bluuebunny/crossref_metadata_2025 huggingface dataset:
Reappraisal of HER2 Amplification in High-Grade Urothelial Carcinoma Based on 2018 ASCO/CAP Clinical Practice Guidelines
Authors: Mohanty Sambit K , Mishra Sourav K , Tiwari Ankit , Sharma Shivani , Bhardwaj Mohit , Pattnaik Niharika , Jaiswal Sunil , Baisakh Manas R , Das Subodh , Pradhan Manas R , Swain Tapas R , Satpathy Kaliprasad , Williamson Sean R , Parwani Anil V
Published: April 2021

Objectives

To examine and compare human epidermal growth factor receptor 2 (HER2) amplification status in high-grade urothelial carcinoma (HGUCa), using both 2013 and 2018 HER2 reporting guidelines for breast carcinoma from the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP).

Methods

HER2 status by fluorescence in situ hybridization (FISH) assay in 78 cases of HGUCa was compared using 2013 and 2018 HER2 reporting guidelines.

Results

HER2 amplification was observed in 22 (28.2%) of 78 tumors, of which 17 were in group 1, 1 in group 2, and 2 each in groups 3 and 4 (FISH assay, 2018). The remaining 14 HER2-amplified tumors (FISH assay, 2013) became negative, falling into group 2 (FISH assay, 2018) and were either negative or equivocal on immunohistochemistry (IHC, 2018). All FISH-negative tumors (n = 37) using 2013 criteria remained negative (group 5, 2018). FISH-equivocal tumors (2013) were further categorized into HER2 amplified (n = 1) and HER2 negative (n = 4) (2018). Overall, 20 (25.6%) tumors had discordant HER2 FISH results (2018 vs 2013).

Conclusions

Implementing 2018 guidelines, HER2 amplification decreased from 36 to 22 cases. The group with a HER2/CEP17 ratio of 2 or more and average HER2 copy number less than 4 (group 2) were predominantly negative by IHC, suggesting a biologically distinct group of HGUCa that is different from HER2-amplified tumors, which may not respond to HER2-targeted therapy.
Algorithm design and the development of a discrete element method for simulating particulate flow and heat transfer
Authors: Liu Bing
Published: April 2021

An algorithm using the discrete element method (DEM) for simulating the particulate behaviour of flow and heat transfer is developed and described, the reasonable hypothesis and the ingenious design of which have been presented in detail. The organizational structure of the developed algorithm contains an efficient method for determining particle collisions, the status analysis for each particle and the particulate-kinematics analysis during the time step. The reasonability and correctness of the developed DEM algorithm are validated by laboratory experiments: the discharge process of glass beads from a silo; and heating of metal alloy particles in a calciner. Afterwards, a group of validated mechanics parameter values for coal and sand have been tested and verified in the article, preparing for the simulation of the pyrolysis process in a downer or screw reactor in subsequent research projects.
The Missing Link: Network Influences on Class Divides in Political Attitudes
Authors: Lindh Arvid , Andersson Anton B , Volker Beate
Published: April 2021

Previous research provides a detailed picture of class differences in political attitudes. Less is however known about the social structures that enforce this political divide across social classes. This article contributes towards filling this gap by considering how the class profile of personal social networks influences political attitudes. We propose a general framework for incorporating an individual’s social network into class analysis of political preferences. Using Sweden as a case, we empirically evaluate our approach using a population survey with information about the respondents’ own employment situation, egocentric networks, and political attitudes in terms of redistribution and welfare chauvinism. We find that there is considerable class segregation in social networks as individuals tend to have more ties within their own and neighbouring class positions. Concerning political preferences, results show that: (i) a substantive part of the class–attitude relationship is shaped by a person’s social network; (ii) the class profile of networks influences attitudes over and above one’s own class position; (iii) class segregation in networks fortifies class divides in political attitudes. We thus conclude that social networks constitute a (hitherto) ‘missing link’ in class analysis of political preferences that merits careful consideration in theoretical models of contemporary politics.
Correlation of Rhs elements with Escherichia coli population structure.
Authors: Hill C W , Feulner G , Brody M S , Zhao S , Sadosky A B , Sandt C H
Published: April 2021

The Rhs family of composite genetic elements was assessed for variation among independent Escherichia coli strains of the ECOR reference collection. The location and content of the RhsA-B-C-F subfamily correlates highly with the clonal structure of the ECOR collection. This correlation exists at several levels: the presence of Rhs core homology in the strain, the location of the Rhs elements present, and the identity of the Rhs core-extensions associated with each element. A provocative finding was that an identical 1518-bp segment, covering core-extension-b1 and its associated downstream open reading frame, is present in two distinct clonal groups, but in association with different Rhs elements. The sequence identity of this segment when contrasted with the divergence of other chromosomal segments suggests that shuffling of Rhs core extensions has been a relatively recent variation. Nevertheless the copies of core-extension-b1 were placed within the respective Rhs elements before the emergence of the clonal groups. In the course of this analysis, two new Rhs elements absent from E. coli K-12 were discovered: RhsF, a fourth member of the RhsA-B-C-F subfamily, and RhsG, the prototype of a third Rhs subfamily.
Isolation and Characterization of HRT1 Using a Genetic Screen for Mutants Unable to Degrade Gic2p in Saccharomyces cerevisiae
Authors: Blondel Marc , Galan Jean-Marc , Peter Matthias
Published: April 2021

Skp1p-cullin-F-box (SCF) protein complexes are ubiquitin ligases required for degradation of many regulatory proteins involved in cell cycle progression, morphogenesis, and signal transduction. Using a genetic screen, we have isolated a novel allele of the HRT1/RBX1 gene in budding yeast (hrt1-C81Y). hrt1-C81Y mutant cells exhibited an aberrant morphology but were viable at all temperatures. The cells displayed multiple genetic interactions with mutations in known SCF components and were defective for the degradation of several SCF targets including Gic2p, Far1p, Sic1p, and Cln2p. In addition, they also failed to degrade the F-box proteins Grr1p, Cdc4p, and Met30p. Wild-type Hrt1p but not Hrt1p-C81Y was able to bind multiple F-box proteins in an F-box-dependent manner. Hrt1p-C81Y harbors a single mutation in its ring-finger domain, which is conserved in subunits of distinct E3 ligases. Finally, Hrt1p was localized in both nucleus and cytoplasm and despite a short half-life was expressed constitutively throughout the cell cycle. Taken together, these results suggest that Hrt1p is a core subunit of multiple SCF complexes.
Abnormal Turning Behavior in Drosophila Larvae: Identification and Molecular Analysis ofscribbler(sbb)
Authors: Yang Ping , Shaver Susan A , Hilliker Arthur J , Sokolowski Marla B
Published: April 2021

Our genetic dissection of behavior has isolated scribbler (sbb), a vital gene that encodes a novel protein expressed in the embryonic and larval nervous systems and in the imaginal discs. Larvae with mutations in sbb exhibit abnormally high amounts of turning behavior in the absence of food. sbb is a large gene spanning >50 kb of genomic DNA with four major developmentally regulated transcripts. Transgenic rescue of scribbler behavior was demonstrated by targeting expression of a normal sbb transgene (sbb+) expressing one of the major transcripts to the nervous system. The vital function of sbb was restored by ubiquitous expression of this transgene throughout development.
A Physical Map of the Polytenized Region (101EF–102F) of Chromosome 4 in Drosophila melanogaster
Authors: Locke John , Podemski Lynn , Aippersbach Nicole , Kemp Hilary , Hodgetts Ross
Published: April 2021

Chromosome 4, the smallest autosome (~5 Mb in length) in Drosophila melanogaster contains two major regions. The centromeric domain (~4 Mb) is heterochromatic and consists primarily of short, satellite repeats. The remaining ~1.2 Mb, which constitutes the banded region (101E–102F) on salivary gland polytene chromosomes and contains the identified genes, is the region mapped in this study. Chromosome walking was hindered by the abundance of moderately repeated sequences dispersed along the chromosome, so we used many entry points to recover overlapping cosmid and BAC clones. In situ hybridization of probes from the two ends of the map to polytene chromosomes confirmed that the cloned region had spanned the 101E–102F interval. Our BAC clones comprised three contigs; one gap was positioned distally in 102EF and the other was located proximally at 102B. Twenty-three genes, representing about half of our revised estimate of the total number of genes on chromosome 4, were positioned on the BAC contigs. A minimal tiling set of the clones we have mapped will facilitate both the assembly of the DNA sequence of the chromosome and a functional analysis of its genes.
Patterns of Variation in the Intergenic Spacers of Ribosomal DNA inDrosophila melanogasterSupport a Model for Genetic Exchanges DuringX-YPairing
Authors: Polanco Carlos , González Ana I , Dover Gabriel A
Published: April 2021

Detailed analysis of variation in intergenic spacer (IGS) and internal transcribed spacer (ITS) regions of rDNA drawn from natural populations of Drosophila melanogaster has revealed contrasting patterns of homogenization although both spacers are located in the same rDNA unit. On the basis of the role of IGS regions in X-Y chromosome pairing, we proposed a mechanism of single-strand exchanges at the IGS regions, which can explain the different evolutionary trajectories followed by the IGS and the ITS regions. Here, we provide data from the chromosomal distribution of selected IGS length variants, as well as the detailed internal structure of a large number of IGS regions obtained from specific X and Y chromosomes. The variability found in the different internal subrepeat regions of IGS regions isolated from X and Y chromosomes supports the proposed mechanism of genetic exchanges and suggests that only the “240” subrepeats are involved. The presence of a putative site for topoisomerase I at the 5′ end of the 18S rRNA gene would allow for the exchange between X and Y chromosomes of some 240 subrepeats, the promoter, and the ETS region, leaving the rest of the rDNA unit to evolve along separate chromosomal lineages. The phenomenon of localized units (modules) of homogenization has implications for multigene family evolution in general.
Joint Effects of Genetic Hitchhiking and Background Selection on Neutral Variation
Authors: Kim Yuseob , Stephan Wolfgang
Published: April 2021

Due to relatively high rates of strongly selected deleterious mutations, directional selection on favorable alleles (causing hitchhiking effects on linked neutral polymorphisms) is expected to occur while a deleterious mutation-selection balance is present in a population. We analyze this interaction of directional selection and background selection and study their combined effects on neutral variation, using a three-locus model in which each locus is subjected to either deleterious, favorable, or neutral mutations. Average heterozygosity is measured by simulations (1) at the stationary state under the assumption of recurrent hitchhiking events and (2) as a transient level after a single hitchhiking event. The simulation results are compared to theoretical predictions. It is shown that known analytical solutions describing the hitchhiking effect without background selection can be modified such that they accurately predict the joint effects of hitchhiking and background on linked, neutral variation. Generalization of these results to a more appropriate multilocus model (such that background selection can occur at multiple sites) suggests that, in regions of very low recombination rates, stationary levels of nucleotide diversity are primarily determined by hitchhiking, whereas in regions of high recombination, background selection is the dominant force. The implications of these results on the identification and estimation of the relevant parameters of the model are discussed.
An Integrated Framework for the Inference of Viral Population History From Reconstructed Genealogies
Authors: Pybus Oliver G , Rambaut Andrew , Harvey Paul H
Published: April 2021

We describe a unified set of methods for the inference of demographic history using genealogies reconstructed from gene sequence data. We introduce the skyline plot, a graphical, nonparametric estimate of demographic history. We discuss both maximum-likelihood parameter estimation and demographic hypothesis testing. Simulations are carried out to investigate the statistical properties of maximum-likelihood estimates of demographic parameters. The simulations reveal that (i) the performance of exponential growth model estimates is determined by a simple function of the true parameter values and (ii) under some conditions, estimates from reconstructed trees perform as well as estimates from perfect trees. We apply our methods to HIV-1 sequence data and find strong evidence that subtypes A and B have different demographic histories. We also provide the first (albeit tentative) genetic evidence for a recent decrease in the growth rate of subtype B.
Codominant Analysis of Banding Data From a Dominant Marker System by Normal Mixtures
Authors: Piepho Hans-Peter , Koch Georg
Published: April 2021

Amplified fragment length polymorphisms (AFLPs) currently are among the most widely used marker systems. In many studies, AFLPs are analyzed on the basis of the presence or absence of a band on an electrophoretic gel. As a result, dominant homozygous individuals are not distinguished from heterozygous individuals, resulting in a considerable loss of information. This article shows how codominant information can be obtained if the amount of PCR products is quantified. Due to measurement variation, genotyping on the basis of such information is not error-free. We propose use of normal mixture distributions to determine the most likely genotype, given the data. The method is exemplified using AFLP data from sugar beet.
Visual Impairment and Objectively Measured Physical Activity in Middle-Aged and Older Adults
Authors: Cai Yurun , Schrack Jennifer A , Wang Hang , E Jian-Yu , Wanigatunga Amal A , Agrawal Yuri , Urbanek Jacek K , Simonsick Eleanor M , Ferrucci Luigi , Swenor Bonnielin K
Published: April 2021

Background

Vision loss is associated with increased risk of falls and restricted physical activity, yet the relationship between multiple vision measures and objectively measured physical activity, especially activity patterns, in mid-to-late life is not well understood.

Method

This study included 603 participants aged 50 years and older (mean age = 73.5) in the Baltimore Longitudinal Study of Aging who had the following assessments: presenting and best-corrected visual acuity, contrast sensitivity, visual fields, stereo acuity, and free-living physical activity using a wrist-worn ActiGraph accelerometer for 7 days. Linear regression models were used to examine the association between vision measures and daily activity counts, active minutes, and activity fragmentation (defined as an active-to-sedentary transition probability), adjusting for potential confounders. Mixed-effects models estimated differences in activity by time of day comparing those with and without each visual impairment.

Results

In the fully adjusted model, worse presenting visual acuity, contrast sensitivity, and visual fields were associated with fewer activity counts, less active time, and more fragmented activity patterns (p < .05 for all). Participants with presenting or best-corrected visual acuity impairment had 19.2 and 29.3 fewer active minutes (p = .05 and p = .03, respectively) per day. Visual field impairment was associated with 268 636 fewer activity counts (p = .02), 46.2 fewer active minutes (p = .02) per day, and 3% greater activity fragmentation (p = .009). Differences in activity levels tended to be greatest from 6 am to 6 pm (p < .05).

Conclusions

Older adults with visual impairment have restricted and more fragmented patterns of daily activity. Longitudinal studies to quantify the long-term impacts of visual impairments on activity decline are warranted.
Multicentre experience with an iliac fenestrated device
Authors: Taher Fadi , Langer Stephan , Falkensammer Juergen , Plimon Markus , Kliewer Miriam , Walter Corinna , Assadian Afshin , Stehr Alexander
Published: April 2021

OBJECTIVES

The aim of this study was to present a multicentre experience of technical results and mid-term follow-up using a custom-made iliac fenestrated device (Terumo Aortic, Inchinnan, Renfrewshire, UK) for the treatment of iliac aneurysms and endoleaks.

METHODS

A multicentre retrospective evaluation of 22 patients (3–12 per institution) with either an iliac artery aneurysm or endoleak treated with an iliac fenestrated device was performed. Data were gathered from 3 departments of vascular and endovascular surgery at 3 European institutions.

RESULTS

Ten of the included patients (45.5%) were treated for an endoleak and 12 had aorto-iliac aneurysms (54.5%). Two patients underwent bilateral fenestrated device implantation for a total of 24 devices included in this analysis. Primary technical success was 91.7% (22 of 24 implanted devices). One of the 24 internal iliac arteries could not be cannulated and was covered (primary assisted technical success rate 95.8%) and 1 patient required a relining of the stent graft due to a mid-grade stenosis opposite the internal iliac artery fenestration. Survival at the last available follow-up (mean 15.2 ± 12.0 months, range 0.5–36.6 months) was 90.9%.

CONCLUSIONS

The present investigation adds to a growing body of literature on custom-made endografts and their usefulness in achieving endovascular repair without compromising blood flow via important arterial branch vessels, such as the internal iliac artery. It presents encouraging technical and mid-term follow-up data from consecutive patients treated for iliac aneurysms or endoleaks using this custom-made device. The technique may help avoid adverse sequelae associated to a coil-and-cover approach when iliac branch devices are not feasible.
Predicting Influenza and Rhinovirus Infections in Airway Cells Utilizing Volatile Emissions
Authors: McCartney Mitchell M , Linderholm Angela L , Yamaguchi Mei S , Falcon Alexandria K , Harper Richart W , Thompson George R , Ebeler Susan E , Kenyon Nicholas J , Davis Cristina E , Schivo Michael
Published: April 2021

Background

Respiratory viral infections are common and potentially devastating to patients with underlying lung disease. Diagnosing viral infections often requires invasive sampling, and interpretation often requires specialized laboratory equipment. Here, we test the hypothesis that a breath test could diagnose influenza and rhinovirus infections using an in vitro model of the human airway.

Methods

Cultured primary human tracheobronchial epithelial cells were infected with either influenza A H1N1 or rhinovirus 1B and compared with healthy control cells. Headspace volatile metabolite measurements of cell cultures were made at 12-hour time points postinfection using a thermal desorption-gas chromatography-mass spectrometry method.

Results

Based on 54 compounds, statistical models distinguished volatile organic compound profiles of influenza- and rhinovirus-infected cells from healthy counterparts. Area under the curve values were 0.94 for influenza, 0.90 for rhinovirus, and 0.75 for controls. Regression analysis predicted how many hours prior cells became infected with a root mean square error of 6.35 hours for influenza- and 3.32 hours for rhinovirus-infected cells.

Conclusions

Volatile biomarkers released by bronchial epithelial cells could not only be used to diagnose whether cells were infected, but also the timing of infection. Our model supports the hypothesis that a breath test could serve to diagnose viral infections.
Outpatient continuous-infusion benzylpenicillin combined with either gentamicin or ceftriaxone for enterococcal endocarditis
Authors: Briggs Simon , Broom Matthew , Duffy Eamon , Everts Richard , Everts Gabrielle , Lowe Boris , McBride Stephen , Bhally Hasan
Published: April 2021

Background

Treatment regimens requiring multiple daily dosing for enterococcal endocarditis are challenging to deliver in the outpatient setting. Continuous-infusion benzylpenicillin via a 24 h elastomeric infusor, combined with either once-daily gentamicin or ceftriaxone, requires only one nursing encounter daily and is commonly used in New Zealand.

Objectives

To assess the therapeutic success and adverse antibiotic effects of these regimens.

Methods

A retrospective observational case series from multiple hospitals of patients aged 15 years or over with enterococcal endocarditis diagnosed between July 2013 and June 2019 who received at least 14 days of outpatient continuous-infusion benzylpenicillin combined with either gentamicin or ceftriaxone for synergy.

Results

Forty-three episodes of enterococcal endocarditis in 41 patients met inclusion criteria. The primary synergy antibiotic was gentamicin in 20 episodes and ceftriaxone in 23 episodes. For the 41 initial treatment courses, 31 (76%) patients were cured, 3 (7%) patients developed relapsed endocarditis during or following antibiotic treatment and 7 (17%) patients continued with long-term suppressive oral amoxicillin following IV antibiotic treatment. There was no difference in the relapse rate between the two groups (P = 0.59). Seven (35%) adverse antibiotic effects were documented in the gentamicin group and none in the ceftriaxone group (P < 0.01). Two deaths (5%) occurred within the 6 month follow-up period.

Conclusions

Outpatient treatment of enterococcal endocarditis with continuous-infusion benzylpenicillin combined with either once-daily gentamicin or ceftriaxone following a period of inpatient treatment is usually effective. A significantly higher rate of adverse effects was seen with gentamicin, favouring ceftriaxone as the initial synergy antibiotic.
Development of biparatopic bispecific antibody possessing tetravalent scFv-Fc capable of binding to ROBO1 expressed in hepatocellular carcinoma cells
Authors: Watanabe Yuji , Tanabe Aki , Hamakubo Takao , Nagatoishi Satoru , Tsumoto Kouhei
Published: April 2021

There is no standard structural format of the biparatopic bispecific antibody (bbsAb) which is used against the target molecule because of the diversity of biophysical features of bispecific antibodies (bsAbs). It is therefore essential that the interaction between the antibody and antigen is quantitatively analyzed to design antibodies that possess the desired properties. Here, we generated bsAbs, namely, a tandem scFv-Fc, a diabody-Fc, and an immunofusion–scFv-Fc–scFv, that possessed four scFv arms at different positions and were capable of recognizing the extracellular domains of ROBO1. We examined the interactions between these bsAbs and ROBO1 at the biophysical and cellular levels. Of these, immunofusion–B2212A scFv-Fc–B5209B scFv was stably expressed with the highest relative yield. The kinetic and thermodynamic features of the interactions of each bsAb with soluble ROBO1 (sROBO1) were validated using surface plasmon resonance and isothermal titration calorimetry. In all bsAbs, the immunofusion–scFv-Fc–scFv format showed homogeneous interaction with the antigen with higher affinity compared with that of monospecific antibodies. In conclusion, our study presents constructive information to design druggable bbsAbs in drug applications.
Characteristic chemical probing patterns of loop motifs improve prediction accuracy of RNA secondary structures
Authors: Cao Jingyi , Xue Yi
Published: April 2021

RNA structures play a fundamental role in nearly every aspect of cellular physiology and pathology. Gaining insights into the functions of RNA molecules requires accurate predictions of RNA secondary structures. However, the existing thermodynamic folding models remain less accurate than desired, even when chemical probing data, such as selective 2′-hydroxyl acylation analyzed by primer extension (SHAPE) reactivities, are used as restraints. Unlike most SHAPE-directed algorithms that only consider SHAPE restraints for base pairing, we extract two-dimensional structural features encoded in SHAPE data and establish robust relationships between characteristic SHAPE patterns and loop motifs of various types (hairpin, internal, and bulge) and lengths (2–11 nucleotides). Such characteristic SHAPE patterns are closely related to the sugar pucker conformations of loop residues. Based on these patterns, we propose a computational method, SHAPELoop, which refines the predicted results of the existing methods, thereby further improving their prediction accuracy. In addition, SHAPELoop can provide information about local or global structural rearrangements (including pseudoknots) and help researchers to easily test their hypothesized secondary structures.
Temporal trends in the quality of deceased donor kidneys and kidney transplant outcomes in Europe: an analysis by the ERA-EDTA Registry
Authors: Pippias Maria , Stel Vianda S , Arnol Miha , Bemelman Frederike , Berger Stefan P , Buturovic Ponikvar Jadranka Buturovic , Kramar Reinhard , Magaz Ángela , Nordio Maurizio , Peters-Sengers Hessel , Reisæter Anna Varberg , Sørensen Søren S , Massy Ziad A , Jager Kitty J
Published: April 2021

Background

We investigated 10-year trends in deceased donor kidney quality expressed as the kidney donor risk index (KDRI) and subsequent effects on survival outcomes in a European transplant population.

Methods

Time trends in the crude and standardized KDRI between 2005 and 2015 by recipient age, sex, diabetic status and country were examined in 24 177 adult kidney transplant recipients in seven European countries. We determined 5-year patient and graft survival probabilities and the risk of death and graft loss by transplant cohort (Cohort 1: 2005–06, Cohort 2: 2007–08, Cohort 3: 2009–10) and KDRI quintile.

Results

The median crude KDRI increased by 1.3% annually, from 1.31 [interquartile range (IQR) 1.08–1.63] in 2005 to 1.47 (IQR 1.16–1.90) in 2015. This increase, i.e. lower kidney quality, was driven predominantly by increases in donor age, hypertension and donation after circulatory death. With time, the gap between the median standardized KDRI in the youngest (18–44 years) and oldest (>65 years) recipients widened. There was no difference in the median standardized KDRI by recipient sex. The median standardized KDRI was highest in Austria, the Netherlands and the Basque Country (Spain). Within each transplant cohort, the 5-year patient and graft survival probability were higher for the lowest KDRIs. There was no difference in the patient and graft survival outcomes across transplant cohorts, however, over time the survival probabilities for the highest KDRIs improved.

Conclusions

The overall quality of deceased donor kidneys transplanted between 2005 and 2015 has decreased and varies between age groups and countries. Overall patient and graft outcomes remain unchanged.
In vivo FRET–FLIM reveals ER-specific increases in the ABA level upon environmental stresses
Authors: Zhou Yeling , Wang Yuzhu , Li Jingwen , Liang Jiansheng
Published: April 2021

Plant hormone abscisic acid (ABA) is essential for regulating plant growth and various stress responses. ABA-mediated signaling depends on local ABA levels rather than the overall cellular ABA concentration. While cellular concentration of ABA can be detected using Förster resonance energy transfer (FRET)-based ABA probes, direct imaging of subcellular ABA levels remains unsolved. Here, we modified the previously reported ABAleon2.1 and generated a new ABA sensor, named ABAleon2.1_Tao3. Via transient expression in tobacco (Nicotiana tabacum) protoplasts, we targeted ABAleon2.1_Tao3s to the endoplasmic reticulum (ER) membrane with the ABA sensing unit facing the cytosol and the ER, respectively, through a nanobody–epitope-mediated protein interaction. Combining FRET with fluorescence lifetime imaging microscopy, ABA-triggered-specific increases in the fluorescence lifetime of the donor mTurquoise in the ABAleon2.1_Tao3 were detected in both transient assays and stably transformed Arabidopsis plants. In tobacco protoplasts, ER membrane-targeted ABAleon2.1_Tao3s showed a generally higher basal level of ABA in the ER than that in the cytosol and ER-specific alterations in the level of ABA upon environmental cues. In ABAleon2.1_Tao3-transformed Arabidopsis roots, mannitol triggered increases in cytosolic ABA in the division zone and increases in ER ABA in the elongation and maturation zone within 1 h after treatment, both of which were abolished in the bg1-2 mutant, suggesting the requirement for BG1 in osmotic stress-triggered early ABA induction in Arabidopsis roots. These data demonstrate that ABAleon2.1_Tao3s can be used to monitor ABA levels in the cytosol and the ER, providing key information on stress-induced changes in the level of ABA in different subcellular compartments.
Herpes zoster following BNT162b2 mRNA COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series
Authors: Furer Victoria , Zisman Devy , Kibari Adi , Rimar Doron , Paran Yael , Elkayam Ori
Published: April 2021

Objectives

As global vaccination campaigns against COVID-19 disease commence, vaccine safety needs to be closely assessed. The safety profile of mRNA-based vaccines in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is unknown. The objective of this report is to raise awareness of reactivation of herpes zoster (HZ) following the BNT162b2 mRNA vaccination in patients with AIIRD.

Methods

The safety of the BNT162b2 mRNA vaccination was assessed in an observational study monitoring post-vaccination adverse effects in patients with AIIRD (n = 491) and controls (n = 99), conducted in two rheumatology departments in Israel.

Results

The prevalence of HZ was 1.2% (n = 6) in patients with AIIRD compared with none in controls. Six female patients aged 49 ± 11 years with stable AIIRD: RA (n = 4), Sjogren’s syndrome (n = 1), and undifferentiated connective disease (n = 1), developed the first in a lifetime event of HZ within a short time after the first vaccine dose in five cases and after the second vaccine dose in one case. In the majority of cases, HZ infection was mild, except a case of HZ ophthalmicus, without corneal involvement, in an RA patient treated with tofacitinib. There were no cases of disseminated HZ disease or postherpetic neuralgia. All but one patient received antiviral treatment with a resolution of HZ-related symptoms up to 6 weeks. Five patients completed the second vaccine dose without other adverse effects.

Conclusion

Epidemiologic studies on the safety of the mRNA-based COVID-19 vaccines in patients with AIIRD are needed to clarify the association between the BNT162b2 mRNA vaccination and reactivation of zoster.
Sleep symptomatology is associated with greater subjective cognitive concerns: findings from the community-based Healthy Brain Project
Authors: Nicolazzo Jessica , Xu Katharine , Lavale Alexandra , Buckley Rachel , Yassi Nawaf , Hamilton Garun S , Maruff Paul , Baril Andree-Ann , Lim Yen Ying , Pase Matthew P
Published: April 2021

Study Objectives

To examine if sleep symptomatology was associated with subjective cognitive concerns or objective cognitive performance in a dementia-free community-based sample.

Methods

A total of 1,421 middle-aged participants (mean ± standard deviation = 57 ± 7; 77% female) from the Healthy Brain Project completed the Pittsburgh Sleep Quality Index, Insomnia Severity Index, and Epworth Sleepiness Scale to measure sleep quality, insomnia symptom severity, and daytime sleepiness, respectively. Participants were classified as having no sleep symptomatology (normal scores on each sleep measure), moderate sleep symptomatology (abnormal scores on one sleep measure), or high sleep symptomatology (abnormal scores on at least two sleep measures), using established cutoff values. Analysis of covariance was used to compare objective cognitive function (Cogstate Brief Battery) and subjective cognitive concerns (Modified Cognitive Function Instrument) across groups.

Results

Following adjustments for age, sex, education, mood, and vascular risk factors, persons classified as having high sleep symptomatology, versus none, displayed more subjective cognitive concerns (d = 0.24) but no differences in objective cognitive performance (d = 0.00–0.18). Subjective cognitive concerns modified the association between sleep symptomatology and psychomotor function. The strength of the relationship between high sleep symptomatology (versus none) and psychomotor function was significantly greater in persons with high as compared with low cognitive concerns (β ± SE = −0.37 ± 0.16; p = 0.02).

Conclusions

More severe sleep symptomatology was associated with greater subjective cognitive concerns. Persons reporting high levels of sleep symptomatology may be more likely to display poorer objective cognitive function in the presence of subjective cognitive concerns.
Patterns of self-monitoring technology use and weight loss in people with overweight or obesity
Authors: Robertson Michael C , Raber Margaret , Liao Yue , Wu Ivan , Parker Nathan , Gatus Leticia , Le Thuan , Durand Casey P , Basen-Engquist Karen M
Published: April 2021

Mobile applications and paired devices allow individuals to self-monitor physical activity, dietary intake, and weight fluctuation concurrently. However, little is known regarding patterns of use of these self-monitoring technologies over time and their implications for weight loss. The objectives of this study were to identify distinct patterns of self-monitoring technology use and to investigate the associations between these patterns and weight change. We analyzed data from a 6-month weight loss intervention for school district employees with overweight or obesity (N = 225). We performed repeated measures latent profile analysis (RMLPA) to identify common patterns of self-monitoring technology use and used multiple linear regression to evaluate the relationship between self-monitoring technology use and weight change. RMLPA revealed four distinct profiles: minimal users (n = 65, 29% of sample), activity trackers (n = 124, 55%), dedicated all-around users (n = 25, 11%), and dedicated all-around users with exceptional food logging (n = 11, 5%). The dedicated all-around users with exceptional food logging lost the most weight (X2[1,225] = 5.27, p = .0217). Multiple linear regression revealed that, adjusting for covariates, only percentage of days of wireless weight scale use (B = −0.05, t(212) = −3.79, p < .001) was independently associated with weight loss. We identified distinct patterns in mHealth self-monitoring technology use for tracking weight loss behaviors. Self-monitoring of weight was most consistently linked to weight loss, while exceptional food logging characterized the group with the greatest weight loss. Weight loss interventions should promote self-monitoring of weight and consider encouraging food logging to individuals who have demonstrated consistent use of self-monitoring technologies.
Enhancing behavioral intervention science: using community-based participatory research principles with the multiphase optimization strategy
Authors: Windsor Liliane Cambraia , Benoit Ellen , Pinto Rogério M , Gwadz Marya , Thompson Warren
Published: April 2021

Innovative methodological frameworks are needed in intervention science to increase efficiency, potency, and community adoption of behavioral health interventions, as it currently takes 17 years and millions of dollars to test and disseminate interventions. The multiphase optimization strategy (MOST) for developing behavioral interventions was designed to optimize efficiency, efficacy, and sustainability, while community-based participatory research (CBPR) engages community members in all research steps. Classical approaches for developing behavioral interventions include testing against control interventions in randomized controlled trials. MOST adds an optimization phase to assess performance of individual intervention components and their interactions on outcomes. This information is used to engineer interventions that meet specific optimization criteria focused on effectiveness, cost, or time. Combining CBPR and MOST facilitates development of behavioral interventions that effectively address complex health challenges, are acceptable to communities, and sustainable by maximizing resources, building community capacity and acceptance. Herein, we present a case study to illustrate the value of combining MOST and CBPR to optimize a multilevel intervention for reducing substance misuse among formerly incarcerated men, for under $250 per person. This integration merged experiential and cutting-edge scientific knowledge and methods, built community capacity, and promoted the development of efficient interventions. Integrating CBPR and MOST principles yielded a framework of intervention development/testing that is more efficient, faster, cheaper, and rigorous than traditional stage models. Combining MOST and CBPR addressed significant intervention science gaps and speeds up testing and implementation of interventions.
Hypertension across the lifespan
Authors: Bruce Kellie , Hilliard Tara C. , Esquibel Karen A. , Mello Inola , Moore Amy
Published: April 2021

Learn how to identify at-risk patients to facilitate timely intervention and promote positive outcomes.
The small (14 Fr) percutaneous catheter (P-CAT) versus large (28–32 Fr) open chest tube for traumatic hemothorax: A multicenter randomized clinical trial
Authors: Kulvatunyou Narong , Bauman Zachary M. , Zein Edine Savo Bou , de Moya Marc , Krause Casandra , Mukherjee Kaushik , Gries Lynn , Tang Andrew L. , Joseph Bellal , Rhee Peter
Published: April 2021

INTRODUCTION

The traditional treatment of traumatic hemothorax (HTX) has been an insertion of a large-bore 36- to 40-Fr chest tube. Our previous single-center randomized controlled trial (RCT) had shown that 14-Fr percutaneous catheters (PCs) (pigtail) were equally as effective as chest tube. We performed a multicenter RCT, hypothesizing that PCs are as equally effective as chest tubes in the management of patients with traumatic HTX (NCT03546764).

METHODS

We performed a multi-institution prospective RCT comparing 14-Fr PCs with 28- to 32-Fr chest tubes in the management of patients with traumatic HTX from July 2015 to September 2020. We excluded patients who were in extremis and required emergent tube placement and those who refused to participate. The primary outcome was failure rate, defined as a retained HTX requiring a second intervention. Secondary outcomes included daily drainage output, tube days, intensive care unit and hospital length of stay, and insertion perception experience (IPE) score on a scale of 1 to 5 (1, tolerable experience; 5, worst experience). Unpaired Student’s t test, χ2, and Wilcoxon rank sum test were used with significance set at p < 0.05.

RESULTS

After exclusion, 119 patients participated in the trial, 56 randomized to PCs and 63 to chest tubes. Baseline characteristics between the two groups were similar. The primary outcome, failure rate, was similar between the two groups (11% PCs vs. 13% chest tubes, p = 0.74). All other secondary outcomes were also similar, except PC patients reported lower IPE scores (median, 1: “I can tolerate it”; interquartile range, 1–2) than chest tube patients (median, 3: “It was a bad experience”; interquartile range, 2–5; p < 0.001).

CONCLUSION

Small caliber 14-Fr PCs are equally as effective as 28- to 32-Fr chest tubes in their ability to drain traumatic HTX with no difference in complications. Patients reported better IPE scores with PCs over chest tubes, suggesting that PCs are better tolerated.

LEVEL OF EVIDENCE

Therapeutic, level II.
Lung proteomic biomarkers associated with chronic obstructive pulmonary disease
Authors: Zhang Yu-Hang , Hoopmann Michael R. , Castaldi Peter J. , Simonsen Kirsten A. , Midha Mukul K. , Cho Michael H. , Criner Gerard J. , Bueno Raphael , Liu Jiangyuan , Moritz Robert L. , Silverman Edwin K.
Published: April 2021

Background

Identifying protein biomarkers for chronic obstructive pulmonary disease (COPD) has been challenging. Most previous studies have utilized individual proteins or pre-selected protein panels measured in blood samples. Mass spectrometry proteomic studies of lung tissue have been based on small sample sizes.

Methods

We utilized mass spectrometry proteomic approaches to discover protein biomarkers from 150 lung tissue samples representing COPD cases and controls. Top COPD-associated proteins were identified based on multiple linear regression analysis with false discovery rate (FDR) < 0.05. Correlations between pairs of COPD-associated proteins were examined. Machine learning models were also evaluated to identify potential combinations of protein biomarkers related to COPD.

Results

We identified 4407 proteins passing quality controls. Twenty-five proteins were significantly associated with COPD at FDR < 0.05, including Interleukin 33, Ferritin (light chain and heavy chain), and two proteins related to caveolae (CAV1 and CAVIN1). Multiple previously reported plasma protein biomarkers for COPD were not significantly associated with proteomic analysis of COPD in lung tissue, although RAGE was borderline significant. Eleven pairs of top significant proteins were highly correlated (r > 0.8), including several strongly correlated with RAGE (EHD2 and CAVIN1). Machine learning models using Random Forests with the top 5% of protein biomarkers demonstrated reasonable accuracy (0.766) and AUC (0.702) for COPD prediction.

Conclusions

Mass spectrometry proteomic analysis of lung tissue is a promising approach for the identification of biomarkers for COPD.
Comparative analysis of SARS-CoV-2 RNA load in wastewater from three different cities of Gujarat, India
Authors: Srivastava Vaibhav , Gupta Shilangi , Patel Arbind Kumar , Joshi Madhvi , Kumar Manish
Published: April 2021

The scientific community has widely supported wastewater monitoring of SARS-CoV-2 due to the early and prolonged excretion of coronavirus in the faecal matter. In the present study, eighteen influent wastewater samples from different wastewater treatment plants and pumping stations (5 samples from Vadodara city, 4 from Gandhinagar, and nine from Ahmedabad city) were collected and analyzed for the occurrence of SARS-CoV-2 RNA in Gujarat province, India. The results showed the highest SARS-CoV-2 genome concentration in Vadodara (3078 copies/ L), followed by Ahmedabad (2968 copies/ L) and Gandhinagar (354 copies/ L). The comparison of genome concentration more or less corresponded to the number of confirmed and active cases in all three cities. The study confirms the potential of the Surveillance of Wastewater for Early Epidemic Prediction (SWEEP) that can be used at a large scale around the globe for better dealing with the pandemic situation.

Graphical abstract
Ethnicity-specific alterations of plasma and hepatic lipidomic profiles are related to high NAFLD rate and severity in Hispanic Americans, a pilot study
Authors: Mazi Tagreed A. , Borkowski Kamil , Newman John W. , Fiehn Oliver , Bowlus Christopher L. , Sarkar Souvik , Matsukuma Karen , Ali Mohamed R. , Kieffer Dorothy A. , Wan Yu-Jui Y. , Stanhope Kimber L. , Havel Peter J. , Medici Valentina
Published: April 2021

Nonalcoholic fatty liver disease (NAFLD) is a progressive condition that includes steatosis (NAFL) and nonalcoholic steatohepatitis (NASH). In the U.S., Hispanics (HIS) are afflicted with NAFLD at a higher rate and severity compared to other ethnicities. To date, the mechanisms underlying this disparity have not been elucidated. In this pilot study, we compared untargeted plasma metabolomic profiles for primary metabolism, complex lipids, choline and related compounds between a group of HIS (n =7) and White Caucasian (CAU, n =8) subjects with obesity and biopsy-characterized NAFL to ethnicity-matched lean healthy controls (n =14 HIS and 8 CAU). We also compared liver and plasma metabolomic profiles in a group of HIS and CAU subjects with obesity and NASH of comparable NAFLD Activity Scores, to BMI-matched NASH-free subjects in both ethnicities. Results highlight signs of metabolic dysregulation observed in HIS, independent of obesity, including higher plasma triglycerides, acylcarnitines, and free fatty acids. With NASH progression, there were ethnicity-related differences in the hepatic profile, including higher free fatty acids and lysophospholipids seen in HIS, suggesting lipotoxicity is involved in the progression of NASH. We also observed greater hepatic triglyceride content, higher plasma triglyceride concentrations and lower hepatic phospholipids with signs of impaired hepatic mitochondrial β-oxidation. These findings provide preliminary evidence indicating ethnicity-related variations that could potentially modulate the risk for progression of NALD to NASH.

Highlights

Hispanic subjects show signs of metabolic dysregulations independent of obesity.

In nonalcoholic fatty liver, plasma metabolomic profiles are differentially altered between ethnicities.

In nonalcoholic steatohepatitis, the hepatic lipidomic profiles are differentially altered between ethnicities.

In Hispanics, nonalcoholic steatohepatitis shows higher triglycerides and lipotoxic lipids with signs of impaired hepatic mitochondrial β-oxidation.

Our results indicate evidence of ethnicity-related variations in the pathogenesis of nonalcoholic fatty liver disease.

Graphical Abstract
Electrophysiological measures from human iPSC-derived neurons are associated with schizophrenia clinical status and predict individual cognitive performance
Authors: Page Stephanie Cerceo , Sripathy Srinidhi Rao , Farinelli Federica , Ye Zengyou , Wang Yanhong , Hiler Daniel J , Pattie Elizabeth A , Nguyen Claudia V , Tippani Madhavi , Moses Rebecca L. , Chen Huei-Ying , Tran Matthew Nguyen , Eagles Nicholas J , Stolz Joshua M , Catallini Joseph L , Soudry Olivia R , Dickinson Dwight , Berman Karen F , Apud Jose A , Weinberger Daniel R , Martinowich Keri , Jaffe Andrew E , Straub Richard E , Maher Brady J
Published: April 2021

Neurons derived from human induced pluripotent stem cells (hiPSCs) have been used to model basic cellular aspects of neuropsychiatric disorders, but the relationship between the emergent phenotypes and the clinical characteristics of donor individuals has been unclear. We analyzed RNA expression and indices of cellular function in hiPSC-derived neural progenitors and cortical neurons generated from 13 individuals with high polygenic risk scores (PRS) for schizophrenia and a clinical diagnosis of schizophrenia, along with 15 neurotypical individuals with low PRS. We identified electrophysiological measures associated with diagnosis that implicated altered Na+channel function and GABA-ergic neurotransmission. Importantly, electrophysiological measures predicted cardinal clinical and cognitive features found in these schizophrenia patients. The identification of basic neuronal physiological properties related to core clinical characteristics of illness is a potentially critical step in generating leads for novel therapeutics.