bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbiological quality of raw drinking milk and unpasteurised dairy products: results from England 2013–2019
Authors: McLauchlin J. , Aird H. , Elliott A. , Forester E. , Jørgensen F. , Willis C.
Published: May 2020

The aim of this study was to review microbiology results from testing >2500 raw drinking milk and dairy products made with unpasteurised milk examined in England between 2013 and 2019. Samples were collected as part of incidents of contamination, investigation of infections or as part of routine monitoring and were tested using standard methods for a range of both pathogens and hygiene indicators. Results from testing samples of raw cow's milk or cheese made from unpasteurised milk for routine monitoring purposes were overall of better microbiological quality than those collected during incident or investigations of infections. Results from routine monitoring were satisfactory for 62% of milks, 82% of cream, 100% of ice-cream, 51% of butter, 63% of kefir and 79% of cheeses, with 5% of all samples being considered potentially hazardous. Analysis of data from cheese demonstrated a significant association between increasing levels of indicator Escherichia coli with elevated levels of coagulase positive staphylococci and decreased probability of isolation of Shiga toxin-producing E. coli. These data highlight the public health risk associated with these products and provide further justification for controls applied to raw drinking milk and dairy products made with unpasteurised milk.
Right aortic arch with an aberrant left subclavian artery: sonographic features by HDlive Flow imaging
Authors: Endo Toyohide , Ochiai Daigo , Tanaka Mamoru
Published: May 2020

The right aortic arch is a congenital vascular anomaly, which may form a vascular ring. However, prenatal identification of the branching pattern of brachiocephalic vessels is often limited. In this paper, we clearly demonstrated the branching pattern of brachiocephalic vessels in a case of right aortic arch with an aberrant left subclavian artery using HDlive Flow imaging.
The Impact of Chemical Bonding on Mass Absorption Coefficients of Soft X-rays
Authors: Rudinsky Samantha , Wilson Nicholas C. , MacRae Colin M. , Yuan Yu , Demers Hendrix , Gibson Mark A. , Gauvin Raynald
Published: May 2020

Accurate elemental quantification of materials by X-ray detection techniques in electron microscopes or microprobes can only be carried out if the appropriate mass absorption coefficients (MACs) are known. With continuous advancements in experimental techniques, databases of MACs must be expanded in order to account for new detection limits. Soft X-ray emission spectroscopy (SXES) is a characterization technique that can detect emitted X-rays whose energies are in the range of 10 eV to 2 keV by using a varied-line-spaced grating. Transitions producing soft X-rays can be detected and accurate MACs are required for use in quantification. This work uses Monte Carlo modeling coupled with multivoltage SXES measurements in an electron probe micro-analyzer (EPMA) to compute MACs for the L2,3-M and Li Kα transitions in a variety of aluminum alloys. Electron depth distribution curves obtained by the software MC X-ray are used in a parametrized fitting equation. The MACs are calculated using a least-squares regression analysis. It is shown that X-ray distribution cross-sections at such low energies need to take into account additional contributions, such as Coster–Kronig transitions, Auger yields, and wave function effects in order to be accurate.
The effect of photon energy on dose distribution in volumetric-modulated arc therapy planning for head and neck cancer
Authors: Nguyen Trang Hong Thi , Takemura Akihiro , Ueda Shinichi , Noto Kimiya , Kojima Hironori , Isomura Naoki
Published: May 2020

Aim:

To investigate the effect of different energies on dose distribution in volumetric-modulated arc therapy (VMAT) plans for head and neck cancer.

Materials and methods:

Data from nine patients undergoing VMAT plans using 6 MV, 10 MV and dual-energy X-ray beams with the Pinnacle 3 V 9.10 treatment planning system (Philips Medical System, Fitchburg, WI, USA) were analysed for quality using the conformity index (CI) and homogeneity index (HI) for planning target volume (PTV), and for mean and maximum dose to the organs at risk (OARs): parotid glands, brainstem, spinal cord and optic nerves.

Results:

There were no clear differences in the HIs of the PTV dose among the different plans. The CIs for 10 MV and dual-energy VMAT plans were superior to that of the 6 MV VMAT plan (0·8 ± 0·3, 0·8 ± 0·3, and 0·7 ± 0·2, respectively; p = 0·001). There were no significant differences in mean/maximum dose to the OARs among the three VMAT plans.

Findings:

Compared with the 6 MV VMAT plan, the dual-energy VMAT plan slightly increased the coverage of the PTV with the prescribed dose but did not decrease dose to the OARs.
Diabetes in Appalachia: providers’ perspectives
Authors: Beverly Elizabeth A. , Ritholz Marilyn D. , Cook Karie , Johnson Lesli K. , Ruhil Anirudh , Singh Rashmi P. , Berryman Darlene E.
Published: May 2020

Background:

Southeastern Appalachian Ohio has more than double the national average of diabetes and a critical shortage of healthcare providers. Paradoxically, there is limited research focused on primary care providers’ experiences treating people with diabetes in this region. This study explored providers’ perceived barriers to and facilitators for treating patients with diabetes in southeastern Appalachian Ohio.

Methods:

We conducted in-depth interviews with healthcare providers who treat people with diabetes in rural southeastern Ohio. Interviews were transcribed, coded, and analyzed via content and thematic analyses using NVivo 12 software (QSR International, Chadstone, VIC, Australia).

Results:

Qualitative analysis revealed four themes: (1) patients’ diabetes fatalism and helplessness: providers recounted story after story of patients believing that their diabetes was inevitable and that they were helpless to prevent or delay diabetes complications. (2) Comorbid psychosocial issues: providers described high rates of depression, anxiety, incest, abuse, and post-traumatic stress disorder among people with diabetes in this region. (3) Inter-connected social determinants interfering with diabetes care: providers identified major barriers including lack of access to providers, lack of access to transportation, food insecurity, housing insecurity, and financial insecurity. (4) Providers’ cultural understanding and recommendations: providers emphasized the importance of understanding of the values central to Appalachian culture and gave culturally attuned clinical suggestions for how to use these values when working with this population.

Conclusions:

Evidence-based interventions tailored to Appalachian culture and training designed to increase the cultural competency and cultural humility of primary care providers may be effective approaches to reduce barriers to diabetes care in Appalachian Ohio.
The Strange Fruit of the Tree of Liberty: Lynch Law and Popular Sovereignty in the United States
Authors: Gorup Michael
Published: May 2020

Lynch mobs regularly called on the language of popular sovereignty in their efforts to authorize lynchings, arguing that, as representatives of the people, they retained the right to wield public violence against persons they deemed beyond the protections of due process. Despite political theorists’ renewed interest in popular sovereignty, scholars have not accounted for this sordid history in their genealogies of modern democracy and popular constituent power. I remedy this omission, arguing that spectacle lynchings—ones that occurred in front of large crowds, sometimes numbering in the thousands—operated as public rituals of racialized people-making. In the wake of Reconstruction, when the boundaries of the polity were deeply contested, spectacle lynchings played a constitutive role in affirming and circulating the notion that the sovereign people were white, and that African Americans were their social subordinates.
Spirals in galaxies
Authors: Sellwood J. A.
Published: May 2020

The venerable problem of what causes the spiral features in disk galaxies is nearing a solution. In previous work, we have shown that transient spirals in simulations result from the superposition of a few coherent waves that have many properties of modes. The new achievement presented here is a clear demonstration that the evolution of one unstable mode leads to scattering at Lindblad resonances, and the depopulation of phase space at such resonances creates a “groove” that is the cause of a new unstable mode. Thus we now understand that the cause of spiral patterns in simulations is a recurrent cycle of groove modes. In other work, we have used Gaia DR2 data, converted to action-angle variables, to identify resonant scattering features in the Solar neighborhood that closely resemble those seen in the simulations, suggesting that the mechanism that causes spirals in simulations may also be at work in the Milky Way.
Dark matter distribution and dynamics of dwarf spheroidal galaxies
Authors: Łokas Ewa L.
Published: May 2020

I review the current status of dynamical modelling of dwarf spheroidal galaxies focusing on estimates of their dark matter content. Starting with the simplest methods using the velocity dispersion profiles I discuss the inherent issues of mass-anisotropy degeneracy and contamination by unbound stars. I then move on to methods of increasing complexity, aiming to break the degeneracy, up to recent applications of the Schwarzschild orbit superposition method. The dynamical modelling is placed in the context of possible scenarios for the formation of dwarf spheroidal galaxies, including the tidal stirring model and mergers of dwarf galaxies. The two scenarios are illustrated with examples from simulations: a comparison between the tidal evolution of dwarfs with cuspy and cored dark matter profiles and the formation of a dwarf spheroidal with prolate rotation.
Infrared space astrometry mission for survey of the Galactic nuclear bulge: Small-JASMINE
Authors: Gouda Naoteru ,   JASMINE team
Published: May 2020

Small-JASMINE will provide astrometric data with high precisions in a near infrared band for stars in the Galactic nuclear bulge and other specific targets. The primary scientific objective is to carry out the Galactic Center Archeology by exploring the Galactic nuclear bulge that leads to the elucidation of the Galactic structures and the evolution of the supermassive black hole at the center. Small-JASMINE has been selected as the unique candidate for the competitive 3rd M-class science satellite mission by ISAS/JAXA. The launch date is mid-2020s.
Dynamical regularities in rotating galaxies
Authors: McGaugh Stacy , Lelli Federico , Li Pengfei , Schombert Jim
Published: May 2020

Galaxies are observed to obey a strict set of dynamical scaling relations. We review these relations for rotationally supported disk galaxies spanning many decades in mass, surface brightness, and gas content. The behavior of these widely varied systems can be summarized with a handful of empirical laws connected by a common acceleration scale.
The face-on views of X-shaped “bulges” - boxy features in the central parts of bars
Authors: Patsis Panos A.
Published: May 2020

Boxiness associated with the morphology of the central parts of bars, is a feature usually encountered in the edge-on profiles of galaxies, or galactic models. However, there are cases where “boxy” isophotes are observed also in the central parts of nearly face-on bars. I summarize here some dynamical mechanisms that support boxy orbits in the central bar regions on the equatorial plane of the disks, or orbits with boxy projections on it. Such orbits could describe the dynamics of face – on boxy “bulges”.
Testing the robustness of black hole mass measurements with ALMA and MUSE
Authors: Thater Sabine , Krajnović Davor , Nguyen Dieu D. , Iguchi Satoru , Weilbacher Peter M.
Published: May 2020

We present our ongoing work of using two independent tracers to estimate the supermassive black hole mass in the nearby early-type galaxy NGC 6958; namely integrated stellar and molecular gas kinematics. We used data from the Atacama Large Millimeter/submillimeter Array (ALMA), and the adaptive-optics assisted Multi-Unit Spectroscopic Explorer (MUSE) and constructed state-of-the-art dynamical models. The different methods provide black hole masses of (2.89±2.05)×108M⊙ from stellar kinematics and (1.35±0.09)×108M⊙ from molecular gas kinematics which are consistent within their 3σ uncertainties. Compared to recent MBH - σe scaling relations, we derive a slightly over-massive black hole. Our results also confirm previous findings that gas-based methods tend to provide lower black hole masses than stellar-based methods. More black hole mass measurements and an extensive analysis of the method-dependent systematics are needed in the future to understand this noticeable discrepancy.
Revisiting the innermost kinematics of M31 galaxy with the OMM Fabry-Perot interferometer
Authors: Zacharie Kam Sié , Carignan Claude , Marcelin Michel , Amram Philippe , Koulidiati Jean
Published: May 2020

We present observations on optical emission lines acquired with the scanning Fabry-Perot interferometer of the observatoire du Mont Mégantic, of the Andromeda galaxy (M31). A 765 order Fabry-Perot were used with a fast readout EM-CCD. From data obtained, kinematic maps and data points for the rotation curve of the innermost part of the galaxy are derived. Several dozen of regions have been scanned with the Fabry-Perot interferometer and narrow band interference filters. The central 10’x10’ were scanned with five different filters. Observations have been made in order to get better Hα data for kinematics purposes.
A full pipeline for modelling low surface brightness galaxies
Authors: Peper Marius , Roukema Boudewijn F. , Bolejko Krzysztof
Published: May 2020

Cosmological simulations are a powerful tool to test various cosmological and galaxy formation scenarios. The discovery of low surface brightness objects has been a challenge for both of these fields. Our work aims to create a fully reproducible pipeline to generate a realistic dark matter halo catalog with corresponding information on galaxy formation and evolution.
Twelve years of Galaxy Zoo
Authors: Masters Karen L. ,   Galaxy Zoo Team
Published: May 2020

The Galaxy Zoo project has provided quantitative visual morphologies for over a million galaxies, and has been part of a reinvigoration of interest in the morphologies of galaxies and what they reveal about galaxy evolution. Morphological information collected by GZ has shown itself to be a powerful tool for studying galaxy evolution, and GZ continues to collect classifications - currently serving imaging from DECaLS in its main site, and running a variety of related projects hosted by the Zooniverse; the citizen science platform which came out of the early success of GZ. I highlight some of the results from the last twelve years, with a particular emphasis on linking morphology and dynamics, look forward to future projects in the GZ family, and provide a quick start guide for how you can easily make use of citizen science techniques to analysis your own large and complex data sets.
New VIRAC proper motion maps show signature of galactic boxy/peanut bulge
Authors: Clarke Jonathan P. , Wegg Christopher , Gerhard Ortwin , Smith Leigh C. , Lucas Phil W. , Wylie Shola M.
Published: May 2020

We have derived absolute proper motions of stars in the Galactic bulge region combining the VVV InfraRed Astrometric Catalogue (VIRAC) and Gaia. We use the proper motions to study the kinematic structure of the bulge both integrated along the line-of-sight and in magnitude intervals using red clump stars as standard candles. In parallel we compare to a made-to-measure barred dynamical model, folding in the VIRAC selection function, to understand and interpret the structures that we observe. The barred dynamical model, which contains a boxy/peanut bulge, and has a pattern speed of 37.5 kms−1 kpc−1, is able to reproduce all structures impressively well.
Structure and dynamics of high-z galaxies
Authors: Wuyts Stijn , Schreiber Natascha M. Förster
Published: May 2020

HST and integral-field spectroscopic observations of star-forming galaxies at cosmic noon provide a view on the spatial distribution of stars, gas and dust, and probe gaseous motions revealing the central gravitational potential and local feedback processes at play. In this paper, we review recent insights gained from such observations, with an emphasis on results obtained through near-infrared imaging spectroscopy. Their context and implications are documented more fully in a forthcoming review article by Förster Schreiber & Wuyts (in prep).
The long-lived inner bar of NGC 1291
Authors: Méndez-Abreu Jairo , de Lorenzo-Cáceres Adriana ,   the TIMER team
Published: May 2020

The question whether stellar bars are either transitory features or long-lived structures is still matter of debate. This problem is more acute for double-barred systems where even the formation of the inner bar remains a challenge for numerical studies. We present a thorough study of the central structures of the double-barred galaxy NGC 1291. We used a two-dimensional multi-component photometric decomposition performed on the 3.6 μm images from S4 G, combined with both stellar kinematics and stellar population analysis carried out using integral field data from the MUSE TIMER project. We report on the discovery of the first Box-Peanut (B/P) structure in an inner bar detected in the face-on galaxy NGC 1291. The B/P structure is detected as bi-symmetric minima of the h4 moment of the line-of-sight velocity distribution along the major axis of the inner bar, as expected from numerical simulations. Our observations demonstrate that inner bars (similarly as outer bars) can suffer buckling instabilities, thus suggesting they can survive a long time after bar formation. The analysis of the star formation history for the structural components shaping the central regions of NGC 1291 also constrains the epoch of dynamical assembly of the inner bar, which took place >6.5 Gyr ago for NGC 1291. Our results imply that the inner bar of NGC 1291 is a long-lived structure.
Ethical Considerations in Working With a Transgender Youth With Osteogenesis Imperfecta
Authors: Olezeski Christy L. , Patel Anisha D.
Published: May 2020

Objective: Psychologists are increasingly working within an interdisciplinary medical setting and are often asked to help patients weigh the risks and benefits of medical treatment. In this case example, we discuss the ethical considerations to be addressed when working with a transgender youth who is also diagnosed with osteogenesis imperfecta. Method: Using a single-study case review, we identify medical considerations for a youth with co-occurring gender dysphoria and osteogenesis imperfecta, including the potential impact of not moving forward with medical intervention. Results: As there are multiple considerations for care with these two co-occurring issues, questions to pose to the family prior to any treatment for gender dysphoria are discussed. The role of the psychologist in an interdisciplinary setting is noted, as well as the importance of decision aids to guide the decision-making process. Conclusions: The presentation of co-occurring gender dysphoria and osteogenesis imperfecta poses multiple considerations for medical treatment. Using the biomedical ethics framework, we posit questions that are important to explore with the patient and family prior to medical interventions.

Implications for Impact Statement

This paper provides an overview of the medical and ethical considerations involved when considering medical interventions with a patient who presents with co-occurring gender dysphoria and osteogenesis imperfecta (brittle-bone disease). The need for interdisciplinary care and continued discussions among the youth, parents and providers are highlighted, as well as resources to utilize if there are disagreements among parties (parents, the family or treatment team).
Fruitbody chemistry underlies the structure of endofungal bacterial communities across fungal guilds and phylogenetic groups
Authors: Pent Mari , Bahram Mohammad , Põldmaa Kadri
Published: May 2020

Eukaryote-associated microbiomes vary across host taxa and environments but the key factors underlying their diversity and structure in fungi are still poorly understood. Here we determined the structure of bacterial communities in fungal fruitbodies in relation to the main chemical characteristics in ectomycorrhizal (EcM) and saprotrophic (SAP) mushrooms as well as in the surrounding soil. Our analyses revealed significant differences in the structure of endofungal bacterial communities across fungal phylogenetic groups and to a lesser extent across fungal guilds. These variations could be partly ascribed to differences in fruitbody chemistry, particularly the carbon-to-nitrogen ratio and pH. Fungal fruitbodies appear to represent nutrient-rich islands that derive their microbiome largely from the underlying continuous soil environment, with a larger overlap of operational taxonomic units observed between SAP fruitbodies and the surrounding soil, compared with EcM fungi. In addition, bacterial taxa involved in the decomposition of organic material were relatively more abundant in SAP fruitbodies, whereas those involved in release of minerals were relatively more enriched in EcM fruitbodies. Such contrasts in patterns and underlying processes of the microbiome structure between SAP and EcM fungi provide further evidence that bacteria can support the functional roles of these fungi in terrestrial ecosystems.
Targeting the ERβ/Angiopoietin-2/Tie-2 signaling-mediated angiogenesis with the FDA-approved anti-estrogen Faslodex to increase the Sunitinib sensitivity in RCC
Authors: Gu Junfei , Zhang Yong , Han Zhenwei , Gao Lei , Cui Jinfeng , Sun Yin , Niu Yuanjie , You Bosen , Huang Chi-Ping , Chang Chawnshang , Wang Xiaolu , Yeh Shuyuan
Published: May 2020

Sunitinib has been used as the main therapy to treat the metastatic clear cell renal cell carcinoma (ccRCC) as it could function via suppressing the tumor growth and angiogenesis. Yet most ccRCC tumors may still regrow due to the development of sunitinib-resistance, and detailed mechanisms remain to be further investigated. The angiopoietin family includes angiopoietin-1 and angiopoietin-2 (ANGPT-1 and -2). It was reported that estradiol regulates expression of ANGPT-1, but not ANGPT-2, through estrogen receptor α (ERα) in an experimental stroke model. To date, there is no finding to link the E2/ER signal on regulating ANGPT-2. Our study is the first to explore (i) how estrogen receptor β (ERβ) can up-regulate ANGPT-2 in RCC cells, and (ii) how ERβ-increased ANGPT-2 can promote the HUVEC tube formation and reduce sunitinib sensitivity. Mechanistic studies revealed that ERβ could function via transcriptional regulation of the cytokine ANGPT-2 in the ccRCC cells. We found the up-regulated ANGPT-2 of RCC cells could then increase the Tie-2 phosphorylation to promote the angiogenesis and increase sunitinib treatment resistance of endothelial cells. In addition to the endothelial cell tube formation and aortic ring assay, preclinical studies with a mouse RCC model also confirmed the finding. Targeting this newly identified ERβ/ANGPT-2/Tie-2 signaling pathway with the FDA-approved anti-estrogen, Faslodex, may help in the development of a novel combined therapy with sunitinib to better suppress the ccRCC progression.
A novel function of IMPA2, plays a tumor-promoting role in cervical cancer
Authors: Zhang Kan , Liu Lei , Wang Min , Yang Min , Li Xianping , Xia Xiaomeng , Tian Jingjing , Tan Shan , Luo Lingli
Published: May 2020

Discovery of genes and molecular mechanism involved in cervical cancer development would promote the prevention and treatment. By comparing gene expression profiles of cervical carcinoma in situ (CCIS) and adjacent normal tissues, we identified a potential cancer-promoting gene, IMPA2. This study aimed to elucidate the role of IMPA2 and underlying molecular mechanisms in cervical cancer progression. To do this expression of IMPA2 was compared between human cervical cancer and corresponding adjacent normal cervical tissues firstly. CCK-8 assay, clone formation assay, wound healing assay, transwell assay, and tumor formation in nude mice were performed to demonstrate the effect of IMPA2 in cervical cancer proliferation and metastasis. Further proteomic profiling and western blotting explored the molecular pathway involved in the IMPA2-regulating process. The results showed that IMPA2 gene expression was upregulated in cervical cancer. Consistently, silencing of IMPA2 suppressed tumor formation in BALB/c nude mice. Short hairpin RNA (shRNA)-mediated IMPA2 silencing significantly inhibited proliferation and colony-forming abilities of cervical cancer cells, while IMPA2 overexpression had little impact. Also, IMPA2 silencing suppressed cellular migration, but overexpression promoted migration. Proteomics analysis revealed the involvement of mitogen-activated protein kinase (MAPK) pathway in tumor-promoting action of IMPA2. Significantly, the inhibition of IMPA2 activated ERK phosphorylation, and its inhibitory effects can be restored by using selective ERK inhibitor, FR180204. In conclusion, IMPA2 acts as an oncogene in the proliferation and migration of cervical cancer. IMPA2 downregulated ERK phosphorylation to promote cervical cancer. These findings identify a new mechanism underlying cervical cancer and suggest a regulating effect of IMPA2 in MAPK signaling pathway.
Restoration of lysosomal function after damage is accompanied by recycling of lysosomal membrane proteins
Authors: Eriksson Ida , Wäster Petra , Öllinger Karin
Published: May 2020

Lysosomes are central organelles for cellular degradation and energy homeostasis. In addition, lysosomal membrane permeabilization (LMP) and subsequent release of lysosomal content to the cytosol can initiate programmed cell death. The extent of LMP and available repair mechanisms determine the cell fate after lysosomal damage. In this study, we aimed to investigate the premises for lysosomal membrane repair after LMP and found that lysosomal membrane damage initiated by l-leucyl-l-leucine methyl ester (LLOMe) caused caspase-dependent apoptosis in almost 50% of the cells, while the rest recovered. Immediately after LLOMe addition, lysosomal proteases were detected in the cytosol and the ESCRT-components ALIX and CHMP4B were recruited to the lysosomal membrane. Next, lysophagic clearance of damaged lysosomes was evident and a concentration-dependent translocation of several lysosomal membrane proteins, including LAMP2, to the cytosol was found. LAMP2 was present in small vesicles with the N-terminal protein chain facing the lumen of the vesicle. We conclude that lysophagic clearance of damaged lysosomes results in generation of lysosomal membrane protein complexes, which constitute small membrane enclosed units, possibly for recycling of lysosomal membrane proteins. These lysosomal membrane complexes enable an efficient regeneration of lysosomes to regain cell functionality.
Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response
Authors: Dufey Estefanie , Bravo-San Pedro José Manuel , Eggers Cristian , González-Quiroz Matías , Urra Hery , Sagredo Alfredo I. , Sepulveda Denisse , Pihán Philippe , Carreras-Sureda Amado , Hazari Younis , Sagredo Eduardo A. , Gutierrez Daniela , Valls Cristian , Papaioannou Alexandra , Acosta-Alvear Diego , Campos Gisela , Domingos Pedro M. , Pedeux Rémy , Chevet Eric , Alvarez Alejandra , Godoy Patricio , Walter Peter , Glavic Alvaro , Kroemer Guido , Hetz Claudio
Published: May 2020

The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.
Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures
Authors: Vander Velde Robert , Yoon Nara , Marusyk Viktoriya , Durmaz Arda , Dhawan Andrew , Miroshnychenko Daria , Lozano-Peral Diego , Desai Bina , Balynska Olena , Poleszhuk Jan , Kenian Liu , Teng Mingxiang , Abazeed Mohamed , Mian Omar , Tan Aik Choon , Haura Eric , Scott Jacob , Marusyk Andriy
Published: May 2020

Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.
Pharmacological inhibition of PRMT7 links arginine monomethylation to the cellular stress response
Authors: Szewczyk Magdalena M. , Ishikawa Yoshinori , Organ Shawna , Sakai Nozomu , Li Fengling , Halabelian Levon , Ackloo Suzanne , Couzens Amber L. , Eram Mohammad , Dilworth David , Fukushi Hideto , Harding Rachel , dela Seña Carlo C. , Sugo Tsukasa , Hayashi Kozo , McLeod David , Zepeda Carlos , Aman Ahmed , Sánchez-Osuna Maria , Bonneil Eric , Takagi Shinji , Al-Awar Rima , Tyers Mike , Richard Stephane , Takizawa Masayuki , Gingras Anne-Claude , Arrowsmith Cheryl H. , Vedadi Masoud , Brown Peter J. , Nara Hiroshi , Barsyte-Lovejoy Dalia
Published: May 2020

Protein arginine methyltransferases (PRMTs) regulate diverse biological processes and are increasingly being recognized for their potential as drug targets. Here we report the discovery of a potent, selective, and cell-active chemical probe for PRMT7. SGC3027 is a cell permeable prodrug, which in cells is converted to SGC8158, a potent, SAM-competitive PRMT7 inhibitor. Inhibition or knockout of cellular PRMT7 results in drastically reduced levels of arginine monomethylated HSP70 family stress-associated proteins. Structural and biochemical analyses reveal that PRMT7-driven in vitro methylation of HSP70 at R469 requires an ATP-bound, open conformation of HSP70. In cells, SGC3027 inhibits methylation of both constitutive and inducible forms of HSP70, and leads to decreased tolerance for perturbations of proteostasis including heat shock and proteasome inhibitors. These results demonstrate a role for PRMT7 and arginine methylation in stress response.
Mitochondrial uncoupler BAM15 reverses diet-induced obesity and insulin resistance in mice
Authors: Alexopoulos Stephanie J. , Chen Sing-Young , Brandon Amanda E. , Salamoun Joseph M. , Byrne Frances L. , Garcia Christopher J. , Beretta Martina , Olzomer Ellen M. , Shah Divya P. , Philp Ashleigh M. , Hargett Stefan R. , Lawrence Robert T. , Lee Brendan , Sligar James , Carrive Pascal , Tucker Simon P. , Philp Andrew , Lackner Carolin , Turner Nigel , Cooney Gregory J. , Santos Webster L. , Hoehn Kyle L.
Published: May 2020

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
Publisher Correction: Neutrophil swarming delays the growth of clusters of pathogenic fungi
Authors: Hopke Alex , Scherer Allison , Kreuzburg Samantha , Abers Michael S. , Zerbe Christa S. , Dinauer Mary C. , Mansour Michael K. , Irimia Daniel
Published: May 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
BICORN: An R package for integrative inference of de novo cis-regulatory modules
Authors: Chen Xi , Gu Jinghua , Neuwald Andrew F. , Hilakivi-Clarke Leena , Clarke Robert , Xuan Jianhua
Published: May 2020

Genome-wide transcription factor (TF) binding signal analyses reveal co-localization of TF binding sites, based on which cis-regulatory modules (CRMs) can be inferred. CRMs play a key role in understanding the cooperation of multiple TFs under specific conditions. However, the functions of CRMs and their effects on nearby gene transcription are highly dynamic and context-specific and therefore are challenging to characterize. BICORN (Bayesian Inference of COoperative Regulatory Network) builds a hierarchical Bayesian model and infers context-specific CRMs based on TF-gene binding events and gene expression data for a particular cell type. BICORN automatically searches for a list of candidate CRMs based on the input TF bindings at regulatory regions associated with genes of interest. Applying Gibbs sampling, BICORN iteratively estimates model parameters of CRMs, TF activities, and corresponding regulation on gene transcription, which it models as a sparse network of functional CRMs regulating target genes. The BICORN package is implemented in R (version 3.4 or later) and is publicly available on the CRAN server at https://cran.r-project.org/web/packages/BICORN/index.html.
Snapshots of human anatomy, locomotion, and behavior from Late Pleistocene footprints at Engare Sero, Tanzania
Authors: Hatala Kevin G. , Harcourt-Smith William E. H. , Gordon Adam D. , Zimmer Brian W. , Richmond Brian G. , Pobiner Briana L. , Green David J. , Metallo Adam , Rossi Vince , Liutkus-Pierce Cynthia M.
Published: May 2020

Fossil hominin footprints preserve data on a remarkably short time scale compared to most other fossil evidence, offering snapshots of organisms in their immediate ecological and behavioral contexts. Here, we report on our excavations and analyses of more than 400 Late Pleistocene human footprints from Engare Sero, Tanzania. The site represents the largest assemblage of footprints currently known from the human fossil record in Africa. Speed estimates show that the trackways reflect both walking and running behaviors. Estimates of group composition suggest that these footprints were made by a mixed-sex and mixed-age group, but one that consisted of mostly adult females. One group of similarly-oriented trackways was attributed to 14 adult females who walked together at the same pace, with only two adult males and one juvenile accompanying them. In the context of modern ethnographic data, we suggest that these trackways may capture a unique snapshot of cooperative and sexually divided foraging behavior in Late Pleistocene humans.
Endocrine disrupter chemicals affect the humoral antimicrobial activities of gilthead seabream males even upon the cease of the exposure
Authors: Valero Yulema , López-Cánovas Amanda E. , Rodenas M. Carmen , Cabas Isabel , García-Hernández Pilar , Arizcun Marta , García-Ayala Alfonsa , Chaves-Pozo Elena
Published: May 2020

17α-ethynilestradiol (EE2) and tamoxifen (Tmx) are pollutants world-wide distributed in aquatic environments. Gilthead seabream, Sparus aurata L., is highlighted as a species model of intensively culture in anthropogenic disturbed environments. The effects of these pollutants on gilthead seabream reproduction and some immune responses have been described but, the humoral innate antimicrobial activities have never received attention. In this work we analysed the latest in the plasma of gilthead seabream males of different ages and reproductive stages treated with 0, 2.5, 5 or 50 μg EE2 or 100 μg Tmx g−1 food during different times of exposure and of reverting to commercial diet (recovery). The peroxidase and protease activities decreased as the spermatogenesis of the first reproductive cycle (RC) proceeded in control fish. However, only protease and antiprotease activities showed different level at different stages of the second RC in control fish, but showed scarce disruption in fish treated with EE2 or Tmx. Peroxidase and bactericide activities are more sensitive to EE2, than to Tmx. The effects induced by EE2 varied depending on the activity analyzed, the dose and the time of exposure and the reproductive stage and the age of the specimens.
Complexity and ultrastructure of infectious extracellular vesicles from cells infected by non-enveloped virus
Authors: Yang Jie E. , Rossignol Evan D. , Chang Deborah , Zaia Joseph , Forrester Isaac , Raja Kiran , Winbigler Holly , Nicastro Daniela , Jackson William T. , Bullitt Esther
Published: May 2020

Enteroviruses support cell-to-cell viral transmission prior to their canonical lytic spread of virus. Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, and picornaviruses in general, transport multiple virions en bloc via infectious extracellular vesicles, 100~1000 nm in diameter, secreted from host cells. Using biochemical and biophysical methods we identify multiple components in secreted microvesicles, including mature PV virions; positive-sense genomic and negative-sense replicative, template viral RNA; essential viral replication proteins; and cellular proteins. Using cryo-electron tomography, we visualize the near-native three-dimensional architecture of secreted infectious microvesicles containing both virions and a unique morphological component that we describe as a mat-like structure. While the composition of these mat-like structures is not yet known, based on our biochemical data they are expected to be comprised of unencapsidated RNA and proteins. In addition to infectious microvesicles, CD9-positive exosomes released from PV-infected cells are also infectious and transport virions. Thus, our data show that, prior to cell lysis, non-enveloped viruses are secreted within infectious vesicles that also transport viral unencapsidated RNAs, viral and host proteins. Understanding the structure and function of these infectious particles helps elucidate the mechanism by which extracellular vesicles contribute to the spread of non-enveloped virus infection.
A Micromorphic Beam Theory for Beams with Elongated Microstructures
Authors: Shaat M. , Ghavanloo E. , Emam S.
Published: May 2020

A novel micromorphic beam theory that considers the exact shape and size of the beam’s microstructure is developed. The new theory complements the beam theories that are based on the classical mechanics by modeling the shape and size of the beam’s microstructure. This theory models the beam with a microstructure that has shape and size and exhibits microstrains that are independent of the beam’s macroscopic strains. This theory postulates six independent degrees of freedom to describe the axial and transverse displacements and the axial and shear microstrains of the beam. The detailed variational formulation of the beam theory is provided based on the reduced micromorphic model. For the first time, the displacement and microstrain fields of beams with elongated microstructures are developed. In addition, six material constants are defined to fully describe the beam’s microscopic and macroscopic stiffnesses, and two length scale parameters are used to capture the beam size effect. A case study of clamped-clamped beams is analytically solved to show the influence of the beam’s microstructural stiffness and size on its mechanical deformation. The developed micromorphic beam theory would find many important applications including the mechanics of advanced beams such as meta-, phononic, and photonic beams.
rTgOWP1-f, a specific biomarker for Toxoplasma gondii oocysts
Authors: Sousa Susana , Almeida André , Delgado Lurdes , Conceição Antónia , Marques Cláudia , da Costa José Manuel Correia , Castro António
Published: May 2020

Toxoplasma gondii oocyst wall protein 1 (TgOWP1) integrates a family of seven proteins, consensually assumed as specific antigens of Toxoplasma gondii oocyst stage, located in the outer layer of the oocyst wall. Herein, we notice the expression of a recombinant antigen, rTgOWP1-f, derived from a fragment selected on basis of its structural homology with Plasmodium MSP1–19. Rabbit polyclonal antibodies anti-rTgOWP1-f evidence ability for specific identification of environmental T. gondii oocysts. We assume, rTgOWP1-f, as a possible biomarker of oocysts. In addition, we present findings supporting this vision, including the development of an immunodetection method for T. gondii oocysts identification.
A novel peroxidase from Ziziphus jujuba fruit: purification, thermodynamics and biochemical characterization properties
Authors: Zeyadi Mustafa , Almulaiky Yaaser Q.
Published: May 2020

In this study, peroxidase from Ziziphus jujuba was purified using ion exchange, and gel filtration chromatography resulting in an 18.9-fold enhancement of activity with a recovery of 20%. The molecular weight of Z. jujuba peroxidase was 56 kDa, as estimated by Sephacryl S-200. The purity was evaluated by SDS, which showed a single prominent band. The optimal activity of the peroxidase was achieved at pH 7.5 and 50 °C. Z. jujuba peroxidase showed catalytic efficiency (Kcat/Km) values of 25 and 43 for guaiacol and H2O2, respectively. It was completely inactivated when incubated with β-mercaptoethanol for 15 min. Hg2+, Zn2+, Cd2+, and NaN3 (5 mM) were effective peroxidase inhibitors, whereas Cu2+ and Ca2+ enhanced the peroxidase activity. The activation energy (Ea) for substrate hydrolysis was 43.89 kJ mol−1, while the Z value and temperature quotient (Q10) were found to be 17.3 °C and 2, respectively. The half-life of the peroxidase was between 117.46 and 14.15 min. For denaturation of the peroxidase, the activation energy for irreversible inactivation Ea*(d) was 120.9 kJmol−1. Thermodynamic experiments suggested a non-spontaneous (∆G*d > 0) and endothermic reaction phase. Other thermodynamic parameters of the irreversible inactivation of the purified enzyme, such as ∆H* and ∆S*, were also studied. Based on these results, the purified peroxidase has a potential role in some industrial applications.
Neural network interpolation of exchange-correlation functional
Authors: Ryabov Alexander , Akhatov Iskander , Zhilyaev Petr
Published: May 2020

Density functional theory (DFT) is one of the most widely used tools to solve the many-body Schrodinger equation. The core uncertainty inside DFT theory is the exchange-correlation (XC) functional, the exact form of which is still unknown. Therefore, the essential part of DFT success is based on the progress in the development of XC approximations. Traditionally, they are built upon analytic solutions in low- and high-density limits and result from quantum Monte Carlo numerical calculations. However, there is no consistent and general scheme of XC interpolation and functional representation. Many different developed parametrizations mainly utilize a number of phenomenological rules to construct a specific XC functional. In contrast, the neural network (NN) approach can provide a general way to parametrize an XC functional without any a priori knowledge of its functional form. In this work, we develop NN XC functionals and prove their applicability to 3-dimensional physical systems. We show that both the local density approximation (LDA) and generalized gradient approximation (GGA) are well reproduced by the NN approach. It is demonstrated that the local environment can be easily considered by changing only the number of neurons in the first layer of the NN. The developed NN XC functionals show good results when applied to systems that are not presented in the training/test data. The generalizability of the formulated NN XC framework leads us to believe that it could give superior results in comparison with traditional XC schemes provided training data from high-level theories such as the quantum Monte Carlo and post-Hartree-Fock methods.
Bright light improves sleep in patients with Parkinson’s disease: possible role of circadian restoration
Authors: Endo Takuyuki , Matsumura Ritsuko , Tokuda Isao T. , Yoshikawa Tomoko , Shigeyoshi Yasufumi , Node Koichi , Sakoda Saburo , Akashi Makoto
Published: May 2020

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. Among the most common manifestations of PD are sleep problems, which are coupled with the adverse effects of dopaminergic therapies (DT). A non-pharmacological solution for these sleep problems has been sought to avoid additional pharmacological intervention. Here, we show that bright light therapy (BLT) is effective for improving sleep in Japanese PD patients receiving DT. Furthermore, experimental evaluation of peripheral clock gene expression rhythms revealed that most PD patients receiving DT who experienced improved sleep following BLT showed a circadian phase shift, indicating the existence of a correlation between circadian modulation and sleep improvement. Conversely, this result indicates that sleep problems in PD patients receiving DT may arise at least in part as a result of circadian dysfunction. Indeed, we found that chronic dopaminergic stimulation induced a rapid attenuation of autonomous oscillations of clock gene expression in ex vivo cultured mouse suprachiasmatic nucleus (SCN) at the single neuron level. In conclusion, BLT is a promising medical treatment for improving sleep in PD patients receiving DT. This BLT-induced improvement may be due to the restoration of circadian function.