinical Trial of Dipyridamole to Decrease Human Immunodeficiency Virus–Associated Chronic Inflammation
Authors: Macatangay Bernard J C , Jackson Edwin K , Abebe Kaleab Z , Comer Diane , Cyktor Joshua , Klamar-Blain Cynthia , Borowski Luann , Gillespie Delbert G , Mellors John W , Rinaldo Charles R , Riddler Sharon A
Published: July 2019

Background

Adenosine is a potent immunoregulatory nucleoside produced during inflammatory states to limit tissue damage. We hypothesized that dipyridamole, which inhibits cellular adenosine uptake, could raise the extracellular adenosine concentration and dampen chronic inflammation associated with human immunodeficiency virus (HIV) type 1.

Methods

Virally suppressed participants receiving antiretroviral therapy were randomized 1:1 for 12 weeks of dipyridamole (100 mg 4 times a day) versus placebo capsules. All participants took open-label dipyridamole during weeks 12–24. Study end points included changes in markers of systemic inflammation (soluble CD163 and CD14, and interleukin 6) and levels of T-cell immune activation (HLA-DR+CD38+).

Results

Of 40 participants who were randomized, 17 dipyridamole and 18 placebo recipients had baseline and week 12 data available for analyses. There were no significant changes in soluble markers, apart from a trend toward decreased levels of soluble CD163 levels (P = .09). There was a modest decrease in CD8+ T-cell activation (−17.53% change for dipyridamole vs +13.31% for placebo; P = .03), but the significance was lost in the pooled analyses (P = .058). Dipyridamole also reduced CD4+ T-cell activation (−11.11% change; P = .006) in the pooled analyses. In post hoc analysis, detectable plasma dipyridamole levels were associated with higher levels of inosine, an adenosine surrogate, and of cyclic adenosine monophosphate.

Conclusion

Dipyridamole increased extracellular adenosine levels and decreased T-cell activation significantly among persons with HIV-1 infection receiving virally suppressive therapy.
Emergence of a hybrid plasmid derived from IncN1-F33:A−:B− and mcr-1-bearing plasmids mediated by IS26
Authors: He Dandan , Zhu Yingying , Li Ruichao , Pan Yushan , Liu Jianhua , Yuan Li , Hu Gongzheng
Published: July 2019

Objectives

To characterize the complete sequences of four plasmids in MCR-1-producing clinical Escherichia coli strain D72, and to depict the formation mechanism and characteristics of the cointegrate plasmid derived from the pD72-mcr1 and pD72-F33 plasmids.

Methods

The genetic profiles of plasmids in strain D72 and its transconjugant were determined by conjugation, S1-PFGE, Southern hybridization, WGS analysis and PCR. Plasmid sequences were analysed with bioinformatic tools. The traits of the fusion plasmid were characterized by cointegration, stability and conjugation assays.

Results

Strain D72, belonging to ST1114, contained four plasmids, including mcr-1-carrying pD72-mcr1, blaCTX-M-55-carrying pD72-F33, blaTEM-238-bearing pD72-IncP and pD72-IncX1 carrying aph(3′)-Ia, qnrS2 and floR. A single plasmid, pD72C, in the transconjugant was found to be larger than any plasmid in the original strain D72. Sequence analysis showed that pD72C was the fusion product of pD72-mcr1 and pD72-F33, and the recombinant event involved an intermolecular replicative mechanism. Plasmid fusion occurred at a frequency of 1.75 × 10−4 cointegrates per transconjugant. The fusion plasmid presented a high stability and conjugation frequency of 8.00 × 10−3.

Conclusions

To our knowledge, this is the first report of the IS26-mediated fusion of an IncN1-F33:A−:B− plasmid and an mcr-1-carrying phage-like plasmid, providing evidence for the important role of IS26 in the recombination of plasmids. The biological advantages of the fusion plasmid indicated that the fusion event presumably plays a potential role in the dissemination of mcr-1.
The role of a clinician amid the rise of mobile health technology
Authors: Yang William E , Shah Lochan M , Spaulding Erin M , Wang Jane , Xun Helen , Weng Daniel , Shan Rongzi , Wongvibulsin Shannon , Marvel Francoise A , Martin Seth S
Published: July 2019

Mobile health (mHealth) interventions have demonstrated promise in improving outcomes by motivating patients to adopt and maintain healthy lifestyle changes as well as improve adherence to guideline-directed medical therapy. Early results combining behavioral economic strategies with mHealth delivery have demonstrated mixed results. In reviewing these studies, we propose that the success of a mHealth intervention links more strongly with how well it connects patients back to routine clinical care, rather than its behavior modification technique in isolation. This underscores the critical role of clinician-patient partnerships in the design and delivery of such interventions, while also raising important questions regarding long-term sustainability and scalability. Further exploration of our hypothesis may increase opportunities for multidisciplinary clinical teams to connect with and engage patients using mHealth technologies in unprecedented ways.
Importance of clinical decision support system response time monitoring: a case report
Authors: Rubins David , Wright Adam , Alkasab Tarik , Ledbetter M Stephen , Miller Amy , Patel Rajesh , Wei Nancy , Zuccotti Gianna , Landman Adam
Published: July 2019

Clinical decision support (CDS) systems are prevalent in electronic health records and drive many safety advantages. However, CDS systems can also cause unintended consequences. Monitoring programs focused on alert firing rates are important to detect anomalies and ensure systems are working as intended. Monitoring efforts do not generally include system load and time to generate decision support, which is becoming increasingly important as more CDS systems rely on external, web-based content and algorithms. We report a case in which a web-based service caused significant increase in the time to generate decision support, in turn leading to marked delays in electronic health record system responsiveness, which could have led to patient safety events. Given this, it is critical to consider adding decision support-time generation to ongoing CDS system monitoring programs.
But-for Causation and the Implementability of Compensatory Damages Rules
Authors: Schweizer Urs
Published: July 2019

A damages rule is called compensatory if it requires compensation of each party who complied with the due care standard for harm caused by deficient precaution of the other party. The two main contributions of this article are as follows. First, we show that any Nash equilibrium of the game induced by a compensatory damages rule enhances welfare compared to the welfare that would have been attained if both parties had complied. This is true irrespective of whether the due care standards are set at their socially optimal level. Second, we provide a general result for evaluating the conditions under which courts have sufficient information to implement compensatory damages rules. This is the case when the available evidence allows courts to determine whether the injurer’s precaution choice was the but-for cause of any harm to the victim. The exact levels of precaution and harm need not be observable (JEL K13).
Upper limits on protolunar disc masses using ALMA observations of directly imaged exoplanets
Authors: Pérez Sebastián , Marino Sebastián , Casassus Simon , Baruteau Clément , Zurlo Alice , Flores Christian , Chauvin Gael
Published: July 2019

The Solar system gas giants are each surrounded by many moons, with at least 50 prograde satellites thought to have formed from circumplanetary material. Just like the Sun is not the only star surrounded by planets, extrasolar gas giants are likely surrounded by satellite systems. Here, we report on Atacama Large Millimeter/Submillimeter Array (ALMA) observations of four <40 Myr old stars with directly imaged companions: PZ Tel, AB Pic, 51 Eri, and κ And. Continuum emission at 1.3 mm is undetected for any of the systems. Since these are directly imaged companions, there is knowledge of their temperatures, masses, and locations. These allow for upper limits on the amount of circumplanetary dust to be derived from detailed radiative transfer models. These protolunar disc models consider two disc sizes: 0.4 and 0.04 times the exoplanet’s Hill radius. The former is representative of hydrodynamic simulations of circumplanetary discs, while the latter a case with significant radial drift of solids. The more compact case is also motivated by the semimajor axis of Callisto, enclosing Jupiter’s Galilean satellites. All upper limits fall below the expected amount of dust required to explain regular satellite systems (∼10−4 times the mass of their central planet). Upper limits are compared with viscous evolution and debris disc models. Our analysis suggests that the non-detections can be interpreted as evidence of dust growth beyond metre sizes to form moonetesimals in time-scales ≲10 Myr. This sample increases by 50 per cent the number of ALMA non-detections of young companions available in the literature.
On the instability of Saturn’s hypothetical retrograde co-orbitals
Authors: Huang Yukun , Li Miao , Li Junfeng , Gong Shengping
Published: July 2019

We find an interesting fact that fictitious retrograde co-orbitals of Saturn, or small bodies inside the retrograde 1:1 resonance with Saturn, are highly unstable in our numerical simulations. It is shown that, in the presence of Jupiter, the retrograde co-orbitals will get ejected from Saturn’s co-orbital space within a time-scale of 10 Myr. This scenario reminds us of the instability of Saturn Trojans caused by both the great inequality and the secular resonances. Therefore, we carry out in-depth inspections of both mechanisms and prove that the retrograde resonance overlap, raised by great inequality, cannot serve as an explanation for the instability of the retrograde co-orbitals, due to the weakness of the retrograde 2:5 resonance with Jupiter at low eccentricity. However, we discover that both ν5 and ν6 secular resonances contribute to the slow growth of the eccentricity and are therefore possibly the primary causes of the instability inside Saturn’s retrograde co-orbital space.
Clustering and redshift-space distortions in modified gravity models with massive neutrinos
Authors: García-Farieta Jorge Enrique , Marulli Federico , Veropalumbo Alfonso , Moscardini Lauro , Casas-Miranda Rigoberto A , Giocoli Carlo , Baldi Marco
Published: July 2019

Modified gravity and massive neutrino cosmologies are two of the most interesting scenarios that have been recently explored to account for possible observational deviations from the concordance Λ cold dark matter (ΛCDM) model. In this context, we investigated the large-scale structure of the Universe by exploiting the dustgrain-pathfinder simulations that implement, simultaneously, the effects of f(R) gravity and massive neutrinos. To study the possibility of breaking the degeneracy between these two effects, we analysed the redshift-space distortions in the clustering of dark matter haloes at different redshifts. Specifically, we focused on the monopole and quadrupole of the two-point correlation function, both in real and redshift space. The deviations with respect to ΛCDM model have been quantified in terms of the linear growth rate parameter. We found that redshift-space distortions provide a powerful probe to discriminate between ΛCDM and modified gravity models, especially at high redshifts (z ≳ 1), even in the presence of massive neutrinos.
Single-molecule analysis of i-motif within self-assembled DNA duplexes and nanocircles
Authors: Megalathan Anoja , Cox Bobby D , Wilkerson Peter D , Kaur Anisa , Sapkota Kumar , Reiner Joseph E , Dhakal Soma
Published: July 2019

The cytosine (C)-rich sequences that can fold into tetraplex structures known as i-motif are prevalent in genomic DNA. Recent studies of i-motif–forming sequences have shown increasing evidence of their roles in gene regulation. However, most of these studies have been performed in short single-stranded oligonucleotides, far from the intracellular environment. In cells, i-motif–forming sequences are flanked by DNA duplexes and packed in the genome. Therefore, exploring the conformational dynamics and kinetics of i-motif under such topologically constrained environments is highly relevant in predicting their biological roles. Using single-molecule fluorescence analysis of self-assembled DNA duplexes and nanocircles, we show that the topological environments play a key role on i-motif stability and dynamics. While the human telomere sequence (C3TAA)3C3 assumes i-motif structure at pH 5.5 regardless of topological constraint, it undergoes conformational dynamics among unfolded, partially folded and fully folded states at pH 6.5. The lifetimes of i-motif and the partially folded state at pH 6.5 were determined to be 6 ± 2 and 31 ± 11 s, respectively. Consistent with the partially folded state observed in fluorescence analysis, interrogation of current versus time traces obtained from nanopore analysis at pH 6.5 shows long-lived shallow blockades with a mean lifetime of 25 ± 6 s. Such lifetimes are sufficient for the i-motif and partially folded states to interact with proteins to modulate cellular processes.
Super-resolution microscopy reveals how histone tail acetylation affects DNA compaction within nucleosomes in vivo
Authors: Otterstrom Jason , Castells-Garcia Alvaro , Vicario Chiara , Gomez-Garcia Pablo A , Cosma Maria Pia , Lakadamyali Melike
Published: July 2019

Chromatin organization is crucial for regulating gene expression. Previously, we showed that nucleosomes form groups, termed clutches. Clutch size correlated with the pluripotency grade of mouse embryonic stem cells and human induced pluripotent stem cells. Recently, it was also shown that regions of the chromatin containing activating epigenetic marks were composed of small and dispersed chromatin nanodomains with lower DNA density compared to the larger silenced domains. Overall, these results suggest that clutch size may regulate DNA packing density and gene activity. To directly test this model, we carried out 3D, two-color super-resolution microscopy of histones and DNA with and without increased histone tail acetylation. Our results showed that lower percentage of DNA was associated with nucleosome clutches in hyperacetylated cells. We further showed that the radius and compaction level of clutch-associated DNA decreased in hyperacetylated cells, especially in regions containing several neighboring clutches. Importantly, this change was independent of clutch size but dependent on the acetylation state of the clutch. Our results directly link the epigenetic state of nucleosome clutches to their DNA packing density. Our results further provide in vivo support to previous in vitro models that showed a disruption of nucleosome-DNA interactions upon hyperacetylation.
Deflating Deflationary Truthmaking
Authors: Asay Jamin , Baron Sam
Published: July 2019

In this paper we confront a challenge to truthmaker theory that is analogous to the objections raised by deflationists against substantive theories of truth. Several critics of truthmaker theory espouse a ‘deflationary’ attitude about truthmaking, though it has not been clearly presented as such. Our goal is to articulate and then object to the underlying rationale behind deflationary truthmaking. We begin by developing the analogy between deflationary truth and deflationary truthmaking, and then show how the latter can be found in the work of Dodd, Hornsby, Schnieder, Williamson, and others. These philosophers believe that the ambitions of truthmaker theory are easily satisfied, without recourse to ambitious ontological investigation—hence the analogy with deflationary truth. We argue that the deflationists’ agenda fails: there is no coherent deflationary theory of truthmaking. Truthmaking, once deflated, fails to address the questions at the heart of truthmaking investigation. Truthmaking cannot be had on the cheap.
Delayed sleep-onset and biological age: late sleep-onset is associated with shorter telomere length
Authors: Wynchank Dora , Bijlenga Denise , Penninx Brenda W , Lamers Femke , Beekman Aartjan T , Kooij J J Sandra , Verhoeven Josine E
Published: July 2019

Study Objectives

We evaluated the relationship between leukocyte telomere length (LTL) and sleep duration, insomnia symptoms, and circadian rhythm, to test whether sleep and chronobiological dysregulations are associated with cellular aging.

Methods

Data from the Netherlands Study of Depression and Anxiety (N = 2,936) were used at two waves 6 years apart, to measure LTL. Telomeres shorten during the life span and are important biomarkers for cellular aging. LTL was assessed by qualitative polymerase chain reaction and converted into base pair number. Sleep parameters were: sleep duration and insomnia symptoms from the Insomnia Rating Scale. Circadian rhythm variables were: indication of Delayed Sleep Phase Syndrome (DSPS), mid-sleep corrected for sleep debt on free days (MSFsc), sleep-onset time, and self-reported chronotype, from the Munich Chronotype Questionnaire. Generalized estimating equations analyzed the associations between LTL, sleep, and chronobiological factors, adjusted for baseline age, sex, North European ancestry, and additionally for current smoking, depression severity, obesity, and childhood trauma.

Results

Indicators of delayed circadian rhythm showed a strong and consistent effect on LTL, after adjustment for sociodemographic and health indicators. Late MSFsc (B = −49.9, p = .004), late sleep-onset time (B = −32.4, p = .001), indication of DSPS (B = −73.8, p = .036), and moderately late chronotype in adulthood (B = −71.6, p = .003) were associated with significantly shorter LTL across both waves; whereas sleep duration and insomnia symptoms were not. Extremely early chronotype showed significantly less LTL shortening than intermediate chronotype (B = 161.40, p = .037). No predictors showed accelerated LTL attrition over 6 years.

Conclusions

Individuals with delayed circadian rhythm have significantly shorter LTL, but not faster LTL attrition rates.
A CALCIUM-RICH MULTI-MINERAL INTERVENTION TO MODULATE COLONIC MICROBIAL COMMUNITIES AND METABOLOMIC PROFILES IN HUMANS: Results from a 90-day trial
Authors: Aslam Muhammad N. , Bassis Christine M. , Bergin Ingrid L. , Knuver Karsten , Zick Suzanna M. , Sen Ananda , Turgeon D. Kim , Varani James
Published: July 2019

Aquamin, a calcium-, magnesium-, and multiple trace element-rich natural product has polyp prevention efficacy based on preclinical studies. The overall goal of this study was to determine the safety and tolerability of Aquamin when used as a dietary chemopreventative in humans. Additionally, we determined the effects of Aquamin on the colonic microbial community and attendant metabolomic profile. Thirty healthy male and female human participants were enrolled in a 90-day trial in which the effects of Aquamin (delivering 800 mg of calcium per day) were compared to those of calcium alone or placebo. Before and after the interventional period, colonic biopsies and stool specimens were obtained. All 30 participants completed the study without serious adverse events. There were no changes in liver function markers. Compared to pretreatment values, intervention with Aquamin led to a reduction in total bacterial DNA and a shift in the microbial community. Treatment with calcium alone also produced a decline in total bacteria, but smaller than seen with Aquamin, while no reduction was observed with placebo. In parallel with microbial changes, a reduction in bile acid levels and a slight increase in the level of the short chain fatty acid (SCFA) acetate in stool specimens from Aquamin-treated participants was noted. No change in bile acids or SCFAs was observed with calcium alone or placebo. We conclude from these studies that Aquamin is safe and tolerable in healthy human participants and may produce beneficial alterations in the colonic microbial community and the attendant metabolomic profile.
Short term supplementation of celecoxib shifted butyrate production on a simulated model of the gut microbial ecosystem and amelioratedin vitroinflammation
Authors: Hernandez-Sanabria Emma , Heiremans Evelien , Arroyo Marta Calatayud , Props Ruben , Leclercq Laurent , Snoeys Jan , Van de Wiele Tom
Published: July 2019

Celecoxib has been demonstrated effective in the prevention and treatment of chronic inflammatory disorders through inhibition of altered cyclooxygenase-2 (COX-2) pathways. Despite the benefits for preventing colorectal cancer (CRC), continuous administration may increase risk of cardiovascular events. Understanding microbiome-drug-host interactions is fundamental for improving drug disposition and safety responses of colon-targeted formulations, but little information is available on the bidirectional interaction between individual microbiomes and celecoxib. Here we conductedin vitrobatch incubations of faecal microbiota to evaluate the short-term impact of celecoxib on activity and composition of colon bacterial communities. Celecoxib-exposed microbiota shifted metabolic activity and community composition, whereas total transcriptionally active bacterial population was not significantly changed. Butyrate production decreased by 50% in a donor-dependent manner, suggesting that celecoxib impactsin vitrofermentation. Microbiota-derived acetate has been associated with inhibition of cancer markers and our results suggest uptake of acetate for bacterial functions when celecoxib was supplied, which potentially favoured bacterial competition for acetyl-CoA. We further assessed whether colon microbiota modulates anti-inflammatory efficacy of celecoxib using both a simplified inflammation model, and a novelin vitrosimulation of the enterohepatic metabolism. Celecoxib was responsible for only 5% of the variance in bacterial community composition but celecoxib-exposed microbiota preserved barrier function and decreased concentrations of IL-8 and CXCL16 in a donor-dependent manner in our two cell models simulating inflammatory milieu in the gut. Our results suggest that celecoxib-microbiome-host interactions may not only elicit adaptations in community composition but also in microbiota functionality and may need to be considered for guaranteeing efficient COX-2 inhibition.

IMPORTANCE

As inter-individual changes in the microbiome composition and functionality may be a confounder on pharmacotherapy, we obtained mechanistic understanding on how short-term celecoxib exposure impacts the functional activities of colon communities. Celecoxib-exposed microbiota shifted metabolic activity without impacting numbers of total active bacteria, but only community composition. Thus, increased relative abundance of particular genera during celecoxib supplementation may just indicate changes in maintenance energy. Focus on the influence of acetyl-CoA on cancer cells and verifying whether changes in acetate:propionate:butyrate ratios rather than in taxonomic diversity can be used as markers of decreased inflammation may be the next frontiers for predicting successful NSAID therapy, and ultimately for developing microbiome-based therapies.
Natural versus Random Proteins: Nouvel Neural Network Approach Based on Time Series Analysis
Authors: Tsygvintsev Alexei
Published: July 2019

Abstract

We study the set of about 35000 primary structures of natural proteins of length more than 360 residues and the same size set generated via partial or total randomization. Associated to every sequence composed of 20 amino acids, a time series is formed from hydropathy values of the first 360 residues. To measure the absolute deviations of hydropathy index on different time scales, the 24-dimensional vector of total log-amplitudes is introduced. We describe then a configuration of the 1-hidden layer neural network which is trained to solve the binary classification problem of natural and random sequences. A satisfactory distinguishing accuracy random/natural of 88% is obtained.
A temporal record of the past with a spectrum of time constants in the monkey entorhinal cortex
Authors: Bright Ian M. , Meister Miriam L.R. , Cruzado Nathanael A. , Tiganj Zoran , Buffalo Elizabeth A. , Howard Marc W.
Published: July 2019

Episodic memory is believed to be intimately related to our experience of the passage of time. Indeed, neurons in the hippocampus and other brain regions critical to episodic memory code for the passage of time at a range of time scales. The origin of this temporal signal, however, remains unclear. Here, we examined temporal responses in the entorhinal cortex of macaque monkeys as they viewed complex images. Many neurons in the entorhinal cortex were responsive to image onset, showing large deviations from baseline firing shortly after image onset but relaxing back to baseline at different rates. This range of relaxation rates allowed for the time since image onset to be decoded on the scale of seconds. Further, these neurons carried information about image content, suggesting that neurons in the entorhinal cortex carry information not only about when an event took place but also the identity of that event. Taken together, these findings suggest that the primate entorhinal cortex uses a spectrum of time constants to construct a temporal record of the past in support of episodic memory.
The Bric-à-Brac transcription factors are necessary for formation of functional germline stem cell niches through control ofdppexpression in theDrosophila melanogasterovary
Authors: Miscopein Saler Laurine , Bartoletti Mathieu , Hauser Virginie , Pret Anne-Marie , Theodore Laurent , Chalvet Fabienne , Netter Sophie
Published: July 2019

Many studies have focused on the mechanisms of stem cell maintenanceviatheir interaction with a particular niche or microenvironment in adult tissues, but how formation of a functional niche is initiated, including how stem cells within a niche are established, is less well understood. AdultDrosophila melanogasterovary Germline Stem Cell (GSC) niches are comprised of somatic cells forming a stack called a Terminal Filament (TF) and underlying Cap Cells (CCs) and Escort Cells (ECs), which are in direct contact with GSCs. In the adult, the Engrailed (En) transcription factor is specifically expressed in niche cells where it directly controls expression of thedecapentaplegicgene (dpp) encoding a member of the Bone Morphogenetic Protein (BMP) family of secreted signaling molecules, which are key factors for GSC maintenance. In late third instar larval ovaries, in response to BMP signaling from newly-formed niches, adjacent primordial germ cells become GSCs. Thebric-à-bracparalogs (bab1andbab2) encode BTB/POZ-domain containing transcription factors, that are also expressed in developing GSCs niches where they are required for TF formation. Here, we demonstrate that Bab1 and Bab2 display redundant cell autonomous function for TF morphogenesis and we identify a new function for these genes in GSC establishment. Moreover, we show that Bab proteins controldppexpression in otherwise correctly specified CCs, independently of En and its paralog Invected (Inv). In fact, our results also indicate thaten/invfunction in larval stages are neither essential for TF formation, nor GSC establishment. Finally, whenbab2was overexpressed in ovarian somatic cells outside of the niche, whereen/invwere not expressed, ectopic BMP signaling activation was induced in adjacent germ cells of adult ovaries, which formed GSC-like tumors. Together, these results indicate that Bab transcription factors are positive regulators of BMP signaling for acquisition of GSC status.
Model reconstruction from Small angle X-ray Scattering data using deep learning methods
Authors: He Hao , Liu Can , Liu Haiguang
Published: July 2019

We present an algorithm based on a deep learning method for model reconstruction from small angle X-ray scattering (SAXS) data. An auto-encoder for protein 3D models was trained to compress 3D shape information into vectors of a 200-dimensional latent space, and the vectors are optimized using genetic algorithms to build 3D models that are consistent with the scattering data. The algorithm was implemented using Python with the TensorFlow framework and tested with experimental data, demonstrating capacity and robustness of accurate model reconstruction even without using prior model size information.

Synopsis

A deep learning method based on the auto-encoder framework for model reconstruction from small angle scattering data