bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipid-targeting pleckstrin homology domain turns its autoinhibitory face toward the TEC kinases
Authors: Amatya Neha , Wales Thomas E. , Kwon Annie , Yeung Wayland , Joseph Raji E. , Fulton D. Bruce , Kannan Natarajan , Engen John R. , Andreotti Amy H.
Published: October 2019

Significance

Bruton’s tyrosine kinase (BTK) is targeted in treatment of immune cancers. As patients experience drug resistance, there is a need for alternative approaches to inhibit BTK. Other recently published findings clarify the role of the BTK pleckstrin homology (PH) domain in mediating activation via dimerization and sensing of ligand concentration at the membrane. Work presented here provides insight into the autoinhibitory BTK structure that has so far been elusive via crystallographic methods. In the resting state, the BTK PH domain binds to the activation loop face of the kinase domain and allosterically alters key sites within the kinase domain. The findings define a new regulatory site, the PH/kinase interface, that can be exploited in drug discovery efforts.
Evidence for sharp increase in the economic damages of extreme natural disasters
Authors: Coronese Matteo , Lamperti Francesco , Keller Klaus , Chiaromonte Francesca , Roventini Andrea
Published: October 2019

Climate change has increased the frequency and intensity of natural disasters. Does this translate into increased economic damages? To date, empirical assessments of damage trends have been inconclusive. Our study demonstrates a temporal increase in extreme damages, after controlling for a number of factors. We analyze event-level data using quantile regressions to capture patterns in the damage distribution (not just its mean) and find strong evidence of progressive rightward skewing and tail-fattening over time. While the effect of time on averages is hard to detect, effects on extreme damages are large, statistically significant, and growing with increasing percentiles. Our results are consistent with an upwardly curved, convex damage function, which is commonly assumed in climate-economics models. They are also robust to different specifications of control variables and time range considered and indicate that the risk of extreme damages has increased more in temperate areas than in tropical ones. We use simulations to show that underreporting bias in the data does not weaken our inferences; in fact, it may make them overly conservative.
Creating a neuroprosthesis for active tactile exploration of textures
Authors: O’Doherty Joseph E. , Shokur Solaiman , Medina Leonel E. , Lebedev Mikhail A. , Nicolelis Miguel A. L.
Published: October 2019

Significance

Sensory neuroprostheses offer the promise of restoring perceptual function to people with impaired sensation. Here, we developed a paradigm using intracortical microstimulation (ICMS) for encoding the sensation of fingertip motion against texture. Monkeys learned to interpret time-varying ICMS patterns, evoked by the interplay of their voluntary movements and specific object textures, and discriminated texture coarseness relying solely on these pulse trains. As such, variations in exploration strategy directly affected the timing of individual stimulation pulses. Crucially, this encoding enabled real-time active exploration of textures. We propose that this approach could equip upper-limb neuroprostheses with functional access to texture features acquired during active exploration of natural objects.
Directing differentiation of human induced pluripotent stem cells toward androgen-producing Leydig cells rather than adrenal cells
Authors: Li Lu , Li Yuchang , Sottas Chantal , Culty Martine , Fan Jinjiang , Hu Yiman , Cheung Garett , Chemes Héctor E. , Papadopoulos Vassilios
Published: October 2019

Significance

Our results suggest that both androgen- and cortisol-producing human Leydig and adrenal cells can be induced from human induced pluripotent stem cells. This bidirectional approach offers insights into the events specifying different steroidogenic cell populations sharing developmental origins. More importantly, our study provides a way to generate possible transplantation materials for clinical therapies. Human Leydig-like cells could also be useful for in vitro studies of testicular development and pathologies of testis-relevant diseases, and for the discovery of new drugs inducing androgen formation for hypogonadism treatment.
Civilian public sector employment as a long-run outcome of military conscription
Authors: Johnson Tim , Conley Dalton
Published: October 2019

Since at least T. H. Marshall, scholars have recognized military service as a form of sacrifice that warrants compensation from the state. War-widow pensions, expansion of the franchise, and subsidized higher education are all examples of rights and benefits “bestowed” in return for wartime mobilization. Similarly, in the United States, governments have hired veterans preferentially for civilian public jobs as recompense for active military service. Although oft overlooked, those policies seem influential: the percentage of job holders identifying as veterans in the civilian US executive branch exceeds the proportion in the wider population by several multiples. This century-old pattern suggests another way that wartime mobilization has influenced the state. Yet, efforts to understand it have struggled to rule out the possibility that those who serve in the armed forces are predisposed to work for the state in both military and civilian capacities. Here, we rule out this possibility by examining whether birthdates randomly called for induction in the Vietnam-Era Selective Service Lotteries (VSSL) appear disproportionately in the population of nonsensitive personnel records of the civilian US executive branch. We find that birthdates called for induction appear with unusually high frequency among employees who were draft eligible and at risk for induction but not among other employees. This finding suggests a treatment effect from military service, thus dovetailing with the hypothesis that wartime mobilization has substantially and continually influenced who works in the contemporary administrative state.
GDGT cyclization proteins identify the dominant archaeal sources of tetraether lipids in the ocean
Authors: Zeng Zhirui , Liu Xiao-Lei , Farley Kristen R. , Wei Jeremy H. , Metcalf William W. , Summons Roger E. , Welander Paula V.
Published: October 2019

Significance

Archaea synthesize distinctive membrane-spanning lipids (GDGTs) that are readily preserved in ancient sediments and utilized as paleotemperature proxies to reconstruct sea surface temperatures deep in Earth’s past. However, properly interpreting GDGT-based biomarker proxies requires an accurate assessment of the archaea that contribute to GDGT pools in modern environments and of the proteins necessary for synthesizing GDGTs. In this study, we identify 2 radical SAM proteins inSulfolobus acidocaldariusthat are required to produce these molecules. Bioinformatics analyses of these GDGT ring synthesis proteins reveal that Thaumarchaeota are the dominant source of cyclized GDGTs in the open ocean, allowing us to constrain one factor of uncertainty in the application of GDGT-based paleotemperature proxies.
A novel chlorophyll protein complex in the repair cycle of photosystem II
Authors: Weisz Daniel A. , Johnson Virginia M. , Niedzwiedzki Dariusz M. , Shinn Min Kyung , Liu Haijun , Klitzke Clécio F. , Gross Michael L. , Blankenship Robert E. , Lohman Timothy M. , Pakrasi Himadri B.
Published: October 2019

In oxygenic photosynthetic organisms, photosystem II (PSII) is a unique membrane protein complex that catalyzes light-driven oxidation of water. PSII undergoes frequent damage due to its demanding photochemistry. It must undergo a repair and reassembly process following photodamage, many facets of which remain unknown. We have discovered a PSII subcomplex that lacks 5 key PSII core reaction center polypeptides: D1, D2, PsbE, PsbF, and PsbI. This pigment–protein complex does contain the PSII core antenna proteins CP47 and CP43, as well as most of their associated low molecular mass subunits, and the assembly factor Psb27. Immunoblotting, mass spectrometry, and ultrafast spectroscopic results support the absence of a functional reaction center in this complex, which we call the “no reaction center” complex (NRC). Analytical ultracentrifugation and clear native PAGE analysis show that NRC is a stable pigment–protein complex and not a mixture of free CP47 and CP43 proteins. NRC appears in higher abundance in cells exposed to high light and impaired protein synthesis, and genetic deletion of PsbO on the PSII luminal side results in an increased NRC population, indicative that NRC forms in response to photodamage as part of the PSII repair process. Our finding challenges the current model of the PSII repair cycle and implies an alternative PSII repair strategy. Formation of this complex may maximize PSII repair economy by preserving intact PSII core antennas in a single complex available for PSII reassembly, minimizing the risk of randomly diluting multiple recycling components in the thylakoid membrane following a photodamage event.
Cooperation mitigates diversity loss in a spatially expanding microbial population
Authors: Gandhi Saurabh R. , Korolev Kirill S. , Gore Jeff
Published: October 2019

Significance

Spatially expanding populations lose genetic diversity rapidly because of repeated bottlenecks formed at the colonization front. However, the rate of diversity loss depends on the specifics of the expanding population, such as its growth and dispersal dynamics. We have previously demonstrated that changing the amount of within-species cooperation leads to a qualitative transition in the nature of expansion from pulled (driven by growth at the low-density tip) to pushed (driven by migration from the high-density region at the front, but behind the tip). Here we demonstrate experimentally that pushed waves result in strongly reduced genetic drift during range expansions, thus preserving genetic diversity in the newly colonized region.
Membrane curvature underlies actin reorganization in response to nanoscale surface topography
Authors: Lou Hsin-Ya , Zhao Wenting , Li Xiao , Duan Liting , Powers Alexander , Akamatsu Matthew , Santoro Francesca , McGuire Allister F. , Cui Yi , Drubin David G. , Cui Bianxiao
Published: October 2019

Significance

Despite a large body of work, little is known about the origin or underlying mechanisms of how cells interact with surface topographic patterns, which has resulted in a primarily phenomenological approach in studying cell–nanotopography interactions. This study illustrates that membrane curvatures induced by nanoscale surface topography can serve as a direct biochemical signal to activate curvature-sensing protein and regulate actin polymerization and mechanotransduction in the intracellular space.
Social, demographic, and economic correlates of food and chemical consumption measured by wastewater-based epidemiology
Authors: Choi Phil M. , Tscharke Benjamin , Samanipour Saer , Hall Wayne D. , Gartner Coral E. , Mueller Jochen F. , Thomas Kevin V. , O’Brien Jake W.
Published: October 2019

Significance

To date, wastewater-based epidemiology has focused on reporting drug and pharmaceutical consumption patterns by analyzing domestic wastewater. Here we explore the relationships between chemicals in wastewater and social, demographic, and economic parameters of the respective populations. We show the extent to which consumption of chemicals such as opioids and illicit drugs are associated with sociodemographics. We also examine chemicals that reflect individuals’ consumption of food components in wastewater and show that disparities in diet are associated with educational level. Our study shows that chemicals in wastewater reflect the social, demographic, and economic properties of the respective populations and highlights the potential value of wastewater in studying the sociodemographic determinants of population health.
Genetic contributions to variation in human stature in prehistoric Europe
Authors: Cox Samantha L. , Ruff Christopher B. , Maier Robert M. , Mathieson Iain
Published: October 2019

Significance

Measurements of prehistoric human skeletal remains provide a record of changes in height and other anthropometric traits over time. Often, these changes are interpreted in terms of plastic developmental response to shifts in diet, climate, or other environmental factors. These changes can also be genetic in origin, but, until recently, it has been impossible to separate the effects of genetics and environment. Here, we use ancient DNA to directly estimate genetic changes in phenotypes and to identify changes driven not by genetics, but by environment. We show that changes over the past 35,000 y are largely predicted by genetics but also identify specific shifts that are more likely to be environmentally driven.
Horsefly object-directed polarotaxis is mediated by a stochastically distributed ommatidial subtype in the ventral retina
Authors: Meglič Andrej , Ilić Marko , Pirih Primož , Škorjanc Aleš , Wehling Martin F. , Kreft Marko , Belušič Gregor
Published: October 2019

The ventral compound eye of many insects contains polarization-sensitive photoreceptors, but little is known about how they are integrated into visual functions. In female horseflies, polarized reflections from animal fur are a key stimulus for host detection. To understand how polarization vision is mediated by the ventral compound eye, we investigated the band-eyed brown horsefly
Tabanus bromius
using anatomical, physiological, and behavioral approaches. Serial electron microscopic sectioning of the retina and single-cell recordings were used to determine the spectral and polarization sensitivity (PS) of photoreceptors. We found 2 stochastically distributed subtypes of ommatidia, analogous to pale and yellow of other flies. Importantly, the pale analog contains an orthogonal analyzer receptor pair with high PS, formed by an ultraviolet (UV)-sensitive R7 and a UV- and blue-sensitive R8, while the UV-sensitive R7 and green-sensitive R8 in the yellow analog always have low PS. We tested horsefly polarotaxis in the field, using lures with controlled spectral and polarization composition. Polarized reflections without UV and blue components rendered the lures unattractive, while reflections without the green component increased their attractiveness. This is consistent with polarotaxis being guided by a differential signal from polarization analyzers in the pale analogs, and with an inhibitory role of the yellow analogs. Our results reveal how stochastically distributed sensory units with modality-specific division of labor serve as separate and opposing input channels for visual guidance.
Constitutive Siglec-1 expression confers susceptibility to HIV-1 infection of human dendritic cell precursors
Authors: Ruffin Nicolas , Gea-Mallorquí Ester , Brouiller Flavien , Jouve Mabel , Silvin Aymeric , See Peter , Dutertre Charles-Antoine , Ginhoux Florent , Benaroch Philippe
Published: October 2019

The human dendritic cell (DC) lineage has recently been unraveled by high-dimensional mapping, revealing the existence of a discrete new population of blood circulating DC precursors (pre-DCs). Whether this new DC population possesses specific functional features as compared to the other blood DC subset upon pathogen encounter remained to be evaluated. A unique feature of pre-DCs among blood DCs is their constitutive expression of the viral adhesion receptor Siglec-1. Here, we show that pre-DCs, but not other blood DC subsets, are susceptible to infection by HIV-1 in a Siglec-1–dependent manner. Siglec-1 mediates pre-DC infection of CCR5- and CXCR4-tropic strains. Infection of pre-DCs is further enhanced in the presence of HIV-2/SIVmac Vpx, indicating that Siglec-1 does not counteract restriction factors such as SAMHD1. Instead, Siglec-1 promotes attachment and fusion of viral particles. HIV-1–infected pre-DCs produce new infectious viral particles that accumulate in intracellular compartments reminiscent of the virus-containing compartment of macrophages. Pre-DC activation by toll-like receptor (TLR) ligands induces an antiviral state that inhibits HIV-1 fusion and infection, but Siglec-1 remains functional and mediates replication-independent transfer of HIV-1 to activated primary T lymphocytes. Altogether, Siglec-1–mediated susceptibility to HIV-1 infection of pre-DCs constitutes a unique functional feature that might represent a preferential relationship of this emerging cell type with viruses.
Nanoscale coupling of junctophilin-2 and ryanodine receptors regulates vascular smooth muscle cell contractility
Authors: Pritchard Harry A. T. , Griffin Caoimhin S. , Yamasaki Evan , Thakore Pratish , Lane Conor , Greenstein Adam S. , Earley Scott
Published: October 2019

Significance

The junctophilins are a family of structural proteins that organize intracellular membrane junctions, such as coupling between the endoplasmic/sarcoplasmic reticulum and plasma membrane. The junctophilins are critically important for cardiac and skeletal muscle function, but little is known about how these proteins influence vascular smooth muscle cells (SMCs). We found that one isotype, junctophilin-2 (JPH2), is abundant in SMCs and is essential for maintaining a subcellular Ca2+signaling pathway that is critically important for regulation of membrane potential and contractility. Our data also show that impaired expression of JPH2 results in hypercontractility of small cerebral arteries. These findings suggest that loss-of-function mutations or decreased expression of JPH2 could contribute to vascular pathologies such as systemic hypertension and vascular cognitive impairment.
Electronic-cigarette smoke induces lung adenocarcinoma and bladder urothelial hyperplasia in mice
Authors: Tang Moon-shong , Wu Xue-Ru , Lee Hyun-Wook , Xia Yong , Deng Fang-Ming , Moreira Andre L. , Chen Lung-Chi , Huang William C. , Lepor Herbert
Published: October 2019

Significance

Electronic-cigarette smoke (ECS) is designed to deliver nicotine, and its use is gaining popularity. Previously, we found that ECS induces DNA damage and inhibits DNA repair in the mouse lungs and bladder urothelium. Nicotine induces the same types of DNA adducts and has a similar effect on DNA repair inhibition in human cells. Nicotine also enhances human cells’ mutation and tumorigenic transformation susceptibility. Our current results show that ECS-exposed mice developed lung adenocarcinoma and bladder urothelial hyperplasia, indicating that ECS is a lung carcinogen and a potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, the threat ECS poses to humans is not yet known and warrants in-depth investigation.
Structural pathway for allosteric activation of the autophagic PI 3-kinase complex I
Authors: Young Lindsey N. , Goerdeler Felix , Hurley James H.
Published: October 2019

Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the proautophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryoelectron microscopy was used to visualize a 2-step PI3KC3-C1 activation pathway driven by NRFB2 MIT domain binding. Binding of a single NRBF2 MIT domain bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes.
The olfactory coreceptor IR8a governs larval feces-mediated competition avoidance in a hawkmoth
Authors: Zhang Jin , Bisch-Knaden Sonja , Fandino Richard A. , Yan Shuwei , Obiero George F. , Grosse-Wilde Ewald , Hansson Bill S. , Knaden Markus
Published: October 2019

Significance

Finding a suitable oviposition site is a challenging task for a gravid female moth. At the same time, it is of paramount importance considering the limited capability of most caterpillars to relocate to alternative host plants. The hawkmoth,
Manduca sexta
, oviposits on solanaceous plants. Larvae hatching on a plant that is already attacked by conspecific caterpillars face food competition. Here, we show that feces from conspecific caterpillars are sufficient to deter a female
M. sexta
from ovipositing on a plant. Furthermore, we not only identify the responsible compound in the feces but also localize the population of sensory neurons that governs the female’s avoidance. Hence, our work increases the understanding of how animals cope with a competitive environment.
The associations between individual differences in working memory and the effectiveness of immediate and delayed corrective feedback
Authors: Fu Mengxia , Li Shaofeng
Published: October 2019

This paper reports on a study investigating the role of working memory in predicting L2 development under immediate and delayed corrective feedback (CF) conditions. A total of 106 seventh-grade EFL learners were assigned to three groups: Immediate CF, Delayed CF, and Task Only. Each group underwent three treatment sessions during which they performed six focused communicative tasks – two in each session – involving the use of the English past tense. The Immediate CF group received feedback on their erroneous use of the target structure during their task performance in Session 1; the Delayed CF group did not receive feedback until the final treatment session; and the Task Only group performed the communicative tasks without receiving any feedback. Treatment effects were measured through a grammaticality judgement test and an elicited imitation test. Working memory was measured by means of an operation span test. The results revealed that working memory was a significant predictor only of the effects of delayed CF, not those of immediate CF or task only. The findings suggest that delayed CF may have imposed a heavier processing burden on the learners’ working memory due to the need to match the delayed feedback with the errors in their procedural knowledge manifested in previous sessions. Based on the results of this and other empirical studies, the authors argue for the superiority of immediate feedback over delayed feedback.
Working memory and planning time as predictors of fluency and accuracy
Authors: Brown Nielson Katharine , DeKeyser Robert
Published: October 2019

Working memory, which accounts for the ability to process information in the face of interference, is critical to
second language acquisition (SLA) and use. The interaction of working memory capacity (WMC) with specific pedagogical
interventions is a logical place for empirical SLA research, both to examine the cognitive processes underpinning second language
performance and to identify instructional treatments that may serve learners differently based on their WMC. This study considers
WMC along with two different types of pre-task planning time (guided and unguided) as predictors of the attempted accuracy and
fluency of learners’ discourse. Seventy-two intermediate ESL students from seven classes at a community college participated by
completing two different working memory span tasks, as well as two different “There-and-Then” oral story-telling tasks. The
treatment condition of the story-telling tasks was manipulated so that learners’ performance could be considered in terms of
provision of pre-task planning (+/− planning), type of planning (guided vs. unguided), and order of planning (planning first or
planning second). Task order had a clear effect on learners’ production, regardless of the provision of planning time. Guided
planning time promoted a focus on attempted accuracy and unguided planning time fostered fluency. Finally, this study indicates
that task conditions can affect high- and low-WMC learners in different ways: the former are more likely to comply with complex
story-telling instructions, requiring them to focus on grammatical form at the expense of fluency, whereas the latter are less
likely to comply with the same instructions.
Prosodic effects on L2 grammars
Authors: Goad Heather , White Lydia
Published: October 2019

This paper provides an overview of the Prosodic Transfer Hypothesis (PTH), which accounts for certain difficulties
that learners experience with L2 morphosyntax. We focus on inflection and articles, which have often been accounted for through
defective syntactic representations or problems with the interface between morphology and syntax (inflection) and between
semantics or discourse/pragmatics and syntax (articles). We argue that some problems in these domains reflect transfer of L1
prosodic constraints: certain forms cannot be prosodically represented as target-like and hence are omitted or mispronounced. We
trace how the PTH has developed over time, from its initial instantiation as involving permanent L1 transfer, to currently, where
L1 representations are seen as adaptable to the needs of the L2, and new representations can in fact be acquired. We provide an
overview of work conducted in this framework and discuss how the theory has been extended beyond production to encompass
comprehension and processing.
Seipin negatively regulates sphingolipid production at the ER–LD contact site
Authors: Su Wei-Cheng , Lin Yi-Hsiu , Pagac Martin , Wang Chao-Wen
Published: October 2019

Seipin is known for its critical role in controlling lipid droplet (LD) assembly at the LD-forming subdomain of the endoplasmic reticulum (ER). Here, we identified a new function of seipin as a negative regulator for sphingolipid production. We show that yeast cells lacking seipin displayed altered sensitivity to sphingolipid inhibitors, accumulated sphingoid precursors and intermediates, and increased serine palmitoyltransferase (SPT) and fatty acid (FA) elongase activities. Seipin associated with SPT and FA elongase, and the interaction was reduced by inhibitors for sphingolipid synthesis in a concentration-dependent manner. We further show that the interactions of seipin with SPT and FA elongase occurred at ER–LD contacts and were likely regulated differentially. Further evidence indicated that LD biogenesis was intact when SPT activity was blocked, whereas excess sphingoid intermediates may affect LD morphology. Expression of human seipin rescued the altered sphingolipids in yeast seipin mutants, suggesting that the negative regulation of sphingolipid synthesis by seipin is likely an evolutionarily conserved process.
An intrinsic compartmentalization code for peripheral membrane proteins in photoreceptor neurons
Authors: Maza Nycole A. , Schiesser William E. , Calvert Peter D.
Published: October 2019

In neurons, peripheral membrane proteins are enriched in subcellular compartments, where they play key roles, including transducing and transmitting information. However, little is known about the mechanisms underlying their compartmentalization. To explore the roles of hydrophobic and electrostatic interactions, we engineered probes consisting of lipidation motifs attached to fluorescent proteins by variously charged linkers and expressed them in Xenopus rod photoreceptors. Quantitative live cell imaging showed dramatic differences in distributions and dynamics of the probes, including presynapse and ciliary OS enrichment, depending on lipid moiety and protein surface charge. Opposing extant models of ciliary enrichment, most probes were weakly membrane bound and diffused through the connecting cilium without lipid binding chaperone protein interactions. A diffusion-binding-transport model showed that ciliary enrichment of a rhodopsin kinase probe occurs via recycling as it perpetually leaks out of the ciliary OS. The model accounts for weak membrane binding of peripheral membrane proteins and a leaky connecting cilium diffusion barrier.
Stable stimulated emission depletion imaging of extended sample regions
Authors: Alvelid Jonatan , Testa Ilaria
Published: October 2019

Stimulated emission depletion (STED) nanoscopy has become one of the most used nanoscopy techniques over the last decade. However, most recordings are done in specimen regions no larger than 10–30  ×  10–30 μm2 due to aberrations, instability and manual mechanical stages. Here, we demonstrate automated 2D and 3D STED nanoscopy of extended sample regions up to 0.5  ×  0.5 mm2 by using a scanning system that maintains stationary beams in the back focal plane. The setup allows up to 80–100  ×  80–100 μm2 field of view (FOV) with uniform spatial resolution, a mechanical stage allowing sequential tiling to record larger sample areas, and a feedback system keeping the sample in focus at all times. Taken together, this allows automated recording of theoretically unlimited-sized sample areas and volumes, without compromising the achievable spatial resolution and image quality.
On the overall polarisation properties of Poincaré beams
Authors: Lopez-Mago Dorilian
Published: October 2019

We analyse the polarisation properties of Poincaré beams. We consider different configurations, such as Laguerre–Poincaré (LP), Bessel–Poincaré (BP), and Lambert–Poincaré (LaP) beams. The former considers the well-known cylindrical vector beams and full-Poincaré beams produced by a collinear superposition of two Laguerre–Gauss beams with orthogonal polarisations. For this configuration, we describe the Stokes statistics and overall invariant parameters. Similarly, BP beams are produced by the collinear superposition of Bessel beams with orthogonal polarisations. We describe their properties under propagation and show that they behave as a free-space polarisation attractor transforming elliptical polarisations to linear polarisations. We also propose a novel type of full Poincaré pattern, one which is generated by a Lambert projection of the Poincaré sphere on the transverse plane, and hence we call them LaP. This configuration, contrary to the LP, provides a finite region containing all polarisation states uniformly distributed on the Poincaré sphere.
Protein intake and transitions between frailty states and to death in very old adults: the Newcastle 85+ study
Authors: Mendonça Nuno , Kingston Andrew , Granic Antoneta , Jagger Carol
Published: October 2019

Objectives

To examine the association of protein intake with frailty progression in very old adults.

Design

The Newcastle 85+ study, a prospective longitudinal study of people aged 85 years old in Northeast England and followed over 5 years.

Setting and Participants

668 community-dwelling older adults (59% women) at baseline, with complete dietary assessment and Fried frailty status (FFS).

Measures

Dietary intake was estimated with 2 × 24-h multiple pass recalls at baseline. FFS was based on five criteria: shrinking, physical endurance/energy, low physical activity, weakness and slow walking speed and was available at baseline and 1.5, 3 and 5 years. The contribution of protein intake (g/kg adjusted body weight/day [g/kg aBW/d]) to transitions to and from FFS (robust, pre-frail and frail) and to death over 5 years was examined by multi-state models.

Results

Increase in one unit of protein intake (g/kg aBW/d) decreased the likelihood of transitioning from pre-frail to frail after adjusting for age, sex, education and multimorbidity (hazard ratios [HR]: 0.44, 95% confidence interval [CI]: 0.25–0.77) but not for the other transitions. Reductions in incident frailty were equally present in individuals with protein intake ≥0.8 (HR: 0.60, 95% CI: 0.43–0.84) and ≥1 g/kg aBW/d (HR: 0.63, 95% CI: 0.44–0.90) from 85 to 90 years. This relationship was attenuated after adjustment for energy intake, but the direction of the association remained the same (e.g. g/kg aBW/d model: HR: 0.71, 95% CI: 0.36–1.41).

Conclusion

High protein intake, partly mediated by energy intake, may delay incident frailty in very old adults. Frailty prevention strategies in this age group should consider adequate provision of protein and energy.
Real-life implementation of guidelines on the hospital-to-home transition for older patients: a cohort study in general practice
Authors: Hurtaud Aline , Lallier François , Heidet Matthieu , Arnoult Charline , Dramé Moustapha , Canouï-Poitrine Florence
Published: October 2019

Background

hospital discharge is a critical event for older patients. The French guidelines recommended the swift transmission of a discharge summary to the general practitioner (GP) and a primary care consultation within 7 days. The relevance and feasibility of these guidelines have not previously been assessed.

Objective

to perform a real-life assessment of compliance with French guidelines on the transmission of discharge summaries and post-discharge medical reviews and to examine these factors’ association with 30-day readmissions.

Design

a prospective multicentre cohort study.

Setting

primary care (general practice) in France.

Subjects

a sample of GPs and the same number of patients aged 75 or over having consulted within 30 days of hospital discharge.

Methods

the main endpoints were the proportion of discharge summaries available and the proportion of patients consulting their GP within 7 days. The 30-day readmission rate was also measured. Factors associated with these endpoints were assessed in univariate and multivariate analyses.

Results

seventy-one GPs (mean ± standard deviation age: 49 ± 11; males: 62%) and 71 patients (mean age: 84 ± 5; males: 52%; living at home: 94%; cognitive disorders: 22%) were included. Forty-six patients (65%, [95% confidence interval [CI]]: 53–76) consulted their GP within 7 days of hospital discharge. At the time of the consultation, 27 GPs (38% [95% CI]: 27–50) had not received the corresponding hospital discharge summary. Discharge summary availability was associated with a lower risk of 30-day readmission (adjusted odds ratio [95% CI] = 0.25 [0.07–0.91]).

Conclusions

compliance with the French guidelines on hospital-to-home transitions is insufficient.
Stratification of Atypical Intraepithelial Prostatic Lesions Based on Basal Cell and Architectural Patterns
Authors: Xiao Guang-Qian , Golestani Reza , Pham Huy , Sherrod Andy E
Published: October 2019

Objectives: High-grade prostatic intraepithelial neoplasia (HPIN) and atypical cribriform lesion of the prostate are considered the precursors or associators of invasive prostate cancer (iPCa). Given loss of basal cells being the hallmark of iPCa, we hypothesized that a subset of these atypical intraepithelial lesions (AILs) with sparse basal cells can be classified as prostatic intraepithelial carcinoma (PIC) with frequent iPCa association and that different morphologic patterns of PIC are associated with specific Gleason (G) patterns and scores for iPCa.

Methods: We stratified 153 foci of AILs from 110 patients based on the integrity of the basal cell layer and architectural patterns and their association with iPCa.

Results: We demonstrated that AILs could be stratified into usual HPIN (intact basal cell layer and simple patterns) with low-risk of iPCa association and PIC (sparse basal cell layer) with high risk of iPCa association. Furthermore, PIC could be divided into low-grade (simple patterns and associated with G3 and G3/4 iPCa) and high-grade PIC (complex patterns and associated with G4 and G3/4/5 iPCa).

Conclusions: Such stratification is of great clinical significance and instrumental to clinical patient management. It not only increases the predictability of AILs for iPCa but also accommodates a clinical scenario for lesions with features of intraductal carcinoma when iPCa is not found, particularly in biopsies.
Serum Retinol and Risk of Overall and Site-Specific Cancer in the ATBC Study
Authors: Hada Manila , Mondul Alison M , Weinstein Stephanie J , Albanes Demetrius
Published: October 2019

Retinol, the most biologically active form of vitamin A, might influence cancer-related biological pathways. However, results from observational studies of serum retinol and cancer risk have been mixed. We prospectively examined serum retinol and risk of overall and site-specific cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (n = 29,104 men), conducted in 1985–1993, with follow-up through 2012. Serum retinol concentration was measured using reverse-phase high-performance liquid chromatography. Cox proportional hazards models estimated the association between baseline serum retinol quintile and overall and site-specific cancer risk in 10,789 cases. After multivariable adjustment, higher serum retinol was not associated with overall cancer risk (highest vs. lowest quintile: hazard ratio (HR) = 0.97, 95% confidence interval (CI): 0.91, 1.03; P for trend = 0.43). Higher retinol concentrations were, however, associated with increased risk of prostate cancer (highest vs. lowest quintile: HR = 1.28, 95% CI: 1.13, 1.45; P for trend < 0.0001) and lower risk of both liver and lung cancers (highest vs. lowest quintile: for liver, HR = 0.62, 95% CI: 0.42, 0.91; P for trend = 0.004; and for lung, HR = 0.80, 95% CI: 0.72, 0.88; P for trend < 0.0001). No associations with other cancers were observed. Understanding the mechanisms that underlie these associations might provide insight into the role of vitamin A in cancer etiology.
The Real Standard Picture, and How Facts Make It Law: a Response to Mark Greenberg
Authors: Goldsworthy Jeffrey
Published: October 2019

Mark Greenberg has attempted to refute what he regards as a popular metaphysical thesis about how law is constituted. He calls it the “Standard Picture,” and it includes a “Communication Theory.” His own “Moral Impact Theory” of law is built partly on that attempted refutation. I defend positions that are very close to the Standard Picture and Communication Theory, albeit different in important respects. In particular, they are not primarily metaphysical theses, although they have metaphysical implications. They are actual fundamental doctrines of constitutional law in Anglo-American legal systems, which I call Legislative Supremacy and Legislative Intention. I argue that: (a) these doctrines, and their metaphysical implications, vindicate much of the Standard Picture, and explain why so many theorists have been attracted to it; (b) the doctrines are inconsistent with Greenberg’s Moral Impact Theory; and (c) the best theory of what makes them part of the law is legal positivism: in other words, facts about legal practices make them law. In arguing for (a) and (b), I examine in detail and respond to Greenberg’s account of the legal principles and practice of statutory interpretation. I distinguish between three kinds of interpretation: clarifying, supplementing and rectifying. In arguing for (c), I contend that legal positivism satisfies Greenberg’s (questionable) insistence that any metaphysical account of what constitutes law must satisfy a “rationality requirement.”
Single-sample landscape entropy reveals the imminent phase transition during disease progression
Authors: Liu Rui , Chen Pei , Chen Luonan
Published: October 2019

Motivation

The time evolution or dynamic change of many biological systems during disease progression is not always smooth but occasionally abrupt, that is, there is a tipping point during such a process at which the system state shifts from the normal state to a disease state. It is challenging to predict such disease state with the measured omics data, in particular when only a single sample is available.

Results

In this study, we developed a novel approach, i.e. single-sample landscape entropy (SLE) method, to identify the tipping point during disease progression with only one sample data. Specifically, by evaluating the disorder of a network projected from a single-sample data, SLE effectively characterizes the criticality of this single sample network in terms of network entropy, thereby capturing not only the signals of the impending transition but also its leading network, i.e. dynamic network biomarkers. Using this method, we can characterize sample-specific state during disease progression and thus achieve the disease prediction of each individual by only one sample. Our method was validated by successfully identifying the tipping points just before the serious disease symptoms from four real datasets of individuals or subjects, including influenza virus infection, lung cancer metastasis, prostate cancer and acute lung injury.

Availability and implementation

https://github.com/rabbitpei/SLE.

Supplementary information

Supplementary data are available at Bioinformatics online.
Deep-learning approach to identifying cancer subtypes using high-dimensional genomic data
Authors: Chen Runpu , Yang Le , Goodison Steve , Sun Yijun
Published: October 2019

Motivation

Cancer subtype classification has the potential to significantly improve disease prognosis and develop individualized patient management. Existing methods are limited by their ability to handle extremely high-dimensional data and by the influence of misleading, irrelevant factors, resulting in ambiguous and overlapping subtypes.

Results

To address the above issues, we proposed a novel approach to disentangling and eliminating irrelevant factors by leveraging the power of deep learning. Specifically, we designed a deep-learning framework, referred to as DeepType, that performs joint supervised classification, unsupervised clustering and dimensionality reduction to learn cancer-relevant data representation with cluster structure. We applied DeepType to the METABRIC breast cancer dataset and compared its performance to state-of-the-art methods. DeepType significantly outperformed the existing methods, identifying more robust subtypes while using fewer genes. The new approach provides a framework for the derivation of more accurate and robust molecular cancer subtypes by using increasingly complex, multi-source data.

Availability and implementation

An open-source software package for the proposed method is freely available at http://www.acsu.buffalo.edu/~yijunsun/lab/DeepType.html.

Supplementary information

Supplementary data are available at Bioinformatics online.
Beyond the Epileptic Focus: Functional Epileptic Networks in Focal Epilepsy
Authors: Gil Francisco , Padilla Nelly , Soria-Pastor Sara , Setoain Xavier , Boget Teresa , Rumiá Jordi , Roldán Pedro , Reyes David , Bargalló Núria , Conde Estefanía , Pintor Luis , Vernet Oriol , Manzanares Isabel , Ådén Ulrika , Carreño Mar , Donaire Antonio
Published: October 2019

Focal epilepsy can be conceptualized as a network disorder, and the functional epileptic network can be described as a complex system of multiple brain areas that interact dynamically to generate epileptic activity. However, we still do not fully understand the functional architecture of epileptic networks. We studied a cohort of 21 patients with extratemporal focal epilepsy. We used independent component analysis of functional magnetic resonance imaging (fMRI) data. In order to identify the epilepsy-related components, we examined the general linear model-derived electroencephalography-fMRI (EEG–fMRI) time courses associated with interictal epileptic activity as intrinsic hemodynamic epileptic biomarkers. Independent component analysis revealed components related to the epileptic time courses in all 21 patients. Each epilepsy-related component described a network of spatially distributed brain areas that corresponded to the specific epileptic network in each patient. We also provided evidence for the interaction between the epileptic activity generated at the epileptic network and the physiological resting state networks. Our findings suggest that independent component analysis, guided by EEG–fMRI epileptic time courses, have the potential to define the functional architecture of the epileptic network in a noninvasive way. These data could be useful in planning invasive EEG electrode placement, guiding surgical resections, and more effective therapeutic interventions.
A Late Critical Period for Frequency Modulated Sweeps in the Mouse Auditory System
Authors: Bhumika Stitipragyan , Nakamura Mari , Valerio Patricia , Solyga Magdalena , Lindén Henrik , Barkat Tania R
Published: October 2019

Neuronal circuits are shaped by experience during time windows of increased plasticity in postnatal development. In the auditory system, the critical period for the simplest sounds—pure frequency tones—is well defined. Critical periods for more complex sounds remain to be elucidated. We used in vivo electrophysiological recordings in the mouse auditory cortex to demonstrate that passive exposure to frequency modulated sweeps (FMS) from postnatal day 31 to 38 leads to long-term changes in the temporal representation of sweep directions. Immunohistochemical analysis revealed a decreased percentage of layer 4 parvalbumin-positive (PV+) cells during this critical period, paralleled with a transient increase in responses to FMS, but not to pure tones. Preventing the PV+ cell decrease with continuous white noise exposure delayed the critical period onset, suggesting a reduction in inhibition as a mechanism for this plasticity. Our findings shed new light on the dependence of plastic windows on stimulus complexity that persistently sculpt the functional organization of the auditory cortex.
Development and Validation of Chromatographic Methods for Simultaneous Determination of Paracetamol, Orphenadrine Citrate and Caffeine in Presence of P-aminophenol; Quantification of P-aminophenol Nephrotoxic Impurity Using LC–MS/MS
Authors: Boltia Shereen A , Soudi Aya T , Elzanfaly Eman S , Zaazaa Hala E
Published: October 2019

Three chromatographic methods were developed, optimized and validated for Paracetamol (PAR), Orphenadrine citrate (Or.cit) and Caffeine (CAF) determination in their mixture and in presence of PAR toxic impurity; P-aminophenol (PAP) in tablets. The first method is based on a thin layer chromatography combined with densitometry. Separation was achieved using silica gel 60 F254 TLC plates and dichloromethane:methanol:acetone:glacial acetic acid (9:1:0.5:0.3, v/v/v) as a developing system at 230 nm. The second method is based on high-performance liquid chromatography with diode array detection. The proposed compounds are separated on a reversed phase C18 analytical column using phosphate buffer (pH 9; 0.05 M) and methanol (80:20, v/v) at 1.2 mL/min. Linear regressions are obtained in the range of 1–500 μg/mL, 25–1000 μg/mL and 1–400 μg/mL for PAR, Or.cit and CAF, respectively. Quantification of the toxic PAP is carried out using LC–MS-MS by electrospray ionization in the positive mode using triple quadrupole mass spectrometry. The limit of quantification for PAP is 1 ng/mL. All methods are validated according to the ICH guidelines and successfully applied to determine PAR, Or.cit, CAF and PAP in pure powder and in combined tablets dosage form without interference from excipients.
The Overton Window and a Less Dogmatic Approach to Antibiotics
Authors: Morgan Daniel J
Published: October 2019

This analysis summarizes a set of recent, innovative trials in infectious diseases that redefine previous, non–evidence based “rules” for antibiotics. Recent trials in infectious diseases have led to reconsidering the traditional treatment of infectious diseases by changing the duration or type of traditional antibiotics or evaluating new antibiotics for approval. These trials have used the noninferiority trial approach. The noninferiority trial design and recent infectious disease trials of relevance are discussed in this viewpoint. My objective was to analyze recent trials in infectious disease and consider needs for future trials.