bluuebunny/crossref_metadata_2025 huggingface dataset:
Pyridinobenzodiazepines (PDDs) as Sequence-selective DNA Mono-alkylating Antibody–Drug Conjugate (ADC) Payloads
Authors: Veillard Nicolas , Cascio Francesco , Jackson Paul J. M. , Thurston David E.
Published: July 2019

Although five ADCs have been approved and over sixty others are in development, the majority contain payloads belonging to two classes: tubulin inhibitors and DNA-interactive agents. Challenges in the development of ADCs include managing off-target toxicity and hydrophobicity. Some DNA-interactive payload classes [e.g. pyrolobenzodiazepine (PBD] dimers) are notably hydrophobic, leading to problems such as aggregation during conjugation, and systemic toxicities of the resultant ADCs are also beginning to emerge in clinical settings. Thus, there is interest in developing novel payloads which retain the potency of DNA cross-linking agents but have lower hydrophobicity and a wider therapeutic window when part of an ADC. The pyridinobenzodiazepines (PDDs) are a new class of sequence-selective, DNA mono-alkylating ADC payload, which contain a polyheterocyclic chain with sufficient molecular span and DNA base-pair recognition properties to guide them to specific DNA sequences (e.g. transcription factor binding sites). The favourable hydrophobicity profile of the PDDs and ease of conjugation, along with their novel mechanism of action, significant in vitro cytotoxicity and in vivo tolerability and efficacy when in an ADC format, indicate that they represent a promising new class of ADC payloads.
Splicing Inhibitors as Antibody–Drug Conjugate (ADC) Payloads
Authors: Subramanyam Chakrapani
Published: July 2019

Targeted therapeutics, such as antibody–drug conjugates (ADCs), have provided a platform for the delivery of highly potent cytotoxic agents which are otherwise too toxic for systemic delivery. While most ADCs either in development or approved are based on DNA-damaging agents and microtubule inhibitors, the discovery of payloads that act via new types of mechanisms should expand the utility of this novel therapeutic class. Natural product spliceosome inhibitors such as Thailanstatin A and Pladienolide B are potent antiproliferative agents that target both actively dividing and quiescent cells, and there is significant interest in exploring them as potential ADC payloads. This chapter describes the discovery of Thailanstatin A-based payloads and their use in the preparation of ADCs which are potent in vitro in antigen-positive cell lines, efficacious in vivo in xenograft models and well-tolerated in single-dose rat studies, thus opening the door to further exploration of splicing inhibition as a potential new mode-of-action for novel ADCs.
Occupational Health and Safety Considerations for the Handling and Manufacture of Antibody–Drug Conjugate (ADC) Payloads
Authors: Procopiou George , Mason-Home Justin
Published: July 2019

Antibody–drug conjugate (ADC) payloads are a relatively new class of potent and highly potent active pharmaceutical ingredients (APIs), with cytotoxic activities often in the low picomolar range, due to mechanisms of action that include tubulin inhibition and DNA cleavage, cross-linking or mono-alkylation. The ability to conjugate such payloads to antibodies to make ADCs, represents a new area in the field of targeted cancer chemotherapy. The very high cytotoxicity of some ADC payloads, requires their manufacture and handling to be carefully managed and worker health and safety protected. Parties handling these materials must apply a systematic and scientific approach to occupational health and safety, including toxicological hazard assessment, exposure risk assessment, engineering control/containment, occupational hygiene and related management systems.
The Future of Antibody–Drug Conjugate (ADC) Payloads
Authors: Lutz Robert J.
Published: July 2019

Historically, the dominance of tubulin inhibitors as the payload of choice for antibody–drug conjugate (ADC) development is probably due to a combination of (1) their tractability as highly potent cytotoxics with the synthetic flexibility required for successful conjugation, (2) an early commitment to their potential by ADC innovators and (3) their intrinsic selectivity for proliferating cells, thus directly contributing to the therapeutic index for an ADC. While regulatory approvals for this class of payload have been achieved, with more hopefully on the way, concerns about the clinical effectiveness of tubulin-targeting agents has led to an expansion in efforts to develop ADC payloads with alternative mechanisms of action. Substantial efforts have been focused on DNA-targeting payloads, with a variety of topoisomerase inhibitors, DNA mono-alkylators and DNA cross-linkers being evaluated pre-clinically and in clinical trials. A wide array of payloads with mechanisms of action beyond targeting tubulin or DNA are also being investigated. This chapter looks across the entire spectrum of payloads under evaluation, attempting to connect where ADC payload development has come from in the past, and where it is going now. Expanding efforts using prodrug approaches to improve tolerability, and the potential for some payloads to synergize with immuno-oncology agents are also highlighted.
Ionic-liquid-based synthesis of tellurium–rhenium carbonyls with specific reaction control
Authors: Wolf Silke , Feldmann Claus
Published: July 2019

The novel tellurium rhenium carbonyls [TeI2Re(CO)5][AlCl4] (1), [BMIm][Te2I4(μ-I)2Re(CO)4] (2), {Te3I2(μ-I)3(μ3-I)}Re(CO)3 (3) and [BMIm][(Te2)3{Re(CO)3}2{Re(CO)4}3] (4) were prepared by reacting TeI4 and Re2(CO)10 in ionic liquids (ILs).
Non-equilibrium effects of molecular motors on polymers
Authors: Foglino M. , Locatelli E. , Brackley C. A. , Michieletto D. , Likos C. N. , Marenduzzo D.
Published: July 2019

We present a generic coarse-grained model to describe molecular motors acting on polymer substrates, mimicking, for example, RNA polymerase on DNA or kinesin on microtubules.
Serum thrombospondin-2 is a candidate diagnosis biomarker for early non-small-cell lung cancer
Authors: Jiang Yi-ming , Yu Dan-lu , Hou Guo-xin , Jiang Jia-lu , Zhou Qiang , Xu Xiao-fang
Published: July 2019

Thrombospondin-2 (THBS2) is a secreted protein overexpressed in numerous cancers and may function as a diagnostic tumor marker. The objective of the present study was to investigate the diagnostic performance of serum THBS2 in early stage non-small-cell lung cancer (NSCLC). Serum THBS2 and Cyfra21-1 level were evaluated in blood samples of 112 patients from NSCLC groups and 51 healthy control (HC) groups. Receiver operator characteristic (ROC) curves were used to evaluate the diagnostic significance. Serum THBS2 level was significantly up-regulated in NSCLC patients compared with healthy control subjects (P<0.0001), and the postoperative THBS2 level decreased significantly (P<0.0001). ROC curves analysis demonstrated that THBS2 was a comparable biomarker as Cyfra21-1 to distinguish early stage NSCLC or lung squamous cell carcinoma (SC) from healthy control subjects. And Cyfra21-1 was observed with significantly improved performances by the combination of THBS2 to distinguish early stage NSCLC (P<0.05) as well as SC (P<0.05) from the control subjects. In addition, THBS2 was estimated to perform well in the diagnosis of patients with Cyfra21-1-negative NSCLC (area under the curve [AUC] = 0.73). In summary, the present study suggested that serum THBS2 might be an early diagnostic biomarker for NSCLC.
The RWST, a comprehensive statistical description of the non-Gaussian structures in the ISM
Authors: Allys E. , Levrier F. , Zhang S. , Colling C. , Regaldo-Saint Blancard B. , Boulanger F. , Hennebelle P. , Mallat S.
Published: July 2019

The interstellar medium (ISM) is a complex nonlinear system governed by the interplay between gravity and magneto-hydrodynamics, as well as radiative, thermodynamical, and chemical processes. Our understanding of it mostly progresses through observations and numerical simulations, and a quantitative comparison between these two approaches requires a generic and comprehensive statistical description of the emerging structures. The goal of this paper is to build such a description, with the purpose of permitting an efficient comparison that is independent of any specific prior or model. We started from the wavelet scattering transform (WST), a low-variance statistical description of non-Gaussian processes, which was developed in data science and encodes long-range interactions through a hierarchical multiscale approach based on the wavelet transform. We performed a reduction of the WST through a fit of its angular dependencies. This allowed us to gather most of the information it contains into a few components whose physical meanings are identified and describe for instance isotropic and anisotropic behaviours. The result of this paper is the reduced wavelet scattering transform (RWST), a statistical description with a small number of coefficients that characterizes complex structures arising from nonlinear phenomena, in particular interstellar magnetohydrodynamical (MHD) turbulence, independently of any specific priors. The RWST coefficients encode moments of order up to four, have reduced variances, and quantify the couplings between scales. To show the efficiency and generality of this description, we applied it successfully to the following three kinds of processes that are a priori very different: fractional Brownian motions, MHD simulations, and Herschel observations of the dust thermal continuum in a molecular cloud. With fewer than 100 RWST coefficients when probing six scales and eight angles on 256 by 256 maps, we were able to perform quantitative comparisons, infer relevant physical properties, and produce realistic synthetic fields.
Kepler Object of Interest Network
Authors: Freudenthal J. , von Essen C. , Ofir A. , Dreizler S. , Agol E. , Wedemeyer S. , Morris B. M. , Becker A. C. , Deeg H. J. , Hoyer S. , Mallonn M. , Poppenhaeger K. , Herrero E. , Ribas I. , Boumis P. , Liakos A.
Published: July 2019

Context. The Kepler Object of Interest Network (KOINet) is a multi-site network of telescopes around the globe organised for follow-up observations of transiting planet candidate Kepler objects of interest with large transit timing variations (TTVs). The main goal of KOINet is the completion of their TTV curves as the Kepler telescope stopped observing the original Kepler field in 2013.

Aims. We ensure a comprehensive characterisation of the investigated systems by analysing Kepler data combined with new ground-based transit data using a photodynamical model. This method is applied to the Kepler-82 system leading to its first dynamic analysis.

Methods. In order to provide a coherent description of all observations simultaneously, we combine the numerical integration of the gravitational dynamics of a system over the time span of observations with a transit light curve model. To explore the model parameter space, this photodynamical model is coupled with a Markov chain Monte Carlo algorithm.

Results. The Kepler-82b/c system shows sinusoidal TTVs due to their near 2:1 resonance dynamical interaction. An additional chopping effect in the TTVs of Kepler-82c hints to a further planet near the 3:2 or 3:1 resonance. We photodynamically analysed Kepler long- and short-cadence data and three new transit observations obtained by KOINet between 2014 and 2018. Our result reveals a non-transiting outer planet with a mass of mf = 20.9 ± 1.0 M⊕ near the 3:2 resonance to the outermost known planet, Kepler-82c. Furthermore, we determined the densities of planets b and c to the significantly more precise values ρb = 0.98−0.14+0.10 g cm−3 and ρc = 0.494−0.077+0.066 g cm−3.
Secreted-Osteopontin Contributes to Brown Adipogenesis In Vitro via a CD44-Dependent Pathway
Authors: Wang Mengxi , Guo Yaoyao , Zhou Yumeng , Yuan Wanwan , Li Huixia , Xiong Shaofeng , Wang Kun , Zeng Guohua , Huang Qiren
Published: July 2019

Osteopontin (OPN), a secreted glycoprotein, is involved in various pathophysiological processes including immune response, inflammation, tumor formation, and metabolism. OPN exists in 2 forms, secreted-OPN (sOPN) and intracellular-OPN (iOPN). While they might have different biological activities, it remains largely unknown whether sOPN and iOPN induce the differentiation of brown adipocytes. To test this possibility, 3T3-L1 cells were induced by DMI induction with or without recombinant human OPN (rhOPN, 10, 50, 100, 200 μM), respectively. Meanwhile, another batch of 3T3-L1 cells were infected with Ad-GFP-ap2-OPN and followed by DMI differentiation. Subsequently, the infected cells were treated with either anti-CD44 antibody or immunoglobulin G (Ig G). Accumulation of lipid droplets was visualized by Oil red O staining and protein levels were assayed by western blotting analysis. The results showed that sOPN and not rhOPN, notably increased the accumulation of lipid droplets and the expression of brown adipocyte-related genes. Moreover, neutralization of CD44 partially abrogated the effects induced by sOPN. These data demonstrate that sOPN and not rhOPN has the capacity to induce the differentiation of white preadipocytes into brown adipocytes through a CD44-dependent mechanism. The findings might provide a potential target for sOPN to combat obesity.
Opposite Effects of Voluntary Physical Exercise on β3-Adrenergic Receptors in the White and Brown Adipose Tissue
Authors: Balagova Lucia , Graban Jan , Puhova Agnesa , Jezova Daniela
Published: July 2019

Catecholamine effects via β3-adrenergic receptors are important for the metabolism of the adipose tissue. Physical exercise is a core component of antiobesity regimens. We have tested the hypothesis that voluntary wheel running results in enhancement of β3-adrenergic receptor gene expression in the white and brown adipose tissues. The secondary hypothesis is that dietary tryptophan depletion modifies metabolic effects of exercise. Male Sprague-Dawley rats were assigned for sedentary and exercise groups with free access to running wheels for 3 weeks. All animals received normal control diet for 7 days. Both groups were fed either by low tryptophan (0.04%) diet or by control diet (0.2%) for next 2 weeks. The β3-adrenergic receptor mRNA levels in response to running increased in the retroperitoneal and epididymal fat pads. The gene expression of uncoupling protein-1 (UCP-1) was increased in the brown, while unchanged in the white fat tissues. Unlike control animals, the rats fed by low tryptophan diet did not exhibit a reduction of the white adipose tissue mass. Tryptophan depletion resulted in enhanced concentrations of plasma aldosterone and corticosterone, but had no influence on exercise-induced adrenal hypertrophy. No changes in β3-adrenergic receptor and cell proliferation measured by 5-bromo-2′-deoxyuridine incorporation in left heart ventricle were observed. The reduced β3-adrenergic receptor but not enhanced uncoupling protein-1 gene expression supports the hypothesis on hypoactive brown adipose tissue during exercise. Reduction in dietary tryptophan had no major influence on the exercise-induced changes in the metabolic parameters measured.
Magnetic Resonance Imaging or Endoscopic Ultrasonography for Detection and Surveillance of Pancreatic Neuroendocrine Neoplasms in Patients with Multiple Endocrine Neoplasia Type 1?
Authors: Daskalakis Kosmas , Tsoli Marina , Alexandraki Krystallenia I. , Angelousi Anna , Chatzellis Eleftherios , Tsolakis Apostolos V. , Karoumpalis Ioannis , Kolomodi Denise , Kassi Evanthia , Kaltsas Gregory
Published: July 2019

Our aim was to compare the clinical utility of Magnetic Resonance Imaging (MRI) and Endoscopic Ultrasonography (EUS) in identifying Pancreatic Neurondocrine Neoplasms (PanNENs) and monitoring size alterations in Multiple Endocrine Neoplasia type 1 (MEN1) patients. Thirty-one MEN1 patients with PanNENs and concurrent screening by EUS and abdominal MRI were included and 129 pancreatic lesions were detected in total. MRI detected fewer lesions than EUS (n=73 vs. 110, p=0.006). MRI sensitivity and specificity compared to EUS at 20 and 10 mm cut-offs of maximal lesion diameter were 96 and 88% (20 mm cut-off) and 90 and 82%(10 mm cut-off), respectively (concordance rates of 97 and 87% and Cohen’s kappa=0.912 and 0.718, respectively). Lesions<1 cm were more often detected with EUS (p=0.025). Data from sequential concurrent imaging on lesion growth rate [n=7 (mean±SD: 2 mm/year±3.4 mm vs. 1.9 mm/year±3.6 mm)] over a period of at least two years as well as pathology data in connection to preoperative concurrent imaging were available in a small number of patients (n=7, p=0.933 for mean differences in maximal lesion diameter). MRI of the pancreas was more readily available and less expensive than EUS in an outpatient setting. In conclusion, MRI performs well compared to EUS for the detection and subsequent surveillance of MEN1-related panNENs larger than 10 mm and seems to be cost-effective. Both modalities could be used at initial assessment and MRI alone could be utilized thereafter in patient surveillance. EUS retains its value in surgical planning and the detection of small mostly functional PanNENs.
How Does Power During Running Change when Measured at Different Time Intervals?
Authors: García-Pinillos Felipe , Soto-Hermoso Víctor M. , Latorre-Román Pedro Á. , Párraga-Montilla Juan A. , Roche-Seruendo Luis E.
Published: July 2019

This study aimed to examine how the power output changes while running at a continuous comfortable velocity on a motorized treadmill by comparing running power averaged during different time intervals. Forty-nine endurance runners performed a running protocol on a treadmill at self-selected comfortable velocity. Power output (W) was estimated with the Stryd™ power meter, and it was examined over six recording intervals within the 3-min recording period: 0–10 s, 0–20 s, 0–30 s, 0–60 s, 0–120 s and 0–180 s. The ANOVAs showed no significant differences in the magnitude of the power output between the recording intervals (p=0.276, F=1.614, partial Eta

2
=0.155). An almost perfect association was also observed in the magnitude of the power output between the recording intervals (ICC≥0.999). Bland-Altman plots revealed no heteroscedasticity of error for the power output in any of the between-intervals comparisons (r
2<0.1), although longer recording intervals yield smaller systematic bias, random errors, and narrower limits of agreement for power output. The results show that power data during running, as measured through the Stryd™ system, is a stable metric with negligible differences, in practical terms, between shorter (i. e., 10, 20, 30, 60 or 120 s) and longer recording intervals (i. e., 180 s).
Esophageal overtubes provide no benefit to safety or technical success in upper gastrointestinal tract endoscopic suturing
Authors: Storm Andrew C. , Vargas Eric J. , Matar Reem , Wong Kee Song Louis M. , Sawas Tarek , Bazerbachi Fateh , Buttar Navtej S. , Topazian Mark D. , Abu Dayyeh Barham K.
Published: July 2019

Background and study aim The role of esophageal overtubes in upper gastrointestinal endoscopic suturing is unknown. This study aimed to determine whether overtube use was associated with technical success or adverse events.

Patients and methods A retrospective review of consecutive patients who underwent endoscopic suturing for various indications was performed.

Results A total of 719 patients underwent endoscopic suturing for various indications, including endoscopic bariatric procedures in 262, stent fixation in 258, defect closure in 190, and hemostasis in nine. An overtube was used in 186 procedures (25.9 %). Technical success was achieved in all cases. Minor mucosal trauma occurred in 15 cases (8.1 %) with use of an overtube, and none without an overtube (P < 0.0001). No full-thickness esophageal perforation or hemorrhage related to overtube use or the suturing device occurred.

Conclusions Endoscopic suturing can be performed safely for a variety of indications, including endoscopic bariatric procedures, defect repair, and stent fixation without an esophageal overtube. Minor esophageal mucosal trauma and equipment cost are increased when an overtube is used.
Highly γ-Regioselective 1,2-Addition of α,β-Unsaturated Oxime Ethers with Allylzinc Bromides: A Straightforward Approach for the Synthesis of Homoallylic Amines
Authors: Yang Bo , Zhang Songlin
Published: July 2019

A highly regioselective reaction between allylzinc bromide reagents and α,β-unsaturated oxime ethers for the one-step synthesis of the homoallylic amines is reported. This process is a regioselective 1,2-addition reaction providing a new γ-position with carbon–carbon bond formation. Furthermore, the reaction substrates are widely applicable and can be produced in a high yield.
On vortex intensification due to stretching out of weak satellites
Authors: Sutyrin G. G.
Published: July 2019

The interaction of two essentially unequal vortices is studied for the two-dimensional inviscid model. The curved stretching out of a weak satellite, localized at the periphery of the main vortex, is described analytically in the passive scalar approximation. The rate of energy transfer from the satellite to the main vortex is shown to increase with the curvature of the satellite orbit characterized by the ratio of the satellite size to its distance from the main vortex center. Such a mechanism of the energy cascade is distinct from previously considered symmetric deformations by external flows with a uniform strain rate when the energy is preserved for localized vortices with zero circulation in an unbounded domain. Therefore, asymmetric stretching out of satellites along curved orbits with the finite circumference is crucial for the vortex intensification and can serve as an important ingredient of inverse energy cascade in the two-dimensional turbulence.
Microelectromechanical control of the state of quantum cascade laser frequency combs
Authors: Burghoff David , Han Ningren , Kapsalidis Filippos , Henry Nathan , Beck Mattias , Khurgin Jacob , Faist Jerome , Hu Qing
Published: July 2019

Chip-scale frequency combs such as those based on quantum cascade lasers (QCLs) or microresonators are attracting tremendous attention because of their potential to solve key challenges in sensing and metrology. Though nonlinearity and proper dispersion engineering can create a comb—light whose lines are perfectly evenly spaced—these devices can enter into different states depending on their history, a critical problem that can necessitate slow and manual intervention. Moreover, their large repetition rates are problematic for applications such as dual comb molecular spectroscopy, requiring gapless tuning of the offset. Here, we show that by blending midinfrared QCL combs with microelectromechanical comb drives, one can directly manipulate the dynamics of the comb and identify new physical effects. Not only do the resulting devices remain on a chip-scale and are able to stably tune over large frequency ranges, but they can also switch between different comb states at extremely high speeds. We use these devices to probe hysteresis in comb formation and develop a protocol for achieving a particular comb state regardless of its initial state.
Modeling and verification of the Richtmyer–Meshkov instability linear growth rate of the dense gas-particle flow
Authors: Meng Baoqing , Zeng Junsheng , Tian Baolin , Li Li , He Zhiwei , Guo Xiaohu
Published: July 2019

The multiphase Richtmyer–Meshkov instability (RMI) often occurs in supernova events and inertial confinement fusion processes, where it plays a critical role. In the evolution of the RMI process, the particle phase may have either a dilute or a dense pattern. Previous studies have mainly focused on the dilute pattern. Currently, there is no published research on the theoretical growth model of the dense gas-particle flow. In this work, a new Atwood number model was developed with the assumption of a small Stokes number and shown to be effective for the RMI of the dense gas-particle flow. The Atwood number model was characterized by the moment coupling parameters and the ratio of the volume fractions of the two phases. Further derivation showed that it was consistent with the original Richtmyer’s model and the dilute gas-particle flow model. In addition, the theoretical growth rate was modeled to predict the evolution law of the mix zone width for the dense gas-particle flow. The presence of the particle phase inhibited the growth rate of the RMI, which emphasized the effect of the solid phase. The corresponding numerical simulations were also performed based on the compressible multiphase particle-in-cell method for different cases of the particle volume fraction. The numerical results demonstrated the accuracy of the theoretical growth rate model. Additionally, a brief analysis of the flow structures and cloud motion during the RMI process was performed.
Imaging an isolated water molecule using a single electron wave packet
Authors: Liu Xinyao , Amini Kasra , Steinle Tobias , Sanchez Aurelien , Shaikh Moniruzzaman , Belsa Blanca , Steinmetzer Johannes , Le Anh-Thu , Moshammer Robert , Pfeifer Thomas , Ullrich Joachim , Moszynski Robert , Lin C. D. , Gräfe Stefanie , Biegert Jens
Published: July 2019

Observing changes in molecular structure requires atomic-scale Ångstrom and femtosecond spatio-temporal resolution. We use the Fourier transform (FT) variant of laser-induced electron diffraction (LIED), FT-LIED, to directly retrieve the molecular structure of H2O+ with picometer and femtosecond resolution without a priori knowledge of the molecular structure nor the use of retrieval algorithms or ab initio calculations. We identify a symmetrically stretched H2O+ field-dressed structure that is most likely in the ground electronic state. We subsequently study the nuclear response of an isolated water molecule to an external laser field at four different field strengths. We show that upon increasing the laser field strength from 2.5 to 3.8 V/Å, the O–H bond is further stretched and the molecule slightly bends. The observed ultrafast structural changes lead to an increase in the dipole moment of water and, in turn, a stronger dipole interaction between the nuclear framework of the molecule and the intense laser field. Our results provide important insights into the coupling of the nuclear framework to a laser field as the molecular geometry of H2O+ is altered in the presence of an external field.
Corrigendum to: An introduction to the CSIRO Oral History Collection
Authors: Wolff Helen A. , Healy Terence J. , Spurling Thomas H.
Published: July 2019

This paper describes a project to record specialised oral histories of key individuals involved with Australia's principal scientific research organisation, the Commonwealth Scientific and Industrial Research Organisation (CSIRO). The oral histories are intended to complement official governance documents in a larger project to write a history of CSIRO. Oral histories typically include perspectives on family backgrounds and childhood, professional training and career histories. Of particular interest in these interviews is the involvement of interviewees in the management of CSIRO and their reflections on the place of CSIRO in the Australian and international scientific environments. The interviews were conducted mainly by two of the authors (Spurling and Healy), both of whom were well known to the interviewees because they were themselves senior managers in CSIRO and familiar with the topics discussed. These histories are intended to illuminate important personal factors that have influenced decision-making in CSIRO. Also covered are plans to use other collections of interview materials in the CSIRO History Project (CHP), including those conducted by CSIRO historian Boris Schedvin, the Australian Academy of Science and the National Library of Australia. Details are provided of preparations for interviews, recording and transcription and preparation of materials for public access through CSIROpedia.
The role of the optic tectum for visually evoked orienting and evasive movements
Authors: Suzuki Daichi G. , Pérez-Fernández Juan , Wibble Tobias , Kardamakis Andreas A. , Grillner Sten
Published: July 2019

Significance

The optic tectum (the superior colliculus in mammals) is central for visuomotor transformation in all vertebrates. Here, we investigate the mechanisms underlying the selection between approaching and evasive movements. We use an isolated eye–brain–spinal cord preparation from the lamprey that allows us to display different types of visual stimuli (e.g., looming stimuli) and, at the same time, record neural activity from specific brain regions and the behavioral output monitored through the ventral roots. We show that 2 classes of brainstem-projecting neurons in the deep layer of tectum, in interaction with local inhibitory interneurons, are responsible for the selective switch between visually triggered approaching or evasive movements. We suggest that these visual decision-making circuits are phylogenetically conserved throughout vertebrate evolution.
#shutdownjnu vs #standwithjnu
Authors: Kumar Ritesh
Published: July 2019

In February 2016, one of the premier Universities of higher education in India, Jawaharlal Nehru University (JNU), suddenly came into the limelight for allegedly raising anti-India slogans at one of the protest cultural programmes in the campus. In this paper, I present a study of the co-emergence and spread of the two opposing hashtags in the context of the controversy –#shutdownjnuand#standwithjnu. The study is based on data collected from Twitter over a period of 2 years from February 2016 – February 2018. I present a quantitative as well as qualitative analysis of the emergence and use of these two hashtags on Twitter and understand these in terms of the process of enregisterment and how conflict (and consequently aggression) became normative and conventionalised in the context of these hashtags. I also take a comparative look at the enregisterment of the two hashtags and argue that despite similar conditions, enregisterment is not guaranteed.
ILC3s integrate glycolysis and mitochondrial production of reactive oxygen species to fulfill activation demands
Authors: Di Luccia Blanda , Gilfillan Susan , Cella Marina , Colonna Marco , Huang Stanley Ching-Cheng
Published: July 2019

Group 3 innate lymphoid cells (ILC3s) are the innate counterparts of Th17 that require the transcription factor RORγt for development and contribute to the defense against pathogens through IL-22 and IL-17 secretion. Proliferation and effector functions of Th17 require a specific mTOR-dependent metabolic program that utilizes high-rate glycolysis, while mitochondrial lipid oxidation and production of reactive oxygen species (mROS) support alternative T reg cell differentiation. Whether ILC3s employ a specific metabolic program is not known. Here, we find that ILC3s rely on mTOR complex 1 (mTORC1) for proliferation and production of IL-22 and IL-17A after in vitro activation and Citrobacter rodentium infection. mTORC1 induces activation of HIF1α, which reprograms ILC3 metabolism toward glycolysis and sustained expression of RORγt. However, in contrast to Th17, ILC3 activation requires mROS production; rather than inducing an alternative regulatory fate as it does in CD4 T cells, mROS stabilizes HIF1α and RORγt in ILC3s and thereby promotes their activation. We conclude that ILC3 activation relies on a metabolic program that integrates glycolysis with mROS production.
APMP key comparison of DC voltage at 10 V and 1.018 V
Authors: Maruyama Michitaka , Chen Shih-Fang , Kim Mun-Seog , Kim Kyu-Tae
Published: July 2019

A key comparison of DC voltage at 10 V and 1.018 V has been conducted from 2013 to 2014 between NMIJ, CMS and KRISS. In this comparison, PJVS systems were compared via Zener travelling standards. All the results agree well to the key comparison reference values, which are provided by a conventional JVS system at KRISS, within 1 part in 107 for 10 V and 2 parts in 107 for 1.018 V, respectively.

Main text

To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.

The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
Linear response theory for quantum Gaussian processes
Authors: Mehboudi Mohammad , Parrondo Juan M R , Acín Antonio
Published: July 2019

Fluctuation dissipation theorems (FDTs) connect the linear response of a physical system to a perturbation to the steady-state correlation functions. Until now, most of these theorems have been derived for finite-dimensional systems. However, many relevant physical processes are described by systems of infinite dimension in the Gaussian regime. In this work, we find a linear response theory for quantum Gaussian systems subject to time dependent Gaussian channels. In particular, we establish a FDT for the covariance matrix that connects its linear response at any time to the steady state two-time correlations. The theorem covers non-equilibrium scenarios as it does not require the steady state to be at thermal equilibrium. We further show how our results simplify the study of Gaussian systems subject to a time dependent Lindbladian master equation. Finally, we illustrate the usage of our new scheme through some examples. Due to broad generality of the Gaussian formalism, we expect our results to find an application in many physical platforms, such as opto-mechanical systems in the presence of external noise or driven quantum heat devices.
The product structure of Newton strata in the good reduction of Shimura varieties of Hodge type
Authors: Hamacher Paul
Published: July 2019

We construct a generalisation of Mantovan’s almost product structure to Shimura varieties of Hodge type with hyperspecial level structure atppand deduce that the perfection of the Newton strata are proétale locally isomorphic to the perfection of the product of a central leaf and a Rapoport-Zink space. The almost product formula can be extended to obtain an analogue of Caraiani and Scholze’s generalisation of the almost product structure for Shimura varieties of Hodge type.
A general semiparametric Bayesian discrete-time recurrent events model
Authors: King Adam J , Weiss Robert E
Published: July 2019

Event time variables are often recorded in a discrete fashion, especially in the case of patient-reported outcomes. This work is motivated by a study of illicit drug users, in which time to drug use cessation has been recorded as a number of whole months. Existing approaches for handling such discrete data include treating the survival times as continuous (with adjustments for inevitable tied outcomes), or using discrete models that omit important features like random effects. We provide a general Bayesian discrete-time proportional hazards model, incorporating a number of features popular in continuous-time models such as competing risks and frailties. Our model also provides flexible baseline hazards for time effects, as well as generalized additive models style semiparametric incorporation of other time-varying covariates. Our specific modeling choices enable efficient Markov chain Monte Carlo inference algorithms, which we provide to the user in the form of a freely available R package called $\texttt{brea}$. We demonstrate that our model performs better on our motivating substance abuse application than existing approaches. We also present a reproducible application of the $\texttt{brea}$ software to a freely available data set from a clinical trial of anesthesia administration methods.
Degree of fragmentation and population size do not adversely affect reproductive success of a rare shrub species, Banksia nivea (Proteaceae), in a naturally fragmented community
Authors: Thavornkanlapachai Rujiporn , Byrne Margaret , Yates Colin J , Ladd Philip G
Published: July 2019

Fragmentation of plant communities is generally considered to be detrimental to the survival of the constituent species, especially those that are rare. We investigated the effects of fragmentation on reproductive biology in nine populations of the rare taxon Banksia nivea subsp. uliginosa, differing in size and habitat context. Small mammals were the main pollinator, with lower contributions from honeybees and birds (honeyeaters). There was no significant relationship between population size, fruit set and seed germinability. Fruit set was marginally highest (25.5 ± 3.4) in medium size populations and was variable over years. Lower fruit set (1.0 ± 0.6) in the smallest population may be due to inbreeding depression or lack of pollinators in a degraded habitat, but low fruit set was also observed in the largest population despite high levels of gene flow, possibly due to low pollinator visitation rate in a low-density population. Seeds from all populations had high germination success (>93.4%). Predation occurred in up to 56% of fruit and increased with increasing population size, but was not significantly different between populations of different size. Our study provided evidence that the reproductive output in species in a naturally fragmented landscape system may be resilient to reduced population size and other influences of anthropogenic fragmentation.
Eight-day Inpatient Directly Observed Therapy for Antiretroviral Therapy (ART) Failure: A Tool For Preventing Unnecessary ART Changes and Optimizing Adherence Support
Authors: Winchester Nicole E , Maldarelli Frank , Mejia Yolanda , Dee Nicola , Dewar Robin , Laidlaw Elizabeth , Kuriakose Safia S , Stoll Pamela , Proschan Michael , Lane H Clifford , Pau Alice K
Published: July 2019

Eight-day inpatient directly observed therapy confirmed nonadherence as the major cause of virologic failure for 9 (45%) of 20 highly treatment-experienced persons with human immunodeficiency virus, extensive antiretroviral drug resistance, and high self-reported adherence rates, preventing unnecessary regimen changes.
Pre-existing Antineuraminidase Antibodies Are Associated With Shortened Duration of Influenza A(H1N1)pdm Virus Shedding and Illness in Naturally Infected Adults
Authors: Maier Hannah E , Nachbagauer Raffael , Kuan Guillermina , Ng Sophia , Lopez Roger , Sanchez Nery , Stadlbauer Daniel , Gresh Lionel , Schiller Amy , Rajabhathor Arvind , Ojeda Sergio , Guglia Andrea F , Amanat Fatima , Balmaseda Angel , Krammer Florian , Gordon Aubree
Published: July 2019

Background

Influenza causes a substantial burden worldwide, and current seasonal influenza vaccine has suboptimal effectiveness. To develop better, more broadly protective vaccines, a more thorough understanding is needed of how antibodies that target the influenza virus surface antigens, hemagglutinin (HA) (including head and stalk regions) and neuraminidase (NA), impact influenza illness and virus transmission.

Methods

We used a case-ascertained, community-based study of household influenza virus transmission set in Managua, Nicaragua. Using data from 170 reverse transcriptase–polymerase chain reaction (RT-PCR)–confirmed influenza virus A(H1N1)pdm infections and 45 household members with serologically confirmed infection, we examined the association of pre-existing NA, hemagglutination inhibiting, and HA stalk antibody levels and influenza viral shedding and disease duration using accelerated failure time models.

Results

Among RT-PCR–confirmed infections in adults, pre-existing anti-NA antibody levels ≥40 were associated with a 69% (95% confidence interval [CI], 34–85%) shortened shedding duration (mean, 1.0 vs 3.2 days). Neuraminidase antibody levels ≥80 were associated with further shortened shedding and significantly shortened symptom duration (influenza-like illness, 82%; 95% CI, 39–95%). Among RT-PCR–confirmed infections in children, hemagglutination inhibition titers ≥1:20 were associated with a 32% (95% CI, 13–47%) shortened shedding duration (mean, 3.9 vs 6.0 days).

Conclusions

Our results suggest that anti-NA antibodies play a large role in reducing influenza illness duration in adults and may impact transmission, most clearly among adults. Neuraminidase should be considered as an additional target in next-generation influenza virus vaccine development.

We found that antibodies against neuraminidase were associated with significantly shortened viral shedding, and among adults they were also associated with shortened symptom duration. These results support neuraminidase as a potential target of next-generation influenza virus vaccines.
National Safety Survey of Animal-use Commercial Probiotics and Their Spillover Effects From Farm to Humans: An Emerging Threat to Public Health
Authors: Fu Songzhe , Yang Qian , He Fenglan , Lan Ruiting , Hao Jingwei , Ni Ping , Liu Ying , Li Ruijun
Published: July 2019

Background

Human-use probiotics have recently been associated with clinical infections and antibiotic resistance transfer, raising public concern over their safety. However, despite their extensive application in aquaculture and animal husbandry, the safety of animal-use probiotics remains poorly described.

Methods

We evaluated the safety of 92 animal-use probiotics from China. The pattern of spread of pathogens from probiotics and the consequent public health implications were also examined by conducting in-field genomic surveillance at 2 farms.

Results

A total of 123 probiotic Bacillus species isolates were obtained from 92 brands of probiotics, of which 45 isolates were resistant to antibiotics. Notably, 33.7% of probiotic products were contaminated with life-threatening pathogens such as Klebsiella pneumoniae. Genomic surveillance at a chicken farm identified an anthrax toxin–positive Bacillus cereus strain in a probiotic product used as a feed supplement, which was transferred into the groundwater and to a nearby fish farm. Following up retrospective analysis of the surveillance data during 2015–2018 in 3 provinces retrieved 2 B. cereus strains from human with intestinal anthrax symptoms and confirmed the transmission of B. cereus from farm to human. Surveillance of anthrax toxin revealed that cya was detected in 8 of 31 farms.

Conclusions

This study provides the first national safety survey of animal-use probiotics in China and confirms the spillover effects of probiotics from the farms to human. These results suggest that the large-scale application of pathogen-containing probiotics leads to the transfer of pathogens, with worrisome implications for public health. Good Manufacturing Practice should be implemented during the production of all probiotics.

Animal-use probiotic products are frequently contaminated with viable pathogenic bacteria. This study revealed that virulent probiotic organisms and contaminating pathogens were colonized with farm animals and shed into the environment, which facilitated the transfer of pathogens to humans.
Community-acquired Bacterial Meningitis in Adults With Cerebrospinal Fluid Leakage
Authors: ter Horst Liora , Brouwer Matthijs C , van der Ende Arie , van de Beek Diederik
Published: July 2019

Background

Cerebrospinal fluid (CSF) leakage is a risk factor for developing bacterial meningitis.

Methods

We analyzed episodes of community-acquired bacterial meningitis associated with CSF leakage from a prospective nationwide cohort study.

Results

CSF leakage was identified in 65 episodes of 2022 episodes (3%) in 53 patients. The cause of CSF leakage was identified in 49 of 65 episodes (75%), which most commonly consisted of ear-nose-throat surgery (19 of 49 episodes [29%]) and remote head trauma (15 of 49 episodes [23%]). The episode was a recurrent meningitis episode in 38 patients (59%). Of the recurrent episodes, 27 had known CSF leakage (71%) of whom 20 (53%) had previous surgery aiming to close the leak. Nine patients (38%) with known CSF leakage had been vaccinated (23-valent pneumococcal vaccine in 9 patients, meningococcal serogroup C vaccine in 2, meningococcal serogroup A and Haemophilus influenzae type b vaccine each in 1 patient). Streptococcus pneumoniae was cultured in 33 episodes (51%) and H. influenzae in 11 episodes (17%). The most common pneumococcal serotypes were 3 (4 episodes), 35B, 9N, 38, and 15C (each 2 episodes). Haemophilus influenzae was unencapsulated in all 10 episodes with known capsule type. The outcome was unfavorable in 8 episodes (12%) and no patient died.

Conclusions

Bacterial meningitis in patients with CSF leakage has a high recurrence rate, despite surgical repair or vaccination, and outcome is generally favorable. CSF leakage should be suspected in patients with bacterial meningitis presenting with liquorrhea, recurrent meningitis, or with disease caused by H. influenzae.
Multiple factors drive the abundance and diversity of the diazotrophic community in typical farmland soils of China
Authors: Han Li-Li , Wang Qing , Shen Ju-Pei , Di Hong J , Wang Jun-Tao , Wei Wen-Xue , Fang Yun-Ting , Zhang Li-Mei , He Ji-Zheng
Published: July 2019

Biological nitrogen fixation plays an important role in nitrogen cycling by transferring atmospheric N2 to plant-available N in the soil. However, the diazotrophic activity and distribution in different types of soils remain to be further explored. In this study, 152 upland soils were sampled to examine the diazotrophic abundance, nitrogenase activity, diversity and community composition by quantitative polymerase chain reaction, acetylene reduction assay and the MiSeq sequencing of nifH genes, respectively. The results showed that diazotrophic abundance and nitrogenase activity varied among the three soil types. The diazotrophic community was mainly dominated by Bradyrhizobium, Azospirillum, Myxobacter, Desulfovibrio and Methylobacterium. The symbiotic diazotroph Bradyrhizobium was widely distributed among soils, while the distribution of free-living diazotrophs showed large variation and was greatly affected by multiple factors. Crop type and soil properties directly affected the diazotrophic ɑ-diversity, while soil properties, climatic factors and spatial distance together influenced the diazotrophic community. Network structures were completely different among all three types of soils, with most complex interactions observed in the Red soil. These findings suggest that diazotrophs have various activities and distributions in the three soil types, which played different roles in nitrogen input in agricultural soil in China, being driven by multiple environmental factors.
Primed to be strong, primed to be fast: modeling benefits of microbial stress responses
Authors: Wesener Felix , Tietjen Britta
Published: July 2019

Organisms are prone to different stressors and have evolved various defense mechanisms. One such defense mechanism is priming, where a mild preceding stress prepares the organism toward an improved stress response. This improved response can strongly vary, and primed organisms have been found to respond with one of three response strategies: a shorter delay to stress, a faster buildup of their response or a more intense response. However, a universal comparative assessment, which response is superior under a given environmental setting, is missing. We investigate the benefits of the three improved responses for microorganisms with an ordinary differential equation model, simulating the impact of an external stress on a microbial population that is either naïve or primed. We systematically assess the resulting population performance for different costs associated with priming and stress conditions. Our results show that independent of stress type and priming costs, the stronger primed response is most beneficial for longer stress phases, while the faster and earlier responses increase population performance and survival probability under short stresses. Competition increases priming benefits and promotes the early stress response. This dependence on the ecological context highlights the importance of including primed response strategies into microbial stress ecology.