bluuebunny/crossref_metadata_2025_split huggingface dataset:
SC5005 dissipates the membrane potential to kill Staphylococcus aureus persisters without detectable resistance
Authors: Lu Chieh-Hsien , Shiau Chung-Wai , Chang Yung-Chi , Kung Hsiu-Ni , Wu Jui-Ching , Lim Chui-Hian , Yeo Hui-Hui , Chang Han-Chu , Chien Han-Sheng , Huang Sheng-Hsuan , Hung Wei-Kang , Wei Jun-Rong , Chiu Hao-Chieh 
Published: March 2021

Abstract

Objectives
In the past few decades, multiple-antibiotic-resistant Staphylococcus aureus has emerged and quickly spread in hospitals and communities worldwide. Additionally, the formation of antibiotic-tolerant persisters and biofilms further reduces treatment efficacy. Previously, we identified a sorafenib derivative, SC5005, with bactericidal activity against MRSA in vitro and in vivo. Here, we sought to elucidate the resistance status, mode of action and anti-persister activity of this compound.

Methods
The propensity of S. aureus to develop SC5005 resistance was evaluated by assessment of spontaneous resistance and by multi-passage selection. The mode of action of SC5005 was investigated using macromolecular synthesis, LIVE/DEAD and ATPlite assays and DiOC2(3) staining. The effect of SC5005 on the mammalian cytoplasmic membrane was measured using haemolytic and lactate dehydrogenase (LDH) assays and flow cytometry.

Results
SC5005 depolarized and permeabilized the bacterial cytoplasmic membrane, leading to reduced ATP production. Because of this mode of action, no resistance of S. aureus to SC5005 was observed after constant exposure to sub-lethal concentrations for 200 passages. The membrane-perturbing activity of SC5005 was specific to bacteria, as no significant haemolysis or release of LDH from human HT-29 cells was detected. Additionally, compared with other bactericidal antibiotics, SC5005 exhibited superior activity in eradicating both planktonic and biofilm-embedded S. aureus persisters.

Conclusions
Because of its low propensity for resistance development and potent persister-eradicating activity, SC5005 is a promising lead compound for developing new therapies for biofilm-related infections caused by S. aureus.
Energy and the TRIMs and GATS agreements
Authors: Zedalis Rex J 
Published: March 2021

Abstract
The international energy sector has always involved a wide range of activities, with energy mineral extraction residing at its core. Technological advancements and job specialisation have resulted in segmentation within the industry as traditionally conceived. With sensitivity to the relationship between energy use and climate change, the growth of interest in renewable energy sources have further contributed to segmentation within the industry. Thus, when writ large, the international energy sector has become increasingly subject to certain WTO rules governing trade-related investment measures and generally agreed rules governing trade in services, Central obligations found in these rules are examined in this commentary and analysed in the context of three hypothetical situations, all with an eye towards an increasing understanding of what relevant countries hosting efforts by the international energy sector may and may not do to affect the sector.
Artificial selection for grain yield has increased net CO2 exchange of the ear leaf in maize crops
Authors: Cagnola Juan I , Parco Martín , Rotili Diego H , Ploschuk Edmundo L , Curin Facundo , Amas Juan I , Luque Sergio F , Maddonni Gustavo A , Otegui María E , Casal Jorge J 
Published: March 2021

Abstract
Identifying the physiological traits indirectly selected during the search for high-yielding maize hybrids is useful for guiding further improvements. To investigate such traits, in this study we focused on the critical period of kernel formation because kernel number is the main yield component affected by breeding. Our results show that breeding has increased the number of florets per ear and ear growth rate but not the vegetative shoot growth rate, suggesting localised effects around the ear. Consistent with this possibility, breeding has increased the net CO2 exchange of the ear leaf in field-grown crops grown at high population densities. This response is largely accounted for by increased light interception (which increases photosynthesis) and by reduced rates of respiration of the ear leaf in modern hybrids compared to older ones. Modern hybrids show increased ear-leaf area per unit leaf dry matter (specific leaf area), which accounts for the reduced respiratory load per unit leaf area. These observations are consistent with a model where the improved ear leaf CO2 exchange helps the additional florets produced by modern hybrids to survive the critical period of high susceptibility to stress and hence to produce kernels.
Adjusting plant nutrient acquisition to fluctuating availability: transcriptional co-regulation of the nitrate and phosphate deprivation responses in roots
Authors: Ludewig Uwe , Vatov Emil , Hedderich Dominik , Neuhäuser Benjamin 
Published: March 2021

This article comments on:
Safi A, Medici A, Szponarski W, Martin F, Clement-Vidal A, Marshall-Colon A, Ruffel S, Gaymard F, Rouached H, Leclercq J, Coruzzi G, Lacombe B, Krouk G. 2021. GARP transcription factors repress Arabidopsis nitrogen starvation response via ROS-dependent and -independent pathways. Journal of Experimental Botany 72, 3881–3901.
Phosphorolytic degradation of leaf starch via plastidic α-glucan phosphorylase leads to optimized plant growth and water use efficiency over the diel phases of Crassulacean acid metabolism
Authors: Ceusters Nathalie , Ceusters Johan , Hurtado-Castano Natalia , Dever Louisa V , Boxall Susanna F , Kneřová Jana , Waller Jade L , Rodick Rebecca , Van den Ende Wim , Hartwell James , Borland Anne M 
Published: March 2021

Abstract
In plants with Crassulacean acid metabolism (CAM), it has been proposed that the requirement for nocturnal provision of phosphoenolpyruvate as a substrate for CO2 uptake has resulted in a re-routing of chloroplastic starch degradation from the amylolytic route to the phosphorolytic route. To test this hypothesis, we generated and characterized four independent RNAi lines of the obligate CAM species Kalanchoë fedtschenkoi with a &gt;10-fold reduction in transcript abundance of plastidic α-glucan phosphorylase (PHS1). The rPHS1 lines showed diminished nocturnal starch degradation, reduced dark CO2 uptake, a reduction in diel water use efficiency (WUE), and an overall reduction in growth. A re-routing of starch degradation via the hydrolytic/amylolytic pathway was indicated by hyperaccumulation of maltose in all rPHS1 lines. Further examination indicated that whilst operation of the core circadian clock was not compromised, plasticity in modulating net dark CO2 uptake in response to changing photoperiods was curtailed. The data show that phosphorolytic starch degradation is critical for efficient operation of the CAM cycle and for optimizing WUE. This finding has clear relevance for ongoing efforts to engineer CAM into non-CAM species as a means of boosting crop WUE for a warmer, drier future.
Constraints on wide-band radiative changes after a glitch in PSR J1452–6036
Authors: Jankowski F , Keane E F , Stappers B W 
Published: March 2021

ABSTRACT
We present high-sensitivity, wide-band observations (704–4032 MHz) of the young to middle-aged radio pulsar J1452–6036, taken at multiple epochs before and, serendipitously, shortly after a glitch occurred on 2019 April 27. We obtained the data using the new ultra-wide-bandwidth low-frequency (UWL) receiver at the Parkes radio telescope, and we used Markov chain Monte Carlo techniques to estimate the glitch parameters robustly. The data from our third observing session began 3 h after the best-fitting glitch epoch, which we constrained to within ∼4 min. The glitch was of intermediate size, with a fractional change in spin frequency of 270.52(3) × 10−9. We measured no significant change in spin-down rate and found no evidence for rapidly decaying glitch components. We systematically investigated whether the glitch affected any radiative parameters of the pulsar and found that its spectral index, spectral shape, polarization fractions, and rotation measure stayed constant within the uncertainties across the glitch epoch. However, its pulse-averaged flux density increased significantly by about 10 per cent in the post-glitch epoch and decayed slightly before our fourth observation a day later. We show that the increase was unlikely caused by calibration issues. While we cannot exclude that it was due to refractive interstellar scintillation, it is hard to reconcile with refractive effects. The chance coincidence probability of the flux density increase and the glitch event is low. Finally, we present the evolution of the pulsar’s pulse profile across the band. The morphology of its polarimetric pulse profile stayed unaffected to a precision of better than 2 per cent.
Exploring a Local Genetic Interaction Network Using Evolutionary Replay Experiments
Authors: Vignogna Ryan C , Buskirk Sean W , Lang Gregory I 
Published: March 2021

Abstract
Understanding how genes interact is a central challenge in biology. Experimental evolution provides a useful, but underutilized, tool for identifying genetic interactions, particularly those that involve non-loss-of-function mutations or mutations in essential genes. We previously identified a strong positive genetic interaction between specific mutations in KEL1 (P344T) and HSL7 (A695fs) that arose in an experimentally evolved Saccharomyces cerevisiae population. Because this genetic interaction is not phenocopied by gene deletion, it was previously unknown. Using “evolutionary replay” experiments, we identified additional mutations that have positive genetic interactions with the kel1-P344T mutation. We replayed the evolution of this population 672 times from six timepoints. We identified 30 populations where the kel1-P344T mutation reached high frequency. We performed whole-genome sequencing on these populations to identify genes in which mutations arose specifically in the kel1-P344T background. We reconstructed mutations in the ancestral and kel1-P344T backgrounds to validate positive genetic interactions. We identify several genetic interactors with KEL1, we validate these interactions by reconstruction experiments, and we show these interactions are not recapitulated by loss-of-function mutations. Our results demonstrate the power of experimental evolution to identify genetic interactions that are positive, allele specific, and not readily detected by other methods, shedding light on an underexplored region of the yeast genetic interaction network.
DNA molecular combing-based replication fork directionality profiling
Authors: Blin Marion , Lacroix Laurent , Petryk Nataliya , Jaszczyszyn Yan , Chen Chun-Long , Hyrien Olivier , Le Tallec Benoît 
Published: March 2021

AbstractThe replication strategy of metazoan genomes is still unclear, mainly because definitive maps of replication origins are missing. High-throughput methods are based on population average and thus may exclusively identify efficient initiation sites, whereas inefficient origins go undetected. Single-molecule analyses of specific loci can detect both common and rare initiation events along the targeted regions. However, these usually concentrate on positioning individual events, which only gives an overview of the replication dynamics. Here, we computed the replication fork directionality (RFD) profiles of two large genes in different transcriptional states in chicken DT40 cells, namely untranscribed and transcribed DMD and CCSER1 expressed at WT levels or overexpressed, by aggregating hundreds of oriented replication tracks detected on individual DNA fibres stretched by molecular combing. These profiles reconstituted RFD domains composed of zones of initiation flanking a zone of termination originally observed in mammalian genomes and were highly consistent with independent population-averaging profiles generated by Okazaki fragment sequencing. Importantly, we demonstrate that inefficient origins do not appear as detectable RFD shifts, explaining why dispersed initiation has remained invisible to population-based assays. Our method can both generate quantitative profiles and identify discrete events, thereby constituting a comprehensive approach to study metazoan genome replication.
Randomized multi-reader evaluation of automated detection and segmentation of brain tumors in stereotactic radiosurgery with deep neural networks
Authors: Lu Shao-Lun , Xiao Fu-Ren , Cheng Jason Chia-Hsien , Yang Wen-Chi , Cheng Yueh-Hung , Chang Yu-Cheng , Lin Jhih-Yuan , Liang Chih-Hung , Lu Jen-Tang , Chen Ya-Fang , Hsu Feng-Ming 
Published: March 2021

Abstract

Background
Stereotactic radiosurgery (SRS), a validated treatment for brain tumors, requires accurate tumor contouring. This manual segmentation process is time-consuming and prone to substantial inter-practitioner variability. Artificial intelligence (AI) with deep neural networks have increasingly been proposed for use in lesion detection and segmentation but have seldom been validated in a clinical setting.

Methods
We conducted a randomized, cross-modal, multi-reader, multispecialty, multi-case study to evaluate the impact of AI assistance on brain tumor SRS. A state-of-the-art auto-contouring algorithm built on multi-modality imaging and ensemble neural networks was integrated into the clinical workflow. Nine medical professionals contoured the same case series in two reader modes (assisted or unassisted) with a memory washout period of 6 weeks between each section. The case series consisted of 10 algorithm-unseen cases, including five cases of brain metastases, three of meningiomas, and two of acoustic neuromas. Among the nine readers, three experienced experts determined the ground truths of tumor contours.

Results
With the AI assistance, the inter-reader agreement significantly increased (Dice similarity coefficient [DSC] from 0.86 to 0.90, P &lt; 0.001). Algorithm-assisted physicians demonstrated a higher sensitivity for lesion detection than unassisted physicians (91.3% vs 82.6%, P = .030). AI assistance improved contouring accuracy, with an average increase in DSC of 0.028, especially for physicians with less SRS experience (average DSC from 0.847 to 0.865, P = .002). In addition, AI assistance improved efficiency with a median of 30.8% time-saving. Less-experienced clinicians gained prominent improvement on contouring accuracy but less benefit in reduction of working hours. By contrast, SRS specialists had a relatively minor advantage in DSC, but greater time-saving with the aid of AI.

Conclusions
Deep learning neural networks can be optimally utilized to improve accuracy and efﬁciency for the clinical workflow in brain tumor SRS.
Adverse Events in Neurosurgery: The Novel Therapy-Disability-Neurology Grade
Authors: Terrapon Alexis Paul Romain , Zattra Costanza Maria , Voglis Stefanos , Velz Julia , Vasella Flavio , Akeret Kevin , Held Ulrike , Schiavolin Silvia , Bozinov Oliver , Ferroli Paolo , Broggi Morgan , Sarnthein Johannes , Regli Luca , Neidert Marian Christoph 
Published: March 2021

Abstract

BACKGROUND
The most widely used classifications of adverse events (AEs) in neurosurgery define their severity according to the therapy used to treat them. This concept has substantial shortcomings because it does not reflect the severity of AEs that are not treated, such as new neurological deficits.

OBJECTIVE
To present a novel multidimensional and patient-centered classification of the severity of AE in neurosurgery and evaluate its applicability.

METHODS
The Therapy-Disability-Neurology (TDN) grading system classifies AEs depending on the associated therapy, disability, and neurological deficits. We conducted a 2-center retrospective observational study on 6071 interventions covering the whole neurosurgical spectrum with data prospectively recorded between 2013 and 2019 at 2 institutions from 2 countries.

RESULTS
Using the first patient cohort (4680 interventions), a positive correlation was found between severity of AE and LOS as well as treatment cost. Each grade was associated with a greater deterioration of the Karnofsky Performance Status Scale (KPS) at discharge and at follow-up. When using the same methods on the external validation cohort (1391 interventions), correlations between the grades of AE, LOS, and KPS at discharge were even more pronounced.

CONCLUSION
Our results suggest that the TDN grade is consistent with clinical and economic repercussions of AE and thus reflects AE severity. It is easily interpreted and enables comparison between different medical centers. The standardized report of the severity of AE in the scientific literature could constitute an important step forward toward a more critical, patient-centered, and evidence-based decision-making in neurosurgery.
Making Milton’s Bogey
Authors: Dodds Lara 
Published: March 2021

Abstract
In The Madwoman in the Attic: The Woman Writer and the Nineteenth-Century Literary Imagination (1979), Gilbert and Gubar posit Milton and Paradise Lost as a ‘bogey’ for women writers. Wittreich’s Feminist Milton (1987) suggests an alternative reception history in which Milton’s poetry provided the basis for a more inclusive literary canon. This chapter re-examines the question of the relationship between Milton’s poetry, primarily Paradise Lost, and women’s literary history through a case study of the poetry of Anne Finch, Countess of Winchilsea (1661–1720). Though Finch acknowledges Milton’s influence explicitly in her blank-verse pastoral ‘Fanscomb Barn’, implicit debts are present throughout Finch’s 1713 Miscellany Poems and the fair-copy manuscript compilation ‘Miscellany Poems with Two Plays by Ardelia’ (1691–1701). The very different status of Milton and his verse in these two contexts illustrates the conflicted legacy of Paradise Lost for women’s literary history.
Clinical use of Jak 1 inhibitors for rheumatoid arthritis
Authors: Nash Peter 
Published: March 2021

Abstract
The uptake of Jak inhibitors in the RA space has been among the most rapid in rheumatology, based on the results of comprehensive clinical trial programmes of five agents. Newer generations of Jak inhibitors, like upadacitinib and filgotinib, target Jak 1 selectively with the aim of maximizing efficacy and to improve safety. This article will review the clinical significance of evidence on: (i) Jak 1 selectivity; (ii) efficacy from the SELECT and FINCH clinical trial programmes including patient intolerant or inadequately responding to MTX (MTX-IR) and other csDMARDs patients who are bDMARD-IR) and those using monotherapy when MTX is not tolerated or contraindicated and those treated when methotrexate naive; and (iii) safety from the clinical trial programmes of these two agents will be discussed.
How Heads of Departments Find It Meaningful to Engage with Gender Balance Policies
Authors: Lagesen Vivian Anette 
Published: March 2021

Abstract
This article investigates how heads of department (HoDs) understand and implement gender balance policies in Norway, considered to be among the most gender-equal countries in the world. Previous studies have found that HoDs often resist enacting gender equality policies. This interview-based study provides a more optimistic and nuanced picture. Employing domestication theory and narrative analysis, this study shows that HoDs understand gender balance as an important goal and responsibility in principle. However, to actively engage with implementation, HoDs needed to see how improving gender balance would benefit their departments and help reach other goals. This sense-making was pivotal for motivation to enact measures and change their practices. The article brings new knowledge on how HoDs may work to improve the gender balance among faculty and generates deeper insight into the critical co-production of sense-making and enactment of practices related to improving gender balance.
‘A British Problem Affecting British People’: Sickle Cell Anaemia, Medical Activism and Race in the National Health Service, 1975–1993
Authors: Redhead Grace 
Published: March 2021

Abstract
Recent historiography has explored a contradiction at the heart of the British welfare state—it was founded on and supported by migrant and non-white labour, whose own healthcare and broader welfare state entitlements were neglected. This article explores how this contradiction was exposed and challenged by some of the health service’s own workforce, who witnessed and contested racism in the National Health Service (NHS). This is discussed through the lens of the treatment of sickle cell anaemia (SCA), a genetic trait and disease more common in people of African, South Asian, Middle Eastern and Mediterranean descent, which has been highly racialized as affecting black people in particular. By pushing for improved responses to pain in sickle cell disease, and demonstrating the need for SCA screening in urban areas, healthcare professionals within the NHS—many of whom were black or migrant nurses, health visitors or doctors—articulated the status and entitlements of Black British citizenship.
Investigation Into the Role of ERK in Tyrosine Kinase Inhibitor-Induced Neuropathy
Authors: Belair David G , Sudak Katelyn , Connelly Kimberly , Collins Nathaniel D , Kopytek Stephan J , Kolaja Kyle L 
Published: March 2021

Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating adverse event that can alter patient treatment options and halt candidate drug development. A case study is presented here describing the preclinical and clinical development of CC-90003, a small molecule extracellular signal-regulated kinase (ERK)1/2 inhibitor investigated as an oncology therapy. In a Phase Ia clinical trial, CC-90003 elicited adverse drug-related neuropathy and neurotoxicity that contributed to discontinued development of CC-90003 for oncology therapy. Preclinical evaluation of CC-90003 in dogs revealed clinical signs and electrophysiological changes consistent with peripheral neuropathy that was reversible. Mice did not exhibit signs of neuropathy upon daily dosing with CC-90003, supporting that rodents generally poorly predict CIPN. We sought to investigate the mechanism of CC-90003-induced peripheral neuropathy using a phenotypic in vitro assay. Translating preclinical neuropathy findings to humans proves challenging as no robust in vitro models of CIPN exist. An approach was taken to examine the influence of CIPN-associated drugs on human-induced pluripotent stem cell-derived peripheral neuron (hiPSC-PN) electrophysiology on multielectrode arrays (MEAs). The MEA assay with hiPSC-PNs was sensitive to CIPN-associated drugs cisplatin, sunitinib, colchicine, and importantly, to CC-90003 in concordance with clinical neuropathy incidence. Biochemical data together with in vitro MEA data for CC-90003 and 12 of its structural analogs, all having similar ERK inhibitory activity, revealed that CC-90003 disrupted in vitro neuronal electrophysiology likely via on-target ERK inhibition combined with off-target kinase inhibition and translocator protein inhibition. This approach could prove useful for assessing CIPN risk and interrogating mechanisms of drug-induced neuropathy.