bluuebunny/crossref_metadata_2025 huggingface dataset:
A quantitative bias analysis to estimate measurement error-related attenuation of the association between self-reported physical activity and colorectal cancer risk
Authors: Mahmood Shahid , Nguyen Nga H , Bassett Julie K , MacInnis Robert J , Karahalios Amalia , Owen Neville , Bruinsma Fiona J , Milne Roger L , Giles Graham G , English Dallas R , Lynch Brigid M
Published: September 2019

Background

Self-reported physical activity is inaccurate, yet few investigators attempt to adjust for measurement error when estimating risks for health outcomes. We estimated what the association between self-reported physical activity and colorectal cancer risk would be if physical activity had been assessed using accelerometry instead.

Methods

We conducted a validation study in which 235 Australian adults completed a telephone-administered International Physical Activity Questionnaire (IPAQ), and wore an accelerometer (Actigraph GT3X+) for 7 days. Using accelerometer-assessed physical activity as the criterion measure, we calculated validity coefficients and attenuation factors using a structural equation model adjusted for age, sex, education and body mass index. We then used a regression calibration approach to apply the attenuation factors to data from the Melbourne Collaborative Cohort Study (MCCS) to compute bias-adjusted hazard ratios (HR) and 95% confidence intervals (CI).

Results

Average daily minutes of physical activity from the short form of the International Physical Activity Questionnaire (IPAQ-short) were substantially higher than accelerometer-measured duration (55 versus 32 min). The validity coefficient (0.32; 95% CI: 0.20, 0.43) and attenuation factor (0.20; 95% CI: 0.12, 0.28) were low. The HRs for colorectal cancer risk for high (75th percentile; 411 min/week) versus low (25th percentile; 62 min/week) levels of self-reported physical activity were 0.95 (95% CI: 0.87, 1.05) before and 0.78 (95% CI: 0.47, 1.28) after bias adjustment.

Conclusions

Over-estimation of physical activity by the IPAQ-short substantially attenuates the association between physical activity and colorectal cancer risk, suggesting that the protective effect of physical activity has been previously underestimated.
Phospho-Ser727 triggers a multistep inactivation of STAT3 by rapid dissociation of pY705–SH2 through C-terminal tail modulation
Authors: Yang Junhao , Kunimoto Hiroyuki , Katayama Bumpei , Zhao Hong , Shiromizu Takashi , Wang Lingyu , Ozawa Toshiyuki , Tomonaga Takeshi , Tsuruta Daisuke , Nakajima Koichi
Published: September 2019

Signal transducer and activator of transcription 3 (STAT3) is involved in many biological processes, including immunity and cancer. STAT3 becomes phosphorylated at Tyr705 and Ser727 on IL-6 stimulation. Phospho-Tyr705 (pY705) stabilizes the STAT3 dimer with reciprocal interactions between pY705 and the SH2 of the other molecule and phospho-Ser727 (pS727) accelerates pY705 dephosphorylation. We study how pS727 regulates STAT3 in both structural and biological perspectives. Using STAT3 reconstituted in HepG2-stat3-knockout cells, we show that pS727, together with a handshake N-terminal domain (NTD) interaction, causes rapid inactivation of STAT3 for pY705 dephosphorylation and a chromosome region maintenance 1 (CRM1)-independent nuclear export, which is critical for faithful STAT3 response to the cellular signals. The various N-terminal tags, GFP-related Ruby and FLAG, rendered the export CRM1-dependent and especially FLAG-tag caused nuclear accumulation of STAT3, indicating the presence of conformational changes in inactivation. Impaired reactivation of STAT3 by S727A or FLAG-tag delayed or inhibited the IL-6-induced saa1 mRNA expression, respectively. The detailed analysis of the pY705–SH2 structure identified the C-terminal tail (CTT) from L706 to P715 as a key regulator of the CTT–CTT intermolecular and the CTT–SH2 intramolecular interactions that support pY705–SH2 association. The functional studies using multiple STAT3 mutants indicated that the degree of the two interactions determines the stability of pY705–SH2 interaction. Importantly, Pro715 was critical for the pS727's destabilizing activity and the known phosphorylation and acetylation at the CTT structurally inhibited the pY705–SH2 interaction. Thus, pS727 triggers pY705–SH2 dissociation by weakening the supportive interactions likely through CTT modulation, inducing rapid cycles of STAT3 activation–inactivation for proper function of STAT3.
Effect of 20-Hydroxyecdysone, a Phytoecdysteroid, on Development, Digestive, and Detoxification Enzyme Activities of Tribolium castaneum (Coleoptera: Tenebrionidae)
Authors: Ajaha Ayoub , Bouayad Noureddin , Aarab Ahmed , Rharrabe Kacem
Published: September 2019

Plants present a delimited reservoir of biologically active compounds. Many plants synthesize several compounds of secondary metabolism, such as alkaloids, terpenoids, phenolics, steroids, etc. Such compounds are generally thought to be involved in plant–insect interactions. Phytoecdysteroids are a class of chemicals that plants synthesize; these compounds are analogues of molting hormones produced by insects. In this work, the effect of the 20-hydroxyecdysone, which is a molecule that belongs to the family of phytoecdysteroids, was tested on an insect pest, Tribolium castaneum (Herbst). Firstly, the effect of this molecule on post-embryonic development parameters was tested after ingestion at 300, 600, 900, and 1,200 ppm. Secondly, the effect of the 20-hydroxyecdysone was also tested on the biological parameters (proteins, alpha-amylase, detoxification enzymes). The results of the post-embryonic parameters test showed an important induction of larval mortality and a significant reduction of pupation and adult emergence rates. On the other hand, the test on the biological parameters showed that the 20-hydroxyecdysone caused a significant decrease in the levels of soluble proteins in treated larvae. In addition, the alpha-amylase activity was significantly inhibited by the ingestion of the phytoecdysteroid. And there was also a disruption of detoxification enzymes. The whole of the disturbances recorded in this work prove that phytoecdysteroids are thought to have potential value on T. castaneum control.
Moving to Keep Fit: Feeding Behavior and Movement of Helicoverpa armigera (Lepidoptera: Noctuidae) on Artificial Diet With Different Protein: Carbohydrate Ratios
Authors: Wang Peng , Furlong Michael J , Walsh Thomas K , Zalucki Myron P
Published: September 2019

Insect herbivores can modify their foraging behavior to obtain a balanced food intake, and they tend to move between food sources with different nutrient values. We investigated this movement in early instar larvae of Helicoverpa armigera (Hübner) (Lepidoptera: Noctuidae) using a putative optimal artificial diet (OP) and high protein (HP) and high carbohydrate (HC) artificial diets based on protein (p) and carbohydrate (c) ratios. Larvae were allowed to choose between the same kind of diet cubes (effectively no-choice), or diet cubes with different p: c ratios. In no-choice tests, we found that first instar larvae remained longest on OP diet and spent the least time on HC diet, while third instar larvae remained longest on HC diet and spent least time on OP diet. First instar larvae moved the most when provided with HC diet, while third instar larvae moved most when provided with OP diet. However, both stages moved the least when allowed to choose between diet cubes with different p: c ratios. The relative growth rate decreased when larvae increased their movement, but this influence was not evident when larvae fed on HC diet. Larvae that fed only on HC diet had the highest relative growth rate, followed by larvae with access to all diets simultaneously, indicating a behavior to mix nutrient intake. We relate these findings to behavior of this major pest species under field conditions.
Mitotic Index Thresholds Do Not Predict Clinical Outcome for IDH-Mutant Astrocytoma
Authors: Yoda Rebecca A , Marxen Troy , Longo Lauren , Ene Chibawanye , Wirsching Hans-Georg , Keene C Dirk , Holland Eric C , Cimino Patrick J
Published: September 2019

Current histological grading recommendations for isocitrate dehydrogenase (IDH)-mutant astrocytoma are imprecise and not reliably predictive of patient outcome, while somatic copy number alterations are emerging as important prognostic biomarkers. One explanation for this relative underperformance of histological grading is that current criteria to distinguish World Health Organization (WHO) grade III anaplastic astrocytomas from lower-grade diffuse astrocytomas (WHO grade II) are vague (“increased mitotic activity”). This qualitative approach ensures diagnostic uncertainty and a broad “gray zone” where both diffuse and anaplastic designations can reasonably be assigned. Thus, we hypothesized that interobserver variability and lack of defined mitotic thresholds for IDH-mutant astrocytomas underlies poor predictive accuracy of current histologic grading approaches. To test this hypothesis, we quantified total mitotic figures and maximum mitotic activity per 10 high-powered fields in an institutional cohort of IDH-mutant astrocytomas. In our cohort, there was no mitotic activity threshold that was reflective of progression-free or overall survival (OS). Furthermore, in a multivariate Cox regression model consisting of mitotic activity, molecular markers, and clinical characteristics, only CDKN2A homozygous deletion was identified as a relevant variant for poor OS. We conclude that lack of defined mitotic figure thresholds may not contribute to underperformance of histological grading for IDH-mutant astrocytomas.
The ethylene receptors CpETR1A and CpETR2B cooperate in the control of sex determination in Cucurbita pepo
Authors: García Alicia , Aguado Encarnación , Martínez Cecilia , Loska Damian , Beltrán Sergi , Valenzuela Juan Luis , Garrido Dolores , Jamilena Manuel
Published: September 2019

High-throughput screening of an ethyl methanesulfonate-generated mutant collection of Cucurbita pepo using the ethylene triple-response test resulted in the identification of two semi-dominant ethylene-insensitive mutants: etr1a and etr2b. Both mutations altered sex determination mechanisms, promoting conversion of female into bisexual or hermaphrodite flowers, and monoecy into andromonoecy, thereby delaying the transition to female flowering and reducing the number of pistillate flowers per plant. The mutations also altered the growth rate and maturity of petals and carpels in pistillate flowers, lengthening the time required for flowers to reach anthesis, as well as stimulating the growth rate of ovaries and the parthenocarpic development of fruits. Whole-genome sequencing allowed identification of the causal mutation of the phenotypes as two missense mutations in the coding region of CpETR1A and CpETR2B, each one corresponding to one of the duplicates of ethylene receptor genes highly homologous to Arabidopsis ETR1 and ETR2. The phenotypes of homozygous and heterozygous single- and double-mutant plants indicated that the two ethylene receptors cooperate in the control of the ethylene response. The level of ethylene insensitivity, which was determined by the strength of each mutant allele and the dose of wild-type and mutant etr1a and etr2b alleles, correlated with the degree of phenotypic changes in the mutants.
Regulation of carbon metabolism in two maize sister lines contrasted for chilling tolerance
Authors: Garzon Catalina Duran , Lequart Michelle , Rautengarten Carsten , Bassard Solène , Sellier-Richard Hélène , Baldet Pierre , Heazlewood Joshua L , Gibon Yves , Domon Jean-Marc , Giauffret Catherine , Rayon Catherine
Published: September 2019

Chilling tolerance in maize is associated with efficient modulation of sucrose/starch metabolism which might be linked to a strong alteration in biosynthesis of nucleotide sugars.
Combined transcriptome and metabolome analysis identifies defence responses in spider mite-infested pepper (Capsicum annuum)
Authors: Zhang Yuanyuan , Bouwmeester Harro J , Kappers Iris F
Published: September 2019

Plants regulate responses towards herbivory through fine-tuning of defence-related hormone production, expression of defence genes, and production of secondary metabolites. Jasmonic acid (JA) plays a key role in plant–herbivorous arthropod interactions. To understand how pepper (Capsicum annuum) responds to herbivory, leaf transcriptomes and metabolomes of two genotypes different in their susceptibility to spider mites were studied. Mites induced both JA and salicylic acid (SA) signalling. However, mite infestation and exogenous JA resulted in distinct transcriptome profiles. Compared with JA, mites induced fewer differentially expressed genes involved in metabolic processes (except for genes involved in the phenylpropanoid pathway) and lipid metabolic processes. Furthermore, pathogen-related defence responses including WRKY transcription factors were more strongly induced upon mite infestation, probably as a result of induced SA signalling. Untargeted analysis of secondary metabolites confirmed that JA treatment induced larger changes in metabolism than spider mite infestation, resulting in higher terpenoid and flavonoid production. The more resistant genotype exhibited a larger increase in endogenous JA and volatile and non-volatile secondary metabolites upon infestation, which could explain its stronger defence. Reasoning that in JA–SA antagonizing crosstalk, SA defences are prioritized over JA defences, we hypothesize that lack of SA-mediated repression of JA-induced defences could result in gain of resistance towards spider mites in pepper.
Identification and evolutionary analysis of chalcone isomerase-fold proteins in ferns
Authors: Ni Rong , Zhu Ting-Ting , Zhang Xiao-Shuang , Wang Piao-Yi , Sun Chun-Jing , Qiao Ya-Nan , Lou Hong-Xiang , Cheng Ai-Xia
Published: September 2019

The emergence of type I CHIs may have occurred at the time of the divergence of the pteridophytes, with CHIL interacting with both CHS and CHI to promote flavonoid synthesis.
Atmospheric scintillation noise in ground-based exoplanet photometry
Authors: Föhring D , Wilson R W , Osborn J , Dhillon V S
Published: September 2019

Atmospheric scintillation caused by optical turbulence in the Earth’s atmosphere can be the dominant source of noise in ground-based photometric observations of bright targets, which is a particular concern for ground-based exoplanet transit photometry. We demonstrate the implications of atmospheric scintillation for exoplanet transit photometry through contemporaneous turbulence profiling and transit observations. We find a strong correlation between measured intensity variations and scintillation determined through optical turbulence profiling. This correlation indicates that turbulence profiling can be used to accurately model the amount of scintillation noise present in photometric observations on another telescope at the same site. We examine the conditions under which scintillation correction would be beneficial for transit photometry through turbulence profiling, and find that for the atmosphere of La Palma, scintillation dominates for bright targets of magnitude above V ∼ 10.1 mag for a 0.5 m telescope, and at V ∼ 11.7 mag for a 4.2 m telescope under median atmospheric conditions. Through Markov-chain Monte Carlo methods we examine the effect of scintillation noise on the uncertainty of the measured exoplanet parameters, and determine the regimes where scintillation correction is especially beneficial. The ability to model the amount of noise in observations due to scintillation, given an understanding of the atmosphere, is a crucial test for our understanding of scintillation and the overall noise budget of our observations.
Relaxation of spherical stellar systems
Authors: Lau Jun Yan , Binney James
Published: September 2019

A total of 10 000 simulations of 1000 particle realizations of the same cluster are computed by direct force summation. After three crossing times self-gravity has amplified the original Poisson noise more than tenfold on large scales, and the amplification is still far from complete. The cluster’s fundamental dipole mode is strongly excited by Poisson noise, and this mode makes a major contribution to driving diffusion of stars in energy. The diffusive flow through action space is computed for the simulations and compared with the predictions of both Chandrasekhar’s local-scattering theory and the Balescu–Lenard (BL) equation. The predictions of local-scattering theory are qualitatively wrong because the latter neglects self-gravity. These results imply that local-scattering theory can account for only a fraction of a cluster’s relaxation. Future work on cluster evolution should employ either N-body simulation or the BL equation. However, significant code development will be required to make use of the BL equation practicable and the way forward may be to merge BL theory with local scattering theory so fluctuations of every scale are efficiently handled.
Transit timing variations in the WASP-4 planetary system
Authors: Southworth John , Dominik M , Jørgensen U G , Andersen M I , Bozza V , Burgdorf M J , D’Ago G , Dib S , Figuera Jaimes R , Fujii Y I , Gill S , Haikala L K , Hinse T C , Hundertmark M , Khalouei E , Korhonen H , Longa-Peña P , Mancini L , Peixinho N , Rabus M , Rahvar S , Sajadian S , Skottfelt J , Snodgrass C , Spyratos P , Tregloan-Reed J , Unda-Sanzana E , von Essen C
Published: September 2019

Transits in the planetary system WASP-4 were recently found to occur 80 s earlier than expected in observations from the TESS satellite. We present 22 new times of mid-transit that confirm the existence of transit timing variations, and are well fitted by a quadratic ephemeris with period decay dP/dt = −9.2 ± 1.1 ms yr−1. We rule out instrumental issues, stellar activity, and the Applegate mechanism as possible causes. The light-time effect is also not favoured due to the non-detection of changes in the systemic velocity. Orbital decay and apsidal precession are plausible but unproven. WASP-4 b is only the third hot Jupiter known to show transit timing variations to high confidence. We discuss a variety of observations of this and other planetary systems that would be useful in improving our understanding of WASP-4 in particular and orbital decay in general.
Aero-resonant migration
Authors: Storch Natalia I , Batygin Konstantin
Published: September 2019

The process of planet conglomeration, which primarily unfolds in a geometrically thin disc of gas and dust, is often accompanied by dynamical excitation of the forming planets and planetesimals. The ensuing orbital crossing can lead to large-scale collisional fragmentation, populating the system with icy and rocky debris. In a gaseous nebula, such leftover solid matter tends to spiral down towards the host star due to aerodynamic drag. Along the way, the inward drifting debris can encounter planets and gravitationally couple to them via mean-motion resonances, sapping them of their orbital energy and causing them to migrate. Here, we develop a simple theory for this migration mechanism, which we call ‘aero-resonant migration’ (ARM), in which small planetesimals (10 m ≲ s ≲ 10 km) undergo orbital decay due to aerodynamic drag and resonantly shepherd planets ahead of them. Using a combination of analytical calculations and numerical experiments, we show that ARM is a robust migration mechanism, able to significantly transport planets on time-scales ≲1 Myr, and present simple formulae for the ARM rate.
Red and dead CANDELS: massive passive galaxies at the dawn of the Universe
Authors: Merlin E , Fortuni F , Torelli M , Santini P , Castellano M , Fontana A , Grazian A , Pentericci L , Pilo S , Schmidt K B
Published: September 2019

We search the five CANDELS fields (COSMOS, EGS, GOODS-North, GOODS-South, and UDS) for passively evolving a.k.a. ‘red and dead’ massive galaxies in the first 2 Gyr after the big bang, integrating and updating the work on GOODS-South presented in a previous paper. We perform SED-fitting on photometric data, with top-hat star-formation histories to model an early and abrupt quenching, and using a probabilistic approach to select only robust candidates. Using libraries without (with) spectral lines emission, starting from a total of more than 20 000 z > 3 sources we end up with 102 (40) candidates, including one at z = 6.7. This implies a minimal number density of 1.73 ± 0.17 × 10−5 (6.69 ± 1.08 × 10−6) Mpc−3 for 3 < z < 5; applying a correction factor to account for incompleteness yields 2.30 ± 0.20 × 10−5. We compare these values with those from five recent hydrodynamical cosmological simulations, finding a reasonable agreement at z < 4; tensions arise at earlier epochs. Finally, we use the star-formation histories from the best-fitting models to estimate the contribution of the high-redshift passive galaxies to the global star formation rate density during their phase of activity, finding that they account for ∼5–10 per cent of the total star formation at 3 < z < 8, despite being only $\sim 0.5{{\ \rm per\ cent}}$ of the total in number. The resulting picture is that early and strong star formation activity, building massive galaxies on short time-scales and followed by a quick and abrupt quenching, is a rare but crucial phenomenon in the early Universe: the evolution of the cosmos must be heavily influenced by the short but powerful activity of these pristine monsters.
The role of the H2 adiabatic index in the formation of the first stars
Authors: Sharda Piyush , Krumholz Mark R , Federrath Christoph
Published: September 2019

The adiabatic index of H$_2\,$ ($\gamma _{\mathrm{H_2}}$) is non-constant at temperatures between $100{\,\rm{and}\,}10^4\, \mathrm{K}$ due to the large energy spacing between its rotational and vibrational modes. For the formation of the first stars at redshifts 20 and above, this variation can be significant because primordial molecular clouds are in this temperature range due to the absence of efficient cooling by dust and metals. We study the possible importance of variations in $\gamma _{\mathrm{H_2}}$ for the primordial initial mass function by carrying out 80 3D gravitohydrodynamic simulations of collapsing clouds with different random turbulent velocity fields, half using fixed $\gamma _{\rm H_2} = 7/5$ in the limit of classical diatomic gas (used in earlier works) and half using an accurate quantum mechanical treatment of $\gamma _{\mathrm{H_2}}$. We use the adaptive mesh refinement code flash with the primordial chemistry network from KROME for this study. The simulation suite produces almost 400 stars, with masses from 0.02 to 50 M⊙ (mean mass ${\sim}10.5\, \mathrm{M_{\odot }}$ and mean multiplicity fraction ∼0.4). While the results of individual simulations do differ when we change our treatment of $\gamma _{\mathrm{H_2}}$, we find no statistically significant differences in the overall mass or multiplicity distributions of the stars formed in the two sets of runs. We conclude that, at least prior to the onset of radiation feedback, approximating H2 as a classical diatomic gas with $\gamma _{\rm H_2} = 7/5$ does not induce significant errors in simulations of the fragmentation of primordial gas. None the less, we recommend using the accurate formulation of the H$_2\,$ adiabatic index in primordial star formation studies since it is not computationally more expensive and provides a better treatment of the thermodynamics.
A toy model for the dynamical discrepancies on galactic scales
Authors: Petersen Jonas , Rosenlyst Martin
Published: September 2019

In this study a simple toy model solution to the missing gravity problem on galactic scales is reverse engineered from galactic data via imposing broad assumptions. It is shown that the toy model solution can be written in terms of baryonic quantities, is highly similar to pseudo-isothermal dark matter on galactic scales and can accommodate the same observations. In this way, the toy model solution is similar to MOND modified gravity in the Bekenstein–Milgrom formulation. However, it differs in the similarity to pseudo-isothermal dark matter and in the functional form. In loose terms, it is shown that pseudo-isothermal dark matter can be written in terms of baryonic quantities. The required form suggests that it may be worth looking into a mechanism that can increase the magnitude of the post-Newtonian correction from general relativity for low accelerations.
VTC J095517.5 + 690813: A radio transient from the accretion-induced collapse of a white dwarf?
Authors: Moriya Takashi J
Published: September 2019

I investigate the possibility that a recently reported radio transient in M81, VTC J095517.5 + 690813, was caused by the accretion-induced collapse of a white dwarf. It became bright in the radio, but no associated optical transient was discovered. An accretion-induced collapse is predicted to be radio-bright but optically faint, satisfying the observed properties. I compare the predicted radio emission from an accretion-induced collapse with that of VTC J095517.5 + 690813 and show that this object can be reasonably explained by an accretion-induced collapse. Although it is difficult to firmly conclude that VTC J095517.5 + 690813 is an accretion-induced collapse, my results show that radio-bright transients without an optical counterpart could be related to stellar deaths.
DNA polymerases in the risk and prognosis of colorectal and pancreatic cancers
Authors: Silvestri Roberto , Landi Stefano
Published: September 2019

Human cancers arise from the alteration of genes involved in important pathways that mainly affect cell growth and proliferation. DNA replication and DNA damages recognition and repair are among these pathways and DNA polymerases that take part in these processes are frequently involved in cancer onset and progression. For example, damaging alterations within the proofreading domain of replicative polymerases, often reported in patients affected by colorectal cancer (CRC), are considered risk factors and drivers of carcinogenesis as they can lead to the accumulation of several mutations throughout the genome. Thus, replicative polymerases can be involved in cancer when losses of their physiological functions occur. On the contrary, reparative polymerases are often involved in cancer precisely because of their physiological role. In fact, their ability to repair and bypass DNA damages, which confers genome stability, can also counteract the effect of most anticancer drugs. In addition, the altered expression can characterise some type of cancers, which exacerbates this aspect. For example, all of the DNA polymerases involved a damage bypass mechanism, known as translesion synthesis, with the only exception of polymerase theta, are downregulated in CRC. Conversely, in pancreatic ductal adenocarcinoma (PDAC), most of these polymerase result upregulated. This suggests that different types of cancer can rely on different reparative polymerases to acquire drug resistance. Here we will examine all of the aspects that link DNA polymerases with CRC and PDAC.
Synthetic metabolic computation in a bioluminescence-sensing system
Authors: Barger Natalia , Litovco Phyana , Li Ximing , Habib Mouna , Daniel Ramez
Published: September 2019

Bioluminescence is visible light produced and emitted by living cells using various biological systems (e.g. luxCDABE cassette). Today, this phenomenon is widely exploited in biological research, biotechnology and medical applications as a quantitative technique for the detection of biological signals. However, this technique has mostly been used to detect a single input only. In this work, we re-engineered the complex genetic structure of luxCDABE cassette to build a biological unit that can detect multi-inputs, process the cellular information and report the computation results. We first split the luxCDABE operon into several parts to create a genetic circuit that can compute a soft minimum in living cells. Then, we used the new design to implement an AND logic function with better performance as compared to AND logic functions based on protein-protein interactions. Furthermore, by controlling the reverse reaction of the luxCDABE cassette independently from the forward reaction, we built a comparator with a programmable detection threshold. Finally, we applied the redesigned cassette to build an incoherent feedforward loop that reduced the unwanted crosstalk between stress-responsive promoters (recA, katG). This work demonstrates the construction of genetic circuits that combine regulations of gene expression with metabolic pathways, for sensing and computing in living cells.
Single-molecule visualization of human BLM helicase as it acts upon double- and single-stranded DNA substrates
Authors: Xue Chaoyou , Daley James M , Xue Xiaoyu , Steinfeld Justin , Kwon Youngho , Sung Patrick , Greene Eric C
Published: September 2019

Bloom helicase (BLM) and its orthologs are essential for the maintenance of genome integrity. BLM defects represent the underlying cause of Bloom Syndrome, a rare genetic disorder that is marked by strong cancer predisposition. BLM deficient cells accumulate extensive chromosomal aberrations stemming from dysfunctions in homologous recombination (HR). BLM participates in several HR stages and helps dismantle potentially harmful HR intermediates. However, much remains to be learned about the molecular mechanisms of these BLM-mediated regulatory effects. Here, we use DNA curtains to directly visualize the activity of BLM helicase on single molecules of DNA. Our data show that BLM is a robust helicase capable of rapidly (∼70–80 base pairs per second) unwinding extensive tracts (∼8–10 kilobases) of double-stranded DNA (dsDNA). Importantly, we find no evidence for BLM activity on single-stranded DNA (ssDNA) that is bound by replication protein A (RPA). Likewise, our results show that BLM can neither associate with nor translocate on ssDNA that is bound by the recombinase protein RAD51. Moreover, our data reveal that the presence of RAD51 also blocks BLM translocation on dsDNA substrates. We discuss our findings within the context of potential regulator roles for BLM helicase during DNA replication and repair.
Electric cell-substrate impedance sensing in kidney research
Authors: Iwakura Takamasa , Marschner Julian A , Zhao Zhi Bo , Świderska Monika Katarzyna , Anders Hans-Joachim
Published: September 2019

Electric cell-substrate impedance sensing (ECIS) is a quantitative, label-free, non-invasive analytical method allowing continuous monitoring of the behaviour of adherent cells by online recording of transcellular impedance. ECIS offers a wide range of practical applications to study cell proliferation, migration, differentiation, toxicity and monolayer barrier integrity. All of these applications are relevant for basic kidney research, e.g. on endothelial cells, tubular and glomerular epithelial cells. This review gives an overview on the fundamental principles of the ECIS technology. We name strengths and remaining hurdles for practical applications, present an ECIS array reuse protocol, and review its past, present and potential future contributions to preclinical kidney research.
Hyperkalemia: pathophysiology, risk factors and consequences
Authors: Hunter Robert W , Bailey Matthew A
Published: September 2019

There have been significant recent advances in our understanding of the mechanisms that maintain potassium homoeostasis and the clinical consequences of hyperkalemia. In this article we discuss these advances within a concise review of the pathophysiology, risk factors and consequences of hyperkalemia. We highlight aspects that are of particular relevance for clinical practice. Hyperkalemia occurs when renal potassium excretion is limited by reductions in glomerular filtration rate, tubular flow, distal sodium delivery or the expression of aldosterone-sensitive ion transporters in the distal nephron. Accordingly, the major risk factors for hyperkalemia are renal failure, diabetes mellitus, adrenal disease and the use of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or potassium-sparing diuretics. Hyperkalemia is associated with an increased risk of death, and this is only in part explicable by hyperkalemia-induced cardiac arrhythmia. In addition to its well-established effects on cardiac excitability, hyperkalemia could also contribute to peripheral neuropathy and cause renal tubular acidosis. Hyperkalemia—or the fear of hyperkalemia—contributes to the underprescription of potentially beneficial medications, particularly in heart failure. The newer potassium binders could play a role in attempts to minimize reduced prescribing of renin–angiotensin inhibitors and mineraolocorticoid antagonists in this context.
The Obligation Dilemma
Authors: Haji Ishtiyaque
Published: September 2019

This book argues for the prima facie plausibility of the surprising and paradoxical conclusion that there are no moral obligations regardless of whether determinism is true. In the form of a dilemma, the primary argument for this skeptical conclusion presupposes that obligation requires freedom. A minimal number of credible principles entail that this is the freedom both to do, and to refrain from doing, what is obligatory. On the deterministic horn of the dilemma, since determinism eliminates freedom to do otherwise, it imperils moral obligation. On the indeterministic horn, pertinent actions are too luck-infected to qualify as obligations. Hence, there are no moral obligations. The book’s principal goal is to develop the obligation dilemma as powerfully and clearly as possible to inspire sustained philosophical work to solve it (assuming that it can be solved). In many respects, the obligation dilemma mirrors the venerable responsibility dilemma: regardless of whether determinism is true, no one is morally responsible for anything. The book shows that various prevalent moves in favor of, or in response to, the responsibility dilemma are, when suitably amended, not promising as supportive of, or retorts to, the obligation dilemma. Exposing the obligation dilemma’s implications for responsibility, and its ramifications for forgiveness (something central to salutary interpersonal relationships), underscores its urgency.
Unfreedom for All
Authors: Donahue Thomas J.
Published: September 2019

It is often said that we live in global systems of injustice. But if so, what are they, and what are their moral consequences? This book offers a theory of global injustice—“Unfreedom for All.” The theory explores and defends the old adage that “No one is free while others are oppressed” by putting five questions: Why and when ought we to combat injustices done to distant others, and does this require joining in solidarity against them? Do we live under global systems of injustice? What counts as systematic injustice or oppression? Who if anyone is made unfree by such injustices? What harms do they do? Unfreedom for All shows that the “No one is free” creed either answers or results from each of these questions. It defends that creed by considering how systematic injustices—such as global severe poverty, male supremacy, or racial oppression—are perpetuated. The book argues that where your society does such an injustice, it systematically suppresses anyone’s resistance to the injustice—including yours. It uses authoritarian tactics against everyone, so you too are subject to arbitrary power. Hence you too are unfree. This holds just as true of systematic injustices done by global society, and this should be the main reason for joining in solidarity against injustice.
The Diagnostics of Injustice
Authors: Donahue-Ochoa Thomas J.
Published: September 2019

Chapter 1 argues that careful diagnosis of injustices is central to understanding what to do about them. This requires differential diagnosis: the comparative assessment of different diagnoses of injustice. Yet present-day political theory treats such diagnostics as only a marginal task, even though past political theory considered it central. Chapter 1 undermines this marginalization, by tracing it to the tradition begun by John Rawls and its faulty practice of non-ideal theory. It argues that by the tradition’s own principles, non-ideal theory cannot succeed without such diagnostics. The chapter then recuperates such diagnostics by describing the leading theories of systematic injustice. These theories constitute the closest thing we have to a nosology (the classification of diseases) and pathology (the study of disease in general) of systematic injustice. If we wish to see political theory once again take seriously the differential diagnosis of injustices, then it will have to take these theories seriously.
Against the Received View
Authors: Donahue-Ochoa Thomas J.
Published: September 2019

Chapter 2 examines the view that prevails among the world’s liberal elites on the book’s questions. Specifically, it examines this received view’s theories of the nature of systematic injustice, whether there are global systematic injustices, and the duty to challenge injustice. The received view argues that oppression or systematic injustice is mainly a form of political subjugation of a group, done chiefly by the state. It argues that there are no global systematic injustices, because a systematic injustice can implicate only those people over whom some agency claims political authority, and no agency claims political authority over the whole globe. And it argues that when groups have duties to challenge injustice, this does not imply that their individual members do, and vice versa. As a result, the view has nothing to say about when individuals should join in solidarity against injustice. Ironically, the view thereby sets groups free: rather than Leviathans composed of atomistic individuals jealous of their liberties, groups become Gullivers released from the Lilliputians’ bonds. The chapter then argues that this results in dangerously unchecked groups and a shortfall of responsible agents.
Between Faith and State
Authors: Cavanaugh Kathleen A.
Published: September 2019

This chapter examines the politics of law that are mapped out in the various trends of analysis within both Islamic and international law. Disrupting the notion of a "fixedness" in these legal discourses and reimagining each in their political self is a critical first step in addressing the challenge--one that preoccupies much of the literature that looks at Islam and rights--as to how to open a space in the human rights project where faith and reason can be accommodated. In undertaking this task, the chapter discusses how the human rights project engages with religion in the public sphere before turning to how these concepts have been engaged where Islam and human rights intersect generally, and then specifically when applied to states in the Middle East. The second part of the chapter focuses on the plural readings of Islamic formulations of law and details the trends of analysis within political transformations that have unfolded (and continue to unfold) across the MENA region in the wake of the so-called Arab Spring.
Lies, Fairytales, and Fallacies
Authors: Carter Niambi Michele
Published: September 2019

This chapter introduces the key ideas animating the text. The twin issues of race and nationhood remain a significant part of the conversation regarding black political incorporation and are rendered most visible in the domain of immigration. Blacks have a different perspective of America that is grounded in their peculiar history and experiences with the country and its institutions. The chapter begins by putting forward the major theoretical underpinnings of existing works in black public opinion. In particular, it focuses on the work on interminority relations and lays out the critical interventions of this text. Chapter outlines and a roadmap to the rest of the text are provided.
The Responsibility of States
Authors: Powers Madison
Published: September 2019

This chapter explores the rationale for the special responsibility of nation-states to secure human rights and structural justice. It explains what makes states unique moral agents, in particular their responsibility to address structurally unjust conditions that give rise to human rights violations within their borders. However, it rejects prominent arguments for the conclusion that states have only a preventive and remedial role in the presence of domestic structural unfairness and human rights violations. The chapter defends the Principle of Interstate Reciprocity, which sets moral limits on the pursuit of national benefit, global advantage, and the exercise of power over others, and it concludes with an account of four unfair forms of control exercised by various supranational institutions, often in combination with powerful states and other non-state institutional agents.
The Central Asian States
Authors: Graney Katherine
Published: September 2019

This chapter argues that with the partial exception of Kazakhstan, by mutual agreement, both European gatekeepers and actors in the Central Asian republics of the former Soviet Union have decided that these states are not in any meaningful way part of Europe, and that no aspect of Europeanization (political, security, or cultural-civilizational) is appropriate for them. Kazakhstan has made some effort to position itself as a “truly Eurasian” state that is a bridge between Europe and Asia but is firmly tied to Russia’s Euro-alternative institutions. None of the other Central Asian states has shown any interest in identifying as European in any way. The chapter explores the various forms of political authoritarianism, security strategy, and national identity that the five Central Asian states (Kazakhstan, Kyrgyzstan, Uzbekistan, Tajikistan, and Turkmenistan) have pursued instead of a policy of Europeanization. In the absence of a real European presence, Russia’s and China’s roles and ambitions in the region are also discussed.
The Harmonic Hero’s Journey
Authors: Sloan Nate , Harding Charlie , Gottlieb Iris
Published: September 2019

Chapter 3 discusses harmony, the musical element that gives color to a melody but can also form a melody of its own when laid out in a chord progression. Certain progressions are so effective that they become evergreen, as is the case with the four-chord cycle that undergirds “We Are Young” by Fun. Known as “ice cream changes” it has been a staple of pop music since the 1920s. Almost a century on, its power remains undiminished, each chord sounding another step on an epic harmonic journey, a quality perfect for Fun’s anthem of youthful nostalgia.
Northern Kenya
Authors: Cox Fletcher D.
Published: September 2019

Chapter 4 presents a critical microlevel case study of civil action in an underanalyzed conflict in Northern Kenya—the Samburu-Turkana Range War. Evidence from the case indicates that civil and uncivil actions co-evolve and coexist. Community-based organizations (CBOs) and traditional authorities effectively use civic action to interrupt violence escalation. At the same time, civic action does not fully eliminate violence, but rather changes the qualities of it. Civil action provides platforms for the coordination of inter- and intragroup relationships, which helps to dampen the frequency of violence and the speed of escalation but also raises the cost of violence. It allows local armed groups to become better armed, better organized, and more capable of accessing detailed, covert information through local relational networks. Violence occurs less often and escalates less rapidly, but when it does occur, it is deadlier. Under conditions of state fragility, civil action plays an unintentional role in increasing militia mobilization and prolonging protracted conflict.
Civil Action against ETA Terrorism in Basque Country
Authors: Argomaniz Javier
Published: September 2019

This study presented in this chapter explores how local and regional authorities, peace organizations, civic groups, and victims’ associations challenged and ultimately delegitimized political violence in Basque country since the 1980s. The chapter demonstrates that civil action, though it was not the only factor in the demise of the armed separatist organization Euskadi Ta Askatasuna (ETA), was an engine for political transformation and helped to precipitate an end to the violence by undermining the support for ETA in Basque society. The Basque case holds a number of relevant insights that could be applied to other contexts, including the importance of discursive and normative changes in public attitudes and collective action against terrorism in democratic societies.
The Colombian Private Sector in Colombia’s Transition to Peace
Authors: Rettberg Angelika
Published: September 2019

During the Colombian civil war, businesses undertook both civil and uncivil actions, but the civil action of a “pro-peace coalition” was among the many factors moving the conflict toward its (uneasy) settlement in 2016. This chapter documents the civil action efforts of a pro-peace coalition, explores how support for these efforts changed over time—particularly in the last two attempts to negotiate peace, in Caguán (1998–2002) and in Havana, Cuba (2012–2016), and focuses on the motivations behind them. Contrary to simplistic analyses, it demonstrates that the profit motive alone cannot explain business strategies in contexts of conflict and peacebuilding. Contextual factors, the type of organization, and access to politics are important in understanding how business factions respond to armed conflict, including those participating in civil action within the “pro-peace coalition” and those aligning themselves with armed actors. The explanation of Colombian business strategies to address armed conflict holds lessons for understanding business-led civil action in other countries.
Conclusion
Authors: Avant Deborah , Chenoweth Erica , Epstein Rachel , Hendrix Cullen
Published: September 2019

This chapter synthesizes what we have learned from our case studies about civil action and how it intersects with various ongoing concerns in the field. It begins by offering a series of propositions and questions to prompt further research on civil action, its causes, and its effects. It then turns to examine how the book’s analysis intersects with ongoing debates. The final section ponders the relevance of civil action in less violent situations, how the growing importance of connections through social media might shape its likelihood and effect, and whether civil action can be a tool for advancing exclusionary goals.
Obsessive-Compulsive Disorder
Authors: Summers Jesse S. , Sinnott-Armstrong Walter
Published: September 2019

Scrupulosity dates back millennia and is widely reported in Catholic and Protestant traditions over the last half-century. This chapter looks more generally at obsessive-compulsive disorder (OCD). OCD is characterized by obsessions and compulsions. Obsessions are recurrent and persistent, intrusive and unwanted, unjustified, and anxiety-evoking. Also, OCD needs to be distinguished from a different condition with a similar name: obsessive-compulsive personality disorder (OCPD). Whereas OCD is an anxiety disorder, OCPD is a personality disorder, that is, a disorder in those stable traits that make up one’s personality. The chapter addresses difficulties in determining whether obsessions are beliefs: normal tests of beliefs fail in the case of OCD and Scrupulosity. It next considers compulsions, repetitive behaviors performed in response to obsessions that aim to prevent or reduce anxiety or distress.
Treatment
Authors: Summers Jesse S. , Sinnott-Armstrong Walter
Published: September 2019

We are sometimes justified in encouraging, pressuring, or requiring those with Scrupulosity to seek treatment, even if they object on moral grounds. The justification for treating OCD does not apply to Scrupulosity. Possible justifications for treatment over moral objection are harm to self or others, distress, future gratitude, community treatment standards, and internal incoherence of one’s beliefs due to arbitrariness, conflation, or fixation. All of these justifications avoid explicit appeals to the therapist’s own moral standards. Some forms of treatment raise no distinctive moral issues, but some raise ethical issues because they require the person to do things the person considers immoral. This can be alleviated in part by good communication with the therapist about the point of such treatment.