bluuebunny/crossref_metadata_2025 huggingface dataset:
Moonsnail hatching success, development timing and early feeding behaviour at the high-latitude White Sea
Authors: Aristov Dmitriy , Flachinskaya Lyudmila , Varfolomeeva Marina
Published: November 2020

As predators, Naticidae (Gastropoda) can shape marine soft-sediment communities. Thus understanding of the reproductive biology and development of moonsnails is of great importance. Most moonsnails lay large egg masses, known as sand or egg collars, which are freely distributed on sand or muddy sediments. Here we report upon the abundance of egg collars of two naticid species,Amauropsis islandicaandEuspira pallida, from the high-latitude White Sea, as well as describe the morphology of egg collars and hatching success, with a brief description of juvenile feeding inA. islandica. While in the subtidal zone, the egg collars ofE. pallidawere 10 times more abundant than ofA. islandica, the egg collars of the latter species were the only ones that occur in the intertidal zone. The morphology of an egg collar ofE. pallidadiffered from the literature descriptions by having a plicated basal margin. The number of egg capsules inside the collars was twice as high inA. islandicacompared withE. pallida, but they were smaller.Amauropsis islandicahatchlings were larger and hatching success was more than twice that inE. pallida. We suggest that these characteristics promote the high abundance ofA. islandicapopulations observed on some tidal flats of the White Sea. Surprisingly,A. islandicajuveniles could perform non-drilling feeding in the first month after hatching. This study fills the gap in the knowledge of naticid reproductive biology at high latitudes.
New insights on the conservation status of the Endangered coastal endemic plant Astragalus berytheus (Fabaceae) in Lebanon
Authors: Abdel Samad Farah , Medail Frederic , Baumel Alex , Siljak Yakovlev Sonja , Roukoz Anthony , Tohme Georges , Tohme Henriette , Bou Dagher Kharrat Magda
Published: November 2020

Coastal vegetation includes unique species with adaptations to the specific conditions of this environment, and in the Mediterranean region urban development of coastal areas has severely affected coastal ecosystems. Astragalus berytheus Boiss. & Blanche is a narrow endemic plant of the eastern Mediterranean coast, occurring in Lebanon and Palestine/Israel; its Red List status has not been previously assessed. As a result of the effects of urban sprawl in coastal areas A. berytheus is one of the most threatened plant taxa in Lebanon. We assess the conservation status of this taxon and propose conservation measures. Only one population of A. berytheus is extant in Lebanon, in the Tyre Coast Nature Reserve. We recommend that A. berytheus should be categorized as Endangered globally and as Critically Endangered at the national level in Lebanon. Unless adequate conservation measures are implemented A. berytheus is likely to go extinct in Lebanon in the near future.
Ovarian activity and antioxidant indices during estrous cycle of Barki ewes under effect of thyme, celery and salinomycin as feed additives
Authors: El-Zaher Hussein M. , Eid Sherif Y. , Shaaban Mahmoud M. , Ahmed-Farid Omar A. , Abd El Tawab Ahmed M. , Khattab Mostafa S.A.
Published: November 2020

This research aimed to examine the effects of thyme, celery and salinomycin on ovarian sex hormones, reproductive traits and antioxidant status during the estrous cycle. Seventy-five mature Barki ewes aged 2–3 years with an average weight of 40 ± 1.5 kg were assigned randomly into five groups (15 head/group). Group 1 was kept as the control; groups 2 and 3 received 20 g/head/day thyme (T) and celery (C) as dried herbs, respectively. Group 4 (T×C) received 10 g thyme + 10 g celery/head/day, and group 5 was treated with salinomycin 1 g/head/day. Blood samples were collected during follicular and luteal phases of the estrous cycle. Thyme and celery and the mixture of T×C increased (P < 0.01) estradiol-17β (E2) during the follicular phase of the estrous cycle, while only the celery group showed a marked (P < 0.001) increase in progesterone (P4) during the luteal phase compared with the control. Salinomycin supplementation decreased (P < 0.05) E2 concentrations during the follicular and luteal phases of the estrous cycle. Supplementation with thyme and celery enhanced (P < 0.001) antioxidant capacity in the luteal phase compared with the follicular stage. The salinomycin group showed increased (P < 0.01) levels of reduced glutathione (GSH) and decreased malondialdehyde (MDA) levels compared with the control group throughout luteal phase. For the interaction between estrous phases and treatments, thyme, celery, and T×C supplementation revealed an increase (P < 0.05) in superoxide dismutase (SOD), GSH, and glutathione disulfide (GSSG) levels compared with the control group during the follicular and luteal phases. Thyme and celery supplementation improved the number of services per conception and fertilization from 1st and 2nd inseminations, respectively. In conclusion, the applied treatment had significant effects on reproductive performance and antioxidant status in ewes throughout the estrous cycle.
Quantum chemical study on the formation of isopropyl cyanide and its linear isomer in the interstellar medium
Authors: Singh Keshav Kumar , Tandon Poonam , Misra Alka , Shivani  , Yadav Manisha , Ahmad Aftab
Published: November 2020

The formation mechanism of linear and isopropyl cyanide (hereafter n-PrCN and i-PrCN, respectively) in the interstellar medium (ISM) has been proposed from the reaction between some previously detected small cyanides/cyanide radicals and hydrocarbons/hydrocarbon radicals. n-PrCN and i-PrCN are nitriles therefore, they can be precursors of amino acids via Strecker synthesis. The chemistry of i-PrCN is especially important since it is the first and only branched molecule in ISM, hence, it could be a precursor of branched amino acids such as leucine, isoleucine, etc. Therefore, both n-PrCN and i-PrCN have significant astrobiological importance. To study the formation of n-PrCN and i-PrCN in ISM, quantum chemical calculations have been performed using density functional theory at the MP2/6-311++G(2d,p)//M062X/6-311+G(2d,p) level. All the proposed reactions have been studied in the gas phase and the interstellar water ice. It is found that reactions of small cyanide with hydrocarbon radicals result in the formation of either large cyanide radicals or ethyl and vinyl cyanide, both of which are very important prebiotic interstellar species. They subsequently react with the radicals CH2 and CH3 to yield n-PrCN and i-PrCN. The proposed reactions are efficient in the hot cores of SgrB2 (N) (where both n-PrCN and i-PrCN were detected) due to either being barrierless or due to the presence of a permeable entrance barrier. However, the formation of n-PrCN and i-PrCN from the ethyl and vinyl cyanide always has an entrance barrier impermeable in the dark cloud; therefore, our proposed pathways are inefficient in the deep regions of molecular clouds. It is also observed that ethyl and vinyl cyanide serve as direct precursors to n-PrCN and i-PrCN and their abundance in ISM is directly related to the abundance of both isomers of propyl cyanide in ISM. In all the cases, reactions in the ice have smaller barriers compared to their gas-phase counterparts.
Using Biomimicry to Support Resilient Infrastructure Design
Authors: Helmrich Alysha M. , Chester Mikhail V. , Hayes Samantha , Markolf Samuel A. , Desha Cheryl , Grimm Nancy B.
Published: November 2020

Infrastructure must be resilient to both known and unknown disturbances. In the past, resilient infrastructure design efforts have tended to focus on principles of robustness and recovery against projected failures. This framing has developed independently from resilience principles in biological and ecological systems. As such, there are open questions as to whether the approaches of natural systems that lead to adaptation and transformation are relevant to engineered systems. To improve engineered system resilience, infrastructure managers may benefit from considering and applying a set of “Life's Principles”—design principles and patterns drawn from the field of biomimicry. Nature has long withstood disturbances within and beyond previous experience. Infrastructure resilience theory and practice are assessed against Life's Principles identifying alignments, contradictions, contentions, and gaps. Resilient infrastructure theory, which emphasizes a need for flexible and agile infrastructure, aligns well with Life's Principles, addressing each principle and most sub‐principles (excluding “breakdown products into benign components” and “do chemistry in water”). Meanwhile, resilient infrastructure practice only occasionally aligns with Life's Principles and contradicts five out of six principles. As resilience theory advances, Life's Principles offer support in broadening how infrastructure managers approach resilience, and by using biomimicry, infrastructure managers can be better equipped to deploy resilience for complexity and uncertainty.
The Coupled Impact of Emergency Responses and Population Flows on the COVID‐19 Pandemic in China
Authors: Cheng Changxiu , Zhang Tianyuan , Song Changqing , Shen Shi , Jiang Yifan , Zhang Xiangxue
Published: November 2020

Coronavirus disease 2019 (COVID‐19) has spread around the world and requires effective control measures. Like the human‐to‐human transmission of the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2), the distribution of COVID‐19 was driven by population flow and required emergency response measures to slow down its spread and degrade the epidemic risk. The local epidemic risk of COVID‐19 is a combination of emergency response measures and population flow. Because of the spatial heterogeneity, the different impacts of coupled emergency responses and population flow on the COVID‐19 epidemic during the outbreak period and a control period are unclear. We examined and compared the impact of emergency response measures and population flow on China's epidemic risk after the Wuhan lockdown during the outbreak period and a control period. We found that the population flow out of Wuhan had a long‐term impact on the epidemic's spread. In the outbreak period, a large population flow out of Wuhan led to nationwide migration mobility, which directly increased the epidemic in each province. Meanwhile, quick emergency responses mitigated the spread. Although low population flow to provinces far from Hubei delayed the outbreak in those provinces, relatively delayed emergency response increased the epidemic in the control period. Consequently, due to the strong transmission ability of the SARS‐CoV‐2 virus, no region correctly estimated the epidemic, and the relaxed emergency response raised the epidemic risks in the context of the outbreak.
A Long‐Lasting Auroral Spiral Rotating Around Saturn's Pole
Authors: Palmaerts B. , Yao Z. H. , Sergis N. , Guo R. L. , Grodent D. , Dialynas K. , Gérard J.‐C. , Mitchell D. G.
Published: November 2020

The main ultraviolet auroral emission at Saturn consists of multiple structures forming a discontinuous ring of emission around the poles, occasionally organized in a global spiral. We present continuous observation of an auroral spiral rotating at ∼85% of rigid corotation during several hours. Simultaneously, energetic neutral atom (ENA) emissions revealed a hot magnetospheric plasma population located in the same local time sector as the ends of the rotating spiral. Following plasma theory, we propose that pressure gradients induced by the energized plasma distorted the magnetospheric current system, resulting in the spiral morphology of the aurora. The rotating hot plasma was several times reenergized in the dusk sector during at least 2 days, generating a long‐lasting auroral spiral. The ultraviolet spiral, the ENA emissions, and the ions revealed by this multi‐instrument data set are three signatures of a magnetosphere‐ionosphere coupling current system and of the associated hot plasma population rotating around Saturn.
Thunderstorm High‐Frequency Radio Bursts With Weak Low‐Frequency Radiation
Authors: Liu Ningyu Y. , Dwyer Joseph R.
Published: November 2020

Brief bursts of high‐frequency (HF) and very high frequency (VHF) radio emissions unaccompanied by strong low‐frequency radiation have been observed during initiation and propagation of lightning or thunderstorm electrical breakdown without leading to fully fledged lightning. This paper investigates a physical mechanism to generate such radio bursts by electrical discharge activity inside a thundercloud. When a discharge consists of many high‐frequency emission sources, such as streamers, that generate currents in random directions, its radiation spectrum peaks in the HF and VHF bands, and the spectral magnitudes in low frequencies are much smaller or even negligible. Combined with recent observational findings, the present study suggests that lightning initiation may begin with a short burst of many randomly occurring small‐scale discharges in a localized thundercloud region.
Eddy‐Induced Transport and Kinetic Energy Budget in the Arabian Sea
Authors: Zhan Peng , Guo Daquan , Hoteit Ibrahim
Published: November 2020

This study investigates the vertical eddy structure, eddy‐induced transport, and eddy kinetic energy (EKE) budget in the Arabian Sea (AS) using an eddy‐resolving reanalysis product. The EKE intensifies during summer in the western AS. Anticyclonic eddies (AEs) and cyclonic eddies (CEs) present warm‐fresh and cold‐salty cores, respectively, with interleaved salinity structures. The eddy‐induced swirl transport is larger in the western AS and tends to compensate for heat transport by the mean flow. Zonal drift transport by AEs and CEs offset each other, and meridional transport is generally weaker. Eddies also produce notable upward heat flux during summer in the western AS, where ageostrophic circulations are induced to maintain a turbulent thermal wind balance. Plausible mechanisms for EKE production are governed by baroclinic and barotropic instabilities, which are enhanced in summer in the western basin, where signals are quantitatively one order larger than the turbulent wind inputs.
The Flux and Provenance of Dust Delivered to the SW Pacific During the Last Glacial Maximum
Authors: Trudgill M. D. , Shuttleworth R. , Bostock H. C. , Burke A. , Cooper M. J. , Greenop R. , Foster G. L.
Published: November 2020

Atmospheric dust is a primary source of iron (Fe) to the open ocean, and its flux is particularly important in the high nutrient, low chlorophyll (HNLC) Southern Ocean where Fe currently limits productivity. Alleviation of this Fe limitation in the Subantarctic Zone of the Atlantic by increased dust‐borne Fe supply during glacial periods has been shown to increase primary productivity. However, previous work has found no such increase in productivity in the Pacific sector. In order to constrain the relative importance of Southern Ocean Fe fertilization on glacial‐interglacial carbon cycles, records of dust fluxes outside of the Atlantic sector of the Southern Ocean at the Last Glacial Maximum (LGM) are required. Here we use grain size and U‐series analyses to reconstruct lithogenic and CaCO3 fluxes and Nd, Sr, and Pb isotopes to ascertain the provenance of terrigenous material delivered to four deep water cores in the SW Pacific Ocean over the last ~30 kyr. We find evidence for an increase in the relative proportion of fine‐grained (0.5–12 μm) terrigenous sediment and higher detrital fluxes during the LGM compared to the Holocene. The provenance of the LGM dust varied spatially, with an older, more “continental” signature (low εNd, high 87Sr/86Sr) sourced from Australia in the northern cores, and a younger, more volcanogenic source in the southern cores (high εNd, low 87Sr/86Sr), likely sourced locally from New Zealand. Given this increase in lithogenic flux to the HNLC subantarctic Pacific Southern Ocean during the LGM, factors besides Fe supply must have regulated the biological productivity here.
A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours
Authors: van Bussel Mark T. J. , Awada Ahmad , de Jonge Maja J. A. , Mau-Sørensen Morten , Nielsen Dorte , Schöffski Patrick , Verheul Henk M. W. , Sarholz Barbara , Berghoff Karin , El Bawab Samer , Kuipers Mirjam , Damstrup Lars , Diaz-Padilla Ivan , Schellens Jan H. M.
Published: November 2020

Background

This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity.

Methods

Adult patients with advanced solid tumours received peposertib 100–200 mg once daily or 150–400 mg twice daily (BID) in 21-day cycles.

Results

Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (medianTmax1.1–2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3–6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients.

Conclusions

Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing.

Clinical trial registration

NCT02316197
Autophagy-mediated metabolic effects of aspirin
Authors: Castoldi Francesca , Humeau Juliette , Martins Isabelle , Lachkar Sylvie , Loew Damarys , Dingli Florent , Durand Sylvère , Enot David , Bossut Noëlie , Chery Alexis , Aprahamian Fanny , Demont Yohann , Opolon Paule , Signolle Nicolas , Sauvat Allan , Semeraro Michaela , Bezu Lucillia , Baracco Elisa Elena , Vacchelli Erika , Pol Jonathan G. , Lévesque Sarah , Bloy Norma , Sica Valentina , Maiuri Maria Chiara , Kroemer Guido , Pietrocola Federico
Published: November 2020

Salicylate, the active derivative of aspirin (acetylsalicylate), recapitulates the mode of action of caloric restriction inasmuch as it stimulates autophagy through the inhibition of the acetyltransferase activity of EP300. Here, we directly compared the metabolic effects of aspirin medication with those elicited by 48 h fasting in mice, revealing convergent alterations in the plasma and the heart metabolome. Aspirin caused a transient reduction of general protein acetylation in blood leukocytes, accompanied by the induction of autophagy. However, these effects on global protein acetylation could not be attributed to the mere inhibition of EP300, as determined by epistatic experiments and exploration of the acetyl-proteome from salicylate-treated EP300-deficient cells. Aspirin reduced high-fat diet-induced obesity, diabetes, and hepatosteatosis. These aspirin effects were observed in autophagy-competent mice but not in two different models of genetic (Atg4b−/− or Bcln1+/−) autophagy-deficiency. Aspirin also improved tumor control by immunogenic chemotherapeutics, and this effect was lost in T cell-deficient mice, as well as upon knockdown of an essential autophagy gene (Atg5) in cancer cells. Hence, the health-improving effects of aspirin depend on autophagy.
Structural insight into the assembly and conformational activation of human origin recognition complex
Authors: Cheng Jiaxuan , Li Ningning , Wang Xiaohan , Hu Jiazhi , Zhai Yuanliang , Gao Ning
Published: November 2020

The function of the origin recognition complex (ORC) in DNA replication is highly conserved in recognizing and marking the initiation sites. The detailed molecular mechanisms by which human ORC is reconfigured into a state competent for origin association remain largely unknown. Here, we present structural characterizations of human ORC1–5 and ORC2–5 assemblies. ORC2–5 exhibits a tightly autoinhibited conformation with the winged-helix domain of ORC2 completely blocking the central DNA-binding channel. The binding of ORC1 partially relieves the autoinhibitory effect of ORC2–5 through remodeling ORC2-WHD, which makes ORC2-WHD away from the central channel creating a still autoinhibited but more dynamic structure. In particular, the AAA+ domain of ORC1 is highly flexible to sample a variety of conformations from inactive to potentially active states. These results provide insights into the detailed mechanisms regulating the autoinhibition of human ORC and its subsequent activation for DNA binding.
A dose–response meta-analysis between serum concentration of 25-hydroxy vitamin D and risk of type 1 diabetes mellitus
Authors: Hou Yilin , Song An , Jin Yuxin , Xia Qiuyang , Song Guangyao , Xing Xiaoping
Published: November 2020

It remains debatable whether vitamin D plays any role as a risk factor for type 1 diabetes mellitus (T1DM). We have summarized the effect of circulating 25-hydroxy vitamin D [25(OH)D] concentration on the risk of developing T1DM via a dose–response meta-analysis. We undertook a database search on PubMed, Embase, and Cochrane Library from inception to January 2020. A meta-analysis based on random-effects model was applied. Subgroup analysis and meta-regression were performed to inspect the source of heterogeneity. Dose–response data were examined using the generalized least squares trend estimation method. This study was registered with the PROSPERO (ID: CRD42020166174). In total, 16 studies including 10,605 participants (3913 case patients) were included. The pooled odds ratios (OR) and 95% confidence intervals (95% CI) for the highest versus the lowest 25(OH)D concentration was 0.39 (0.27, 0.57), with a high heterogeneity (I2 = 76.7%, P < 0.001). Meta-regression analysis identified latitude (P = 0.02), adjustment for gender (P = 0.001), and 25(OH)D stratification (P < 0.001) as sources of heterogeneity. Furthermore, the nonlinear dose–response analysis determined the OR (95% CI) of T1DM to be 0.91 (0.90, 0.93) per 10 nmol/L increase in the 25(OH)D concentration. A ‘U’-shaped association was found between serum 25(OH)D concentration and risk of T1DM. The present study highlights the significant inverse association between the circulating 25(OH)D concentration and the risk of T1DM.
Biomineral armor in leaf-cutter ants
Authors: Li Hongjie , Sun Chang-Yu , Fang Yihang , Carlson Caitlin M. , Xu Huifang , Ješovnik Ana , Sosa-Calvo Jeffrey , Zarnowski Robert , Bechtel Hans A. , Fournelle John H. , Andes David R. , Schultz Ted R. , Gilbert Pupa U. P. A. , Currie Cameron R.
Published: November 2020

Although calcareous anatomical structures have evolved in diverse animal groups, such structures have been unknown in insects. Here, we report the discovery of high-magnesium calcite [CaMg(CO3)2] armor overlaying the exoskeletons of major workers of the leaf-cutter ant Acromyrmex echinatior. Live-rearing and in vitro synthesis experiments indicate that the biomineral layer accumulates rapidly as ant workers mature, that the layer is continuously distributed, covering nearly the entire integument, and that the ant epicuticle catalyzes biomineral nucleation and growth. In situ nanoindentation demonstrates that the biomineral layer significantly hardens the exoskeleton. Increased survival of ant workers with biomineralized exoskeletons during aggressive encounters with other ants and reduced infection by entomopathogenic fungi demonstrate the protective role of the biomineral layer. The discovery of biogenic high-magnesium calcite in the relatively well-studied leaf-cutting ants suggests that calcareous biominerals enriched in magnesium may be more common in metazoans than previously recognized.
Recent evolution of a TET-controlled and DPPA3/STELLA-driven pathway of passive DNA demethylation in mammals
Authors: Mulholland Christopher B. , Nishiyama Atsuya , Ryan Joel , Nakamura Ryohei , Yiğit Merve , Glück Ivo M. , Trummer Carina , Qin Weihua , Bartoschek Michael D. , Traube Franziska R. , Parsa Edris , Ugur Enes , Modic Miha , Acharya Aishwarya , Stolz Paul , Ziegenhain Christoph , Wierer Michael , Enard Wolfgang , Carell Thomas , Lamb Don C. , Takeda Hiroyuki , Nakanishi Makoto , Bultmann Sebastian , Leonhardt Heinrich
Published: November 2020

Genome-wide DNA demethylation is a unique feature of mammalian development and naïve pluripotent stem cells. Here, we describe a recently evolved pathway in which global hypomethylation is achieved by the coupling of active and passive demethylation. TET activity is required, albeit indirectly, for global demethylation, which mostly occurs at sites devoid of TET binding. Instead, TET-mediated active demethylation is locus-specific and necessary for activating a subset of genes, including the naïve pluripotency and germline markerDppa3(Stella, Pgc7). DPPA3 in turn drives large-scale passive demethylation by directly binding and displacing UHRF1 from chromatin, thereby inhibiting maintenance DNA methylation. Although unique to mammals, we show that DPPA3 alone is capable of inducing global DNA demethylation in non-mammalian species (Xenopus and medaka) despite their evolutionary divergence from mammals more than 300 million years ago. Our findings suggest that the evolution ofDppa3facilitated the emergence of global DNA demethylation in mammals.
Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR
Authors: Smith Alicia K. , Ratanatharathorn Andrew , Maihofer Adam X. , Naviaux Robert K. , Aiello Allison E. , Amstadter Ananda B. , Ashley-Koch Allison E. , Baker Dewleen G. , Beckham Jean C. , Boks Marco P. , Bromet Evelyn , Dennis Michelle , Galea Sandro , Garrett Melanie E. , Geuze Elbert , Guffanti Guia , Hauser Michael A. , Katrinli Seyma , Kilaru Varun , Kessler Ronald C. , Kimbrel Nathan A. , Koenen Karestan C. , Kuan Pei-Fen , Li Kefeng , Logue Mark W. , Lori Adriana , Luft Benjamin J. , Miller Mark W. , Naviaux Jane C. , Nugent Nicole R. , Qin Xuejun , Ressler Kerry J. , Risbrough Victoria B. , Rutten Bart P. F. , Stein Murray B. , Ursano Robert J. , Vermetten Eric , Vinkers Christiaan H. , Wang Lin , Youssef Nagy A. ,   INTRuST Clinical Consortium, Marx Christine , Grant Gerry , Stein Murray , Qin Xue-Jun , Jain Sonia , McAllister Thomas W. , Zafonte Ross , Lang Ariel , Coimbra Raul , Andaluz Norberto , Shutter Lori , George Mark S. ,   VA Mid-Atlantic MIRECC Workgroup, Brancu Mira , Calhoun Patrick S. , Dedert Eric , Elbogen Eric B. , Fairbank John A. , Hurley Robin A. , Kilts Jason D. , Kirby Angela , Marx Christine E. , McDonald Scott D. , Moore Scott D. , Morey Rajendra A. , Naylor Jennifer C. , Rowland Jared A. , Swinkels Cindy , Szabo Steven T. , Taber Katherine H. , Tupler Larry A. , Van Voorhees Elizabeth E. , Yoash-Gantz Ruth E. ,   PGC PTSD Epigenetics Workgroup, Basu Archana , Brick Leslie A. , Dalvie Shareefa , Daskalakis Nikolaos P. , Ensink Judith B. M. , Hemmings Sian M. J. , Herringa Ryan , Ikiyo Sylvanus , Koen Nastassja , Kuan Pei Fen , Montalvo-Ortiz Janitza , Nispeling Danny , Pfeiffer John , Qin XueJun , Ressler Kerry J. , Schijven Dick , Seedat Soraya , Shinozaki Gen , Sumner Jennifer A. , Swart Patricia , Tyrka Audrey , Van Zuiden Mirjam , Wani Agaz , Wolf Erika J. , Zannas Anthony , Uddin Monica , Nievergelt Caroline M.
Published: November 2020

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
S-nitrosylated and non-nitrosylated COX2 have differential expression and distinct subcellular localization in normal and breast cancer tissue
Authors: Jindal Sonali , Pennock Nathan D. , Klug Alex , Narasimhan Jayasri , Calhoun Andrea , Roberts Michelle R. , Tamimi Rulla M. , Eliassen A. Heather , Weinmann Sheila , Borges Virginia F. , Schedin Pepper
Published: November 2020

Immunohistochemical (IHC) staining in breast cancer shows both gain and loss of COX2 expression with disease risk and progression. We investigated four common COX2 antibody clones and found high specificity for purified human COX2 for three clones; however, recognition of COX2 in cell lysates was clone dependent. Biochemical characterization revealed two distinct forms of COX2, with SP21 recognizing an S-nitrosylated form, and CX229 and CX294 recognizing non-nitrosylated COX2 antigen. We found S-nitrosylated and non-nitrosylated COX2 occupy different subcellular locations in normal and breast cancer tissue, implicating distinct synthetic/trafficking pathways and function. Dual stains of ~2000 breast cancer cases show early-onset breast cancer had increased expression of both forms of COX2 compared to postmenopausal cases. Our results highlight the strengths of using multiple, highly characterized antibody clones for COX2 IHC studies and raise the prospect that S-nitrosylation of COX2 may play a role in breast cancer biology.
Chest imaging representing a COVID-19 positive rural U.S. population
Authors: Desai Shivang , Baghal Ahmad , Wongsurawat Thidathip , Jenjaroenpun Piroon , Powell Thomas , Al-Shukri Shaymaa , Gates Kim , Farmer Phillip , Rutherford Michael , Blake Geri , Nolan Tracy , Sexton Kevin , Bennett William , Smith Kirk , Syed Shorabuddin , Prior Fred
Published: November 2020

As the COVID-19 pandemic unfolds, radiology imaging is playing an increasingly vital role in determining therapeutic options, patient management, and research directions. Publicly available data are essential to drive new research into disease etiology, early detection, and response to therapy. In response to the COVID-19 crisis, the National Cancer Institute (NCI) has extended the Cancer Imaging Archive (TCIA) to include COVID-19 related images. Rural populations are one population at risk for underrepresentation in such public repositories. We have published in TCIA a collection of radiographic and CT imaging studies for patients who tested positive for COVID-19 in the state of Arkansas. A set of clinical data describes each patient including demographics, comorbidities, selected lab data and key radiology findings. These data are cross-linked to SARS-COV-2 cDNA sequence data extracted from clinical isolates from the same population, uploaded to the GenBank repository. We believe this collection will help to address population imbalance in COVID-19 data by providing samples from this normally underrepresented population.
Factors related with sarcopenia and sarcopenic obesity among low- and middle-income settings: the 10/66 DRG study
Authors: Daskalopoulou Christina , Wu Yu-Tzu , Pan William , Giné Vázquez Iago , Prince Martin , Prina Matthew , Tyrovolas Stefanos
Published: November 2020

Sarcopenia and sarcopenic obesity research in low- and middle- income countries (LMICs) is limited. We investigated sarcopenia and sarcopenic obesity prevalence and sociodemographic, bio-clinical and lifestyle factors in LMICs settings. For the purposes of this study, the 10/66 Dementia Research Group follow-up wave information from individuals aged 65 and over in Cuba, Dominican Republic, Peru, Mexico, Puerto Rico, China, was employed and analysed (n = 8.694). Based on indirect population formulas, we calculated body fat percentage (%BF) and skeletal muscle mass index (SMI). Sarcopenia prevalence ranged from 12.4% (Dominican Republic) to 24.6% (rural Peru); sarcopenic obesity prevalence ranged from 3.0% (rural China) to 10.2% (rural Peru). Odds ratios (OR) with 95% confidence intervals (CI) for sarcopenia were higher for men 2.82 (2.22–3.57) and those with higher %BF 1.08 (1.07–1.09), whereas higher number of assets was associated with a decreased likelihood 0.93 (0.87–1.00). OR of sarcopenic obesity were higher for men 2.17 (1.70–2.76), those reporting moderate alcohol drinking 1.76 (1.21–2.57), and those with increased number of limiting impairments 1.54 (1.11–2.14). We observed heterogeneity in the prevalence of sarcopenia and sarcopenic obesity in the 10/66 settings. We also found a variety of factors to be associated with those. Our results reveal the need for more research among the older population of LMICs.
Phylogenetic analysis of cell-cycle regulatory proteins within the Symbiodiniaceae
Authors: Gorman Lucy M. , Wilkinson Shaun P. , Kitchen Sheila A. , Oakley Clinton A. , Grossman Arthur R. , Weis Virginia M. , Davy Simon K.
Published: November 2020

In oligotrophic waters, cnidarian hosts rely on symbiosis with their photosynthetic dinoflagellate partners (family Symbiodiniaceae) to obtain the nutrients they need to grow, reproduce and survive. For this symbiosis to persist, the host must regulate the growth and proliferation of its symbionts. One of the proposed regulatory mechanisms is arrest of the symbiont cell cycle in the G1phase, though the cellular mechanisms involved remain unknown. Cell-cycle progression in eukaryotes is controlled by the conserved family of cyclin-dependent kinases (CDKs) and their partner cyclins. We identified CDKs and cyclins in different Symbiodiniaceae species and examined their relationship to homologs in other eukaryotes. Cyclin proteins related to eumetazoan cell-cycle-related cyclins A, B, D, G/I and Y, and transcriptional cyclin L, were identified in the Symbiodiniaceae, alongside several alveolate-specific cyclin A/B proteins, and proteins related to protist P/U-type cyclins and apicomplexan cyclins. The largest expansion of Symbiodiniaceae cyclins was in the P/U-type cyclin groups. Proteins related to eumetazoan cell-cycle-related CDKs (CDK1) were identified as well as transcription-related CDKs. The largest expansion of CDK groups was, however, in alveolate-specific groups which comprised 11 distinct CDK groups (CDKA-J) with CDKB being the most widely distributed CDK protein. As a result of its phylogenetic position, conservation across Symbiodiniaceae species, and the presence of the canonical CDK motif, CDKB emerged as a likely candidate for aSaccharomyces cerevisiaeCdc28/Pho85-like homolog in Symbiodiniaceae. Similar to cyclins, two CDK-groups found in Symbiodiniaceae species were solely associated with apicomplexan taxa. A comparison ofBreviolum minutumCDK and cyclin gene expression between free-living and symbiotic states showed that several alveolate-specific CDKs and two P/U-type cyclins exhibited altered expressionin hospite, suggesting that symbiosis influences the cell cycle of symbionts on a molecular level. These results highlight the divergence of Symbiodiniaceae cell-cycle proteins across species. These results have important implications for host control of the symbiont cell cycle in novel cnidarian–dinoflagellate symbioses.
Metabolomics and psychological features in fibromyalgia and electromagnetic sensitivity
Authors: Piras Cristina , Conte Stella , Pibiri Monica , Rao Giacomo , Muntoni Sandro , Leoni Vera Piera , Finco Gabriele , Atzori Luigi
Published: November 2020

Fibromyalgia (FM) as Fibromyalgia and Electromagnetic Sensitivity (IEI-EMF) are a chronic and systemic syndrome. The main symptom is represented by strong and widespread pain in the musculoskeletal system. The exact causes that lead to the development of FM and IEI-EMF are still unknown. Interestingly, the proximity to electrical and electromagnetic devices seems to trigger and/or amplify the symptoms. We investigated the blood plasma metabolome in IEI-EMF and healthy subjects using1H NMR spectroscopy coupled with multivariate statistical analysis. All the individuals were subjected to tests for the evaluation of psychological and physical features. No significant differences between IEI-EMF and controls relative to personality aspects, Locus of Control, and anxiety were found. Multivariate statistical analysis on the metabolites identified by NMR analysis allowed the identification of a distinct metabolic profile between IEI-EMF and healthy subjects. IEI-EMF were characterized by higher levels of glycine and pyroglutamate, and lower levels of 2-hydroxyisocaproate, choline, glutamine, and isoleucine compared to healthy subjects. These metabolites are involved in several metabolic pathways mainly related to oxidative stress defense, pain mechanisms, and muscle metabolism. The results here obtained highlight possible physiopathological mechanisms in IEI-EMF patients to be better defined.
Immortalisation of primary human alveolar epithelial lung cells using a non-viral vector to study respiratory bioreactivity in vitro
Authors: Katsumiti Alberto , Ruenraroengsak Pakatip , Cajaraville Miren P. , Thorley Andrew J. , Tetley Teresa D.
Published: November 2020

To overcome the scarcity of primary human alveolar epithelial cells for lung research, and the limitations of current cell lines to recapitulate the phenotype, functional and molecular characteristics of the healthy human alveolar epithelium, we have developed a new method to immortalise primary human alveolar epithelial lung cells using a non-viral vector to transfect the telomerase catalytic subunit (hTERT) and the simian virus 40 large-tumour antigen (SV40). Twelve strains of immortalised cells (ICs) were generated and characterised using molecular, immunochemical and morphological techniques. Cell proliferation and sensitivity to polystyrene nanoparticles (PS) were evaluated. ICs expressed caveolin-1, podoplanin and receptor for advanced glycation end-products (RAGE), and most cells were negative for alkaline phosphatase staining, indicating characteristics of AT1-like cells. However, most strains also contained some cells that expressed pro-surfactant protein C, classically described to be expressed only by AT2 cells. Thus, the ICs mimic the cellular heterogeneity in the human alveolar epithelium. These ICs can be passaged, replicate rapidly and remain confluent beyond 15 days. ICs showed differential sensitivity to positive and negatively charged PS nanoparticles, illustrating their potential value as an in vitro model to study respiratory bioreactivity. These novel ICs offer a unique resource to study human alveolar epithelial biology.
Subtype specific expression and survival prediction of pivotal lncRNAs in muscle invasive bladder cancer
Authors: Rinaldetti Sebastien , Worst Thomas Stefan , Rempel Eugen , Kriegmair Maximilian C. , Hartmann Arndt , Porubsky Stefan , Bolenz Christian , Erben Philipp
Published: November 2020

Comprehensive transcriptome expression analyses of bladder cancer revealed distinct lncRNA clusters with differential molecular and clinical characteristics. In this study, pivotal lncRNAs were assessed for their impact on survival and their differential expression between the molecular bladder cancer subtypes. FFPE samples from chemotherapy-naïve patients with muscle invasive bladder cancer (MIBC) were analyzed on the Nanostring nCounter platform for absolute quantification. An established 36-gene panel was used for molecular subtype classification into basal, luminal and infiltrated MIBC. In a second step, 14 pivotal lncRNAs were assessed for their molecular subtype attribution, and their predictive value in disease-specific survival. In silico validation was performed on a total of 487 MIBC patients (MDA, TGCA and Chungbuk cohort). Several pivotal lncRNAs showed a distinct molecular subtype attribution: e.g. MALAT1 showed a downregulation in the basal subtype (p = 0.009), TUG1 and CBR3AS1 showed an upregulation in the luminal subtype (p ≤ 0.001). High transcript levels of SNHG16, CBR3AS1 and H19 appeared to be predictive for a shorter disease-specific survival. Patients overexpressing putative oncogenes MALAT1 and TUG1 in MIBC tissue presented prolonged survival, suggesting tumor suppressive effects of both lncRNAs. The Nanostring nCounter proved to be a valid platform for the quantification of low-abundance transcripts including lncRNAs.
Effect of membrane fusion protein AdeT1 on the antimicrobial resistance of Escherichia coli
Authors: Barlow Victoria L. , Lai Shu-Jung , Chen Chia-Yu , Tsai Cheng-Han , Wu Shih-Hsiung , Tsai Yu-Hsuan
Published: November 2020

Acinetobacter baumannii is a prevalent pathogen that can rapidly acquire resistance to antibiotics. Indeed, multidrug-resistant A. baumannii is a major cause of hospital-acquired infections and has been recognised by the World Health Organization as one of the most threatening bacteria to our society. Resistance-nodulation-division (RND) type multidrug efflux pumps have been demonstrated to convey antibiotic resistance to a wide range of pathogens and are the primary resistance mechanism employed by A. baumannii. A component of an RND pump in A. baumannii, AdeT1, was previously demonstrated to enhance the antimicrobial resistance of Escherichia coli. Here, we report the results of experiments which demonstrate that wild-type AdeT1 does not confer antimicrobial resistance in E. coli, highlighting the importance of verifying protein production when determining minimum inhibitory concentrations (MICs) especially by broth dilution. Nevertheless, using an agar-based MIC assay, we found that propionylation of Lys280 on AdeT1 renders E. coli cells more resistant to erythromycin.
Impact of carbon monoxide poisoning on the risk of breast cancer
Authors: Huang Chien-Cheng , Ho Chung-Han , Chen Yi-Chen , Hsu Chien-Chin , Lin Hung-Jung , Tian Yu-Feng , Wang Jhi-Joung , Guo How-Ran
Published: November 2020

Carbon monoxide (CO) is a toxic gas and an endogenous signaling molecule. Some studies involving cell lines have revealed the potential antibreast cancer effects of CO. Data on such effects in humans, however, are limited. Thus, we conducted a study on patients with CO poisoning (COP) to evaluate the effects of CO on the risk of breast cancer. We identified female patients who were diagnosed with COP over the period of 2002 and 2009 from the Nationwide Poisoning Database of Taiwan. For comparison, we selected females without COP from the National Health Insurance Research Database. Participants in the COP and comparison cohorts were matched on the index year, age, monthly income, and geographic region of residence at a 1:6 ratio. We followed up the two cohorts until the end of 2014 and compared their risks of developing breast cancer. We included 7053 participants with COP and 42,318 participants without COP. Participants with COP were at a lower risk of developing breast cancer than those without COP (0.7% vs. 1.0%, p < 0.001). Cox proportional hazard regression analyses revealed that COP was associated with a hazard ratio of 0.67 (95% confidence interval [95% CI] 0.50–0.90) for breast cancer after we adjusted for age, monthly income, geographic region, and comorbidities of hypertension, diabetes, and hyperlipidemia. Our result provides evidence for the potential protective effects of CO against breast cancer in humans. Further studies that directly evaluate the potential effects are warranted.
Multiple gene substitution by Target-AID base-editing technology in tomato
Authors: Hunziker Johan , Nishida Keiji , Kondo Akihiko , Kishimoto Sanae , Ariizumi Tohru , Ezura Hiroshi
Published: November 2020

The use of Target activation-induced cytidine deaminase (Target-AID) base-editing technology with the CRISPR-Cas 9 system fused with activation-induced cytidine deaminase (AID) resulted in the substitution of a cytidine with a thymine. In previous experiments focusing on a single target gene, this system has been reported to work in several plant species, including tomato (Solanum lycopersicum L.). In this research, we used Target-AID technology to target multiple genes related to carotenoid accumulation in tomato. We selected 3 genes, SlDDB1, SlDET1 and SlCYC-B, for their roles in carotenoid accumulation. Among 12 edited T0 lines, we obtained 10 independent T0 lines carrying nucleotide substitutions in the three targeted genes, with several allelic versions for each targeted gene. The two edited lines showed significant differences in carotenoid accumulation. These results demonstrate that Target-AID technology is a highly efficient tool for targeting multiple genes with several allelic versions.
α-Synuclein promotes IAPP fibril formation in vitro and β-cell amyloid formation in vivo in mice
Authors: Mucibabic Marija , Steneberg Pär , Lidh Emmelie , Straseviciene Jurate , Ziolkowska Agnieszka , Dahl Ulf , Lindahl Emma , Edlund Helena
Published: November 2020

Type 2 diabetes (T2D), alike Parkinson’s disease (PD), belongs to the group of protein misfolding diseases (PMDs), which share aggregation of misfolded proteins as a hallmark. Although the major aggregating peptide in β-cells of T2D patients is Islet Amyloid Polypeptide (IAPP), alpha-synuclein (αSyn), the aggregating peptide in substantia nigra neurons of PD patients, is expressed also in β-cells. Here we show that αSyn, encoded by Snca, is a component of amyloid extracted from pancreas of transgenic mice overexpressing human IAPP (denoted hIAPPtg mice) and from islets of T2D individuals. Notably, αSyn dose-dependently promoted IAPP fibril formation in vitro and tail-vein injection of αSyn in hIAPPtg mice enhanced β-cell amyloid formation in vivo whereas β-cell amyloid formation was reduced in hIAPPtg mice on a Snca −/− background. Taken together, our findings provide evidence that αSyn and IAPP co-aggregate both in vitro and in vivo, suggesting a role for αSyn in β-cell amyloid formation.
No modulation of postprandial metabolism by transcutaneous auricular vagus nerve stimulation: a cross-over study in 15 healthy men
Authors: Vosseler Andreas , Zhao Dongxing , Fritsche Louise , Lehmann Rainer , Kantartzis Konstantinos , Small Dana M. , Peter Andreas , Häring Hans-Ulrich , Birkenfeld Andreas L. , Fritsche Andreas , Wagner Robert , Preißl Hubert , Kullmann Stephanie , Heni Martin
Published: November 2020

Experimental evidence suggests a crucial role of the autonomic nervous system in whole body metabolism with major regulatory effects of the parasympathetic branch in postprandial adaptation. However, the relative contribution of this mechanism is still not fully clear in humans. We therefore compared the effects of transcutaneous auricular vagus nerve stimulation (taVNS, Cerbomed Nemos) with sham stimulation during an oral glucose tolerance test in a randomized, single-blind, cross-over design in 15 healthy lean men. Stimulation was performed for 150 min, 30 min before and during the entire oral glucose tolerance test with stimulation cycles of 30 s of on-phase and 30 s of off-phase and a 25 Hz impulse. Heart rate variability and plasma catecholamine levels were assessed as proxies of autonomic tone in the periphery. Neither analyzed heart rate variability parameters nor plasma catecholamine levels were significantly different between the two conditions. Plasma glucose, insulin sensitivity and insulin secretion were also comparable between conditions. Thus, the applied taVNS device or protocol was unable to achieve significant effects on autonomic innervation in peripheral organs. Accordingly, glucose metabolism remained unaltered. Therefore, alternative approaches are necessary to investigate the importance of the autonomic nervous system in postprandial human metabolism.