bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting Fentanyl Analogs in Urine Using Precursor Ion Scan Mode
Authors: Budelier Melissa M , Franks Caroline E , Farnsworth Christopher W , Roper Stephen M
Published: January 2021

The opioid crisis has led many providers to inquire about the capabilities of urine drug testing (UDT) to detect contemporary compounds such as fentanyl and fentanyl analogs (FAs). However, current methods for clinical UDT, including immunoassays and targeted liquid chromatography tandem mass spectrometry, are not designed to broadly screen for the variety of FAs that may be encountered. In this proof-of-principle study, we developed a precursor ion scan (PIS) method to enable semi-targeted data acquisition for structurally related FAs. Based on the knowledge that many analogs fragment to m/z = 188 and m/z = 105, data were acquired on all precursor ions of 250–400 Da that fragmented to these product ions. Using a tandem mass spectrometer, we analyzed 102 residual urine specimens, in which we identified fentanyl, acetylfentanyl and acrylfentanyl. In 30 contrived urine samples, the PIS was also able to identify furanylfentanyl, butyrylfentanyl, 4-fluoroisobutyrylfentanyl and despropionylfentanyl with accuracy ranging from 83% to 100%.
Solidarity, Social Justice, and Faith: Humanitarian Action on the U.S.-Mexico Border
Authors: Panter-Brick Catherine
Published: January 2021

This article examines how notions of solidarity, social justice, and faith guide humanitarian work at the U.S.-Mexico border. Based on interviews and participant observation in three regions, it examines the narratives of lay and religious actors serving migrants, refugees, and asylum-seekers, to understand the moral and political resonance of their work in the context of border surveillance, migrant detentions, and mass deportation. Different notions of solidarity and justice jostle one another, espousing political and structural dimensions, whilst faith inspires the conviction that change can be enacted. A radical message for social action is, notably, fuelled by anger and courage, and used to confront pain and fear in the humanitarian and political sphere. This article contributes to a better understanding of how notions of human dignity, justice, and advocacy are articulated by humanitarian actors at the border, a site of striking civic and faith-based resistance to the criminalization of refugee and undocumented communities.
Functional Divergence of Multiple Duplicated Foxl2 Homeologs and Alleles in a Recurrent Polyploid Fish
Authors: Gan Rui-Hai , Wang Yang , Li Zhi , Yu Zhao-Xi , Li Xi-Yin , Tong Jin-Feng , Wang Zhong-Wei , Zhang Xiao-Juan , Zhou Li , Gui Jian-Fang
Published: January 2021

Evolutionary fates of duplicated genes have been widely investigated in many polyploid plants and animals, but research is scarce in recurrent polyploids. In this study, we focused on foxl2, a central player in ovary, and elaborated the functional divergence in gibel carp (Carassius gibelio), a recurrent auto-allo-hexaploid fish. First, we identified three divergent foxl2 homeologs (Cgfoxl2a-B, Cgfoxl2b-A, and Cgfoxl2b-B), each of them possessing three highly conserved alleles and revealed their biased retention/loss. Then, their abundant sexual dimorphism and biased expression were uncovered in hypothalamic–pituitary–gonadal axis. Significantly, granulosa cells and three subpopulations of thecal cells were distinguished by cellular localization of CgFoxl2a and CgFoxl2b, and the functional roles and the involved process were traced in folliculogenesis. Finally, we successfully edited multiple foxl2 homeologs and/or alleles by using CRISPR/Cas9. Cgfoxl2a-B deficiency led to ovary development arrest or complete sex reversal, whereas complete disruption of Cgfoxl2b-A and Cgfoxl2b-B resulted in the depletion of germ cells. Taken together, the detailed cellular localization and functional differences indicate that Cgfoxl2a and Cgfoxl2b have subfunctionalized and cooperated to regulate folliculogenesis and gonad differentiation, and Cgfoxl2b has evolved a new function in oogenesis. Therefore, the current study provides a typical case of homeolog/allele diversification, retention/loss, biased expression, and sub-/neofunctionalization in the evolution of duplicated genes driven by polyploidy and subsequent diploidization from the recurrent polyploid fish.
Human pathways in animal models: possibilities and limitations
Authors: Doncheva Nadezhda T , Palasca Oana , Yarani Reza , Litman Thomas , Anthon Christian , Groenen Martien A M , Stadler Peter F , Pociot Flemming , Jensen Lars J , Gorodkin Jan
Published: January 2021

Animal models are crucial for advancing our knowledge about the molecular pathways involved in human diseases. However, it remains unclear to what extent tissue expression of pathways in healthy individuals is conserved between species. In addition, organism-specific information on pathways in animal models is often lacking. Within these limitations, we explore the possibilities that arise from publicly available data for the animal models mouse, rat, and pig. We approximate the animal pathways activity by integrating the human counterparts of curated pathways with tissue expression data from the models. Specifically, we compare whether the animal orthologs of the human genes are expressed in the same tissue. This is complicated by the lower coverage and worse quality of data in rat and pig as compared to mouse. Despite that, from 203 human KEGG pathways and the seven tissues with best experimental coverage, we identify 95 distinct pathways, for which the tissue expression in one animal model agrees better with human than the others. Our systematic pathway-tissue comparison between human and three animal modes points to specific similarities with human and to distinct differences among the animal models, thereby suggesting the most suitable organism for modeling a human pathway or tissue.
Epidemiology of Trauma History and Body Pain: A Retrospective Study of Community-Based Australian Women
Authors: Flehr Alison , Coles Jan , Dixon John B , Gibson Stephen J , Brilleman Samuel L , Harris Melissa L , Loxton Deborah
Published: January 2021

Objective

To assess whether body pain was associated with different trauma histories (physical injury vs. interpersonal injury [IPI]) within Australian women, along with body pain and trauma history associations with biological and psychological (biopsycho) confounders.

Methods

A retrospective cross-sectional analysis was conducted on the Australian Longitudinal Study on Women’s Health (ALSWH) 1973–1978 birth cohort wave 6 data. Relevant life events were categorized into two types of traumatic experience and included as exposure variables in a multinomial regression model for body pain subgroups. Also, subgroup analyses considered trauma and pain effects and interactions on biopsycho burden.

Results

The unadjusted multinomial regression model revealed that a history of physical injury was found to be significantly associated with body pain severity, as was a history of IPI trauma. After the model was adjusted to include biopsycho confounders, the association between IPI and body pain was no longer significant, and post hoc analysis revealed the relationship was instead mediated by biopsycho confounders. Women with a history of IPI and body pain were also found to have the greatest biopsycho (physical functioning, stress, anxiety, and depression) burden.

Discussion

The relationship between IPI and body pain was found to be mediated by biopsycho burden, whereas the relationship between physical injury and body pain was not. Also, a history of IPI was associated with a greater biopsycho burden than was a history of physical injury. These results suggest there is clinical value in considering the comprehensive trauma history of patients with pain when developing their biopsychosocial model of care.
Influence of Fusarium virguliforme Temporal Colonization of Corn, Tillage, and Residue Management on Soybean Sudden Death Syndrome and Soybean Yield
Authors: Baetsen-Young Amy M. , Araldi Da Silva Grazieli , Kandel Yuba R. , Jacobs Janette L. , Byrne Adam M. , Mueller Daren S. , Smith Damon L. , Tenuta Albert U. , Wise Kiersten A. , Day Brad , Chilvers Martin I.
Published: January 2021

The asymptomatic host range of Fusarium virguliforme includes corn, a common crop rotated with soybean that we hypothesize may alter F. virguliforme population dynamics and disease management. A field-based approach explored the temporal dynamics of F. virguliforme colonization of corn and soybean roots under different tillage and residue managements. Experiments were conducted in Iowa, Indiana, Michigan, and Wisconsin, United States and Ontario, Canada from 2016 to 2018. Corn and soybean roots were sampled at consecutive timepoints between 1 and 16 weeks after planting. DNA was extracted from all roots and analyzed by real-time quantitative PCR for F. virguliforme quantification. Trials were rotated between corn and soybean, containing a two-by-two factorial of tillage (no-tilled or tilled) and corn residue (with or without) in several experimental designs. In 2016, low amounts (approximately 100 fg per 10 mg of root tissue) of F. virguliforme were detected in the inoculated Iowa, Indiana, and Michigan locations and noninoculated Wisconsin corn fields. However, in 2017, greater levels of F. virguliforme DNA were detected in Iowa, Indiana, and Michigan across sampling timepoints. Tillage practices showed inconsistent effects on F. virguliforme root colonization and sudden death syndrome (SDS) foliar symptoms among trials and locations. However, residue management did not alter root colonization of corn or soybean by F. virguliforme. Plots with corn residue had greater SDS foliar disease index in Iowa in 2016. However, this trend was not observed across the site-years, indicating that corn residue may occasionally increase SDS foliar symptoms depending on the disease level and soil and weather factors.
The Scarf Osteotomy
Authors: Weigelt Lizzy , Heyes Gavin J. , Mason Lyndon , Molloy Andrew
Published: January 2021

The Scarf osteotomy is one of the most widely used techniques for hallux valgus deformity correction. We present a literature review on the evolution of this technique and our results with a specific remark to flat foot deformity as a risk factor for the recurrence of hallux valgus deformity.

Level of Evidence: Diagnostic Level V. See Instructions for Authors for a complete description of levels of evidence.
TNF-α Inhibitors for the Management of Intractable Corneal Melt: Report of Three Cases and Review of the Literature
Authors: Utine Canan Asli , Birlik Merih , Özizmirliler Denizcan , Karakaş Ali , Akbulut Betül , Durak Ismet
Published: January 2021

Objective:

To report three consecutive cases with noninfectious corneal melting, whose disease progression could only be halted with tumor necrosis-α (TNF-α) inhibitor infusion, with a review of the relevant literature.

Materials and methods:

Patients with toxic epidermal necrolysis, severe alkaline burn, and Sjögren syndrome had experienced severe corneal melting following penetrating keratoplasty, Boston type 1 keratoprosthesis implantation or spontaneously, respectively. Topical autologous serum eye-drops, medroxyprogesterone, and acetylcysteine formulations; frequent nonpreserved lubrication; systemic tetracyclines and vitamin-C supplements; topical and systemic steroids and steroid-sparing agents; surgical approaches including amniotic membrane transplantation, tectonic graft surgery; and tarsorraphy failed to alter the disease courses.

Results:

Upon consultation with the rheumatology clinic, TNF-α inhibitor infliximab (Remicade; Centocor Ortho Biotech Inc, Horsham, PA) 5 mg/kg infusion was planned for each patient. After 0-, 2-, and 6-week doses, monthly infusion at the same dose was maintained for 12 months because of severe and intractable course of their diseases. Each case showed dramatic improvements in corneal melts; and sterile vitritis in the eye with Boston keratoprosthesis responded, as well.

Conclusions:

Inhibiting TNF-α-mediated expression of matrix metalloproteinases responsible for collagen breakdown should be considered in refractory cases, as a means of globe salvage.
Anterior Segment Ischemia After Peripheral Annular Lamellar Sclerokeratoplasty for Advanced Terrien Marginal Degeneration
Authors: Mudgil Tanvi , Fernandes Merle
Published: January 2021

A man with 360° bilateral peripheral thinning, peripheral vascularization, and lipid deposition diagnosed with Terrien marginal degeneration, underwent a 360° peripheral annular lamellar sclerokeratoplasty (PALK) (tuck-in) in the right eye for 90% peripheral thinning and high astigmatism. One-week postoperatively, a sudden drop in vision to counting fingers 1 m from 20/50 with circumciliary congestion, diffuse corneal edema, intense anterior chamber inflammation, keratic precipitates with fixed dilated pupil, and hypotony led to a diagnosis of suspected anterior segment ischemia. Anterior segment fluorescein angiography was suggestive of ischemia. After intensive topical and systemic steroids tapered over 6 months, his symptoms and signs improved. At the last follow-up 4 years later, his best contact lens-corrected visual acuity was 20/30. Anterior segment ischemia has not been reported after a PALK for advanced corneal ectatic disorders. Prompt diagnosis and commencement of intensive steroids was helpful in reversing this condition.
Good Visual Outcomes After Pituitary Tumor Surgery Are Associated With Increased Visual Cortex Functional Connectivity
Authors: Lang Stefan T. , Ryu Won Hyung A. , Starreveld Yves P. , Costello Fiona E. ,   the PITNET Study Group
Published: January 2021

Background:

Patients presenting with visual impairment secondary to pituitary macroadenomas often experience variable recovery after surgery. Several factors may impact visual outcomes including the extent of neuroaxonal damage in the afferent visual pathway and cortical plasticity. Optical coherence tomography (OCT) measures of retinal structure and resting-state functional MRI (rsfMRI) can be used to evaluate the impact of neuroaxonal injury and cortical adaptive processes, respectively. The purpose of this study was to determine whether rsfMRI patterns of functional connectivity (FC) distinguish patients with good vs poor visual outcomes after surgical decompression of pituitary adenomas.

Methods:

In this retrospective cohort study, we compared FC patterns between patients who manifested good (GO) vs poor (PO) visual outcomes after pituitary tumor surgery. Patients (n = 21) underwent postoperative rsfMRI a minimum of 1 year after tumor surgery. Seed-based connectivity of the visual cortex (primary [V1], prestriate [V2], and extrastriate [V5]) was compared between GO and PO patients and between patients and healthy controls (HCs) (n = 19). Demographics, visual function, and OCT data were compared preoperatively and postoperatively between patient groups. The threshold for GO was visual field mean deviation equal or less than −5.00 dB and/or visual acuity equal to or better than 20/40.

Results:

Increased postoperative FC of the visual system was noted for GO relative to PO patients. Specifically, good visual outcomes were associated with increased connectivity of right V5 to the bilateral frontal cortices. Compared with HCs, GO patients showed increased connectivity of V1 and left V2 to sensorimotor cortex, increased connectivity of right and left V2 to medial prefrontal cortex, and increased connectivity of right V5 the right temporal and frontal cortices.

Conclusions:

Increased visual cortex connectivity is associated with good visual outcomes in patients with pituitary tumor, at late phase of recovery. Our findings suggest that rsfMRI does distinguish GO and PO patients after pituitary tumor surgery. This imaging modality may have a future role in characterizing the impact of cortical adaptation on visual recovery.
Novosphingobium olei sp. nov., with the ability to degrade diesel oil, isolated from oil-contaminated soil and proposal to reclassify Novosphingobium stygium as a later heterotypic synonym of Novosphingobium aromaticivorans
Authors: Chaudhary Dhiraj Kumar , Dahal Ram Hari , Kim Dong-Uk , Kim Jaisoo
Published: January 2021

Two yellow-pigmented, non-motile, Gram-stain-negative, and rod-shaped bacteria, designated TW-4T and TNP-2 were obtained from oil-contaminated soil. Both strains degrade diesel oil, hydrolyse aesculin, DNA, Tween 40 and Tween 60. A phylogenetic analysis based on its 16S rRNA gene sequence revealed that strain TW-4T formed a lineage within the family

Erythrobacteraceae

and clustered as members of the genus

Novosphingobium

. The closest members of strain TW-4T were

Novosphingobium subterraneum

DSM 12447T (97.9 %, sequence similarity),

Novosphingobium lubricantis

KSS165-70T (97.8 %),

Novosphingobium taihuense

T3-B9T (97.8 %),

Novosphingobium aromaticivorans

DSM 12444T (97.7 %),

Novosphingobium flavum

UCT-28T (97.7 %), and

Novosphingobium bradum

STM-24T (97.6 %). The sequence similarity for other members was ≤97.6 %. The genome of strain TW-4T was 4 683 467 bp long with 44 scaffolds and 4280 protein-coding genes. The sole respiratory quinone was Q-10. The major cellular fatty acids were summed feature 8 (C18 : 1
 ω7c and/or C18 : 1
 ω6c), summed feature 3 (C16 : 1
 ω7c and/or C16 : 1
 ω6c), C16 : 0 and C14 : 0 2-OH. The major polar lipids were phosphatidylethanolamine (PE), phosphatidylglycerol (PG), diphosphatidylglycerol (DPG), phosphatidylcholine (PC), phosphatidyl-n-methylethanolamine (PME) and sphingoglycolipid (SGL). The DNA G+C content of the type strain was 65.0 %. The average nucleotide identity (ANIu) and in silico DNA–DNA hybridization (dDDH) relatedness values between strain TW-4T and closest members were below the threshold value for species delineation. Based on polyphasic taxonomic analyses, strain TW-4T represents novel species in the genus

Novosphingobium

, for which the name Novosphingobium olei sp. nov. is proposed. The type strain is TW-4T (=KACC 21628T=NBRC 114364T) and strain TNP-2 (=KACC 21629=NBRC 114365) represents an additional strain. Based on new data obtained in this study, it is also proposed to reclassify

Novosphingobium stygium

as a later heterotypic synonym of

Novosphingobium aromaticivorans

.
Protein scaffold-based multimerization of soluble ACE2 efficiently blocks SARS-CoV-2 infectionin vitroandin vivo
Authors: Kayabolen Alisan , Akcan Ugur , Ozturan Dogancan , Ulbegi-Polat Hivda , Sahin Gizem Nur , Degirmenci Nareg Pinarbasi , Bayraktar Canan , Soyler Gizem , Sarayloo Ehsan , Nurtop Elif , Ozer Berna , Guney-Esken Gulen , Barlas Tayfun , Yildirim Ismail Selim , Dogan Ozlem , Karahuseyinoglu Sercin , Lack Nathan A. , Kaya Mehmet , Albayrak Cem , Can Fusun , Solaroglu Ihsan , Bagci-Onder Tugba
Published: January 2021

Soluble ACE2 (sACE2) decoy receptors are promising agents to inhibit SARS-CoV-2, as their efficiency is less likely to be affected by common escape mutations in viral proteins. However, their success may be limited by their relatively poor potency. To address this challenge, we developed a large decoy library of sACE2 fusion proteins, generated with several protease inhibitors or multimerization tags. Among these decoys, multimeric sACE2 consisting of SunTag or MoonTag systems, which were originally utilized for signal amplification or gene activation systems, were extremely effective in neutralizing SARS-CoV-2 in pseudoviral systems and in clinical isolates. These novel sACE2 fusion proteins exhibited greater than 100-fold SARS-CoV-2 neutralization efficiency, compared to monomeric sACE2. SunTag or MoonTag in combination with a more potent version of sACE2, which has multiple point mutations for greater binding (v1), achieved near complete neutralization at a sub-nanomolar range, comparable with clinical monoclonal antibodies. Pseudoviruses bearing mutant versions of Spike, alpha, beta, gamma or delta variants, were also neutralized efficiently with SunTag or MoonTag fused sACE2(v1). Finally, therapeutic treatment of sACE2(v1)-MoonTag provided protection against SARS-CoV-2 infection in anin vivomouse model. Overall, we suggest that the superior activity of the sACE2-SunTag or sACE2-MoonTag fusions is due to the greater occupancy of the multimeric sACE2 receptors on Spike protein as compared to monomeric sACE2. Therefore, these highly potent multimeric sACE2 decoy receptors may offer a promising treatment approach against SARS-CoV-2 infections.

One Sentence Summary

Multimerization of sACE2 markedly enhanced the neutralization of SARS-CoV-2 by blocking multiple viral spike proteins simultaneously.
Natural variation inCaenorhabditis elegansresponses to the anthelmintic emodepside
Authors: Wit Janneke , Rodriguez Briana C. , Andersen Erik. C.
Published: January 2021

Treatment of parasitic nematode infections depends primarily on the use of anthelmintics. However, this drug arsenal is limited, and resistance against most anthelmintics is widespread. Emodepside is a new anthelmintic drug effective against gastrointestinal and filarial nematodes. Nematodes that are resistant to other anthelmintic drug classes are susceptible to emodepside, indicating that the emodepside mode of action is distinct from previous anthelmintics. The laboratory-adaptedCaenorhabditis elegansstrain N2 is sensitive to emodepside, and genetic selection andin vitroexperiments implicatedslo-1, a BK potassium channel gene, in emodepside mode of action. In an effort to understand how natural populations will respond to emodepside, we measured brood sizes and developmental rates of wildC. elegansstrains after exposure to the drug and found natural variation across the species. Some of the observed variation inC. elegansemodepside responses correlates with amino acid substitutions inslo-1, but genetic mechanisms other thanslo-1coding variants likely underlie emodepside resistance in wildC. elegansstrains. Additionally, the assayed strains have higher offspring production in low concentrations of emodepside (a hormetic effect), which could impact treatment strategies when parasites are underdosed. We find that natural variation affects emodepside sensitivity, supporting the suitability ofC. elegansas a model system to study emodepside responses across natural nematode populations.

Graphical abstract

Highlights

Emodepside responses vary across theC. elegansspecies.

Wild strains ofC. elegansmodel natural differences in parasite emodepside responses.

Variation in the emodepside targetslo-1and other loci correlate with resistance.

Low doses of emodepside cause a hormetic effect on offspring production.
Adipocyte-specific deletion of the oxygen-sensor PHD2 sustains elevated energy expenditure at thermoneutrality
Authors: Salazar Mario Gomez , Cervera Iris Pruñonosa , Wang Rongling , French Karen , García-Martín Ruben , Blüher Matthias , Schofield Christopher J , Stimson Roland H , Chavakis Triantafyllos , Gudmundsson Elias F , Jennings Lori L , Gudnason Vilmundur G , Morton Nicholas M , Emilsson Valur , Michailidou Zoi
Published: January 2021

Enhancing brown adipose tissue (BAT) function to combat metabolic disease is a promising therapeutic strategy. A major obstacle to this strategy is that a thermoneutral environment, relevant to most modern human living conditions, deactivates functional BAT. We showed that we can overcome the dormancy of BAT at thermoneutrality by inhibiting the main oxygen sensor HIF-prolyl hydroxylase, PHD2, specifically in adipocytes. Mice lacking adipocyte PHD2 (P2KOad) and housed at thermoneutrality maintained greater BAT mass, had detectable UCP1 protein expression in BAT and higher energy expenditure. Mouse brown adipocytes treated with the pan-PHD inhibitor, FG2216, exhibited higherUcp1mRNA and protein levels, effects that were abolished by antagonising the canonical PHD2 substrate, HIF-2a. Induction ofUCP1mRNA expression by FG2216, was also confirmed in human adipocytes isolated from obese individuals. Human serum proteomics analysis of 5457 participants in the deeply phenotyped Age, Gene and Environment Study revealed that serum PHD2 (aka EGLN1) associates with increased risk of metabolic disease. Our data suggest adipose–selective PHD2 inhibition as a novel therapeutic strategy for metabolic disease and identify serum PHD2 as a potential biomarker.
Cellular feedback to organotelluranes displays modulation of antioxidant proteins gene expression
Authors: Pessoto Felipe S. , Yokomizo César H. , Cunha Rodrigo L. O. R. , Nantes-Cardoso Iseli L.
Published: January 2021

Organotelluranes RT3 and RT4 are thiol reagents that induce mitochondrial transition pore (MTP) opening in a sensitive and insensitive manner to cyclosporin A. Although RT3 and RT4 promote glutathione depletion, paradoxically, they are also an efficient antioxidant for membrane lipids. These compounds’ antagonistic effects elicited the challenging question of how the gene expression of antioxidant enzymes would respond to treatment with these compounds. The influence of RT3 and RT4 on antioxidant enzyme expression was investigated in cultured aortic smooth muscle cells (ASMC). RT3 and RT4 promoted disruption of ionic calcium homeostasis, mitochondrial transmembrane potential (ΔΨ), and cell death in a dose-dependent manner. The cell death mechanisms responded qualitatively to the increase of the organotellurane concentration and changed from apoptosis to necrosis. RT3 and RT4 increased the expression of thioredoxin significantly. RT3 also increased the expression of glutaredoxin and glutathione peroxidase, slightly the catalase expression without significant effects on SOD expression. The results are consistent with GSH and protein thiol depletion and discussed based on the cell toxicity mechanism exhibited by these compounds.

Abstract Figure
Chromosomal Characteristics of Salt Stress Heritable Gene Expression in the Rice Genome
Authors: McGowan Matthew T. , Zhang Zhiwu , Ficklin Stephen P.
Published: January 2021

Background

Gene expression is potentially an important heritable quantitative trait that mediates between genetic variation and higher-level complex phenotypes through time and condition-dependent regulatory interactions. Increasing quantities of high-throughput DNA and RNA sequencing and standardization of research populations has resulted in the accumulation of overlapping -omics data allowing for deeper investigation into the genomic structure and conditional stability of gene expression traits. Therefore, we sought to explore both the genomic and condition-specific characteristics of gene expression heritability within the context of chromosomal structure, using a diverse, 84-line,Oryza sativa(rice) population under optimal and salt-stressed conditions.

Results

Heritability was estimated for the 84 genotypes with common tools and an approach using biological gene expression replicates similar to a twin study in humans. Overall, 5,936 genes were found to have heritable expression regardless of condition and 1,377 genes were found to have heritable expression only during salt stress. These genes with salt-specific heritable expression are enriched for functional terms associated with response to stimulus and transcription factor activity. Additionally, we discovered that highly and lowly expressed genes, and genes with heritable expression are distributed differently along the chromosomes in patterns that follow previously identified chromosomal conformation capture (Hi-C) A/B chromatin compartments. Furthermore, multiple genomic hot-spots enriched for genes with salt-specific heritability were identified on chromosomes 1, 4, 6, and 8. These hotspots were found to contain genes functionally enriched for transcriptional regulation and overlaps with a previously identified major QTL for salt-tolerance in rice.

Conclusions

Investigating the heritability of traits, and in-particular gene expression traits, is important towards a basic understanding of how regulatory networks behave across a population. Additionally, heritable gene expression architecture can be used for further exploration of gene-trait relationships, assist in interpretation and analysis of eQTLs, used as priors for approaches seeking to identification of potential biomarkers, or used in genomic selection modules with potential applications in plant breeding. This work provides insights into patterns of expression and spatial patterns at the chromosomal level.
Genomic signatures of UV resistance evolution inEscherichia colidepend on the growth phase during exposure
Authors: Selveshwari S , Lele Kasturi , Dey Sutirth
Published: January 2021

Physiological states can determine the ability of organisms to handle stress. Does this mean that the same selection pressure will lead to different evolutionary outcomes, depending on the organisms’ physiological state? If yes, what will be the genomic signatures of such adaptation(s)? We used experimental evolution inEscherichia colifollowed by whole-genome whole-population sequencing to investigate these questions. The sensitivity ofEscherichia colito ultraviolet (UV) radiation depends on the growth phase during which it experiences the radiation. We evolved replicateE. colipopulations under two different conditions of UV exposures, namely exposure during the lag and the exponential growth phases. Initially, the UV sensitivity of the ancestor was greater during the exponential phase than the lag phase. However, at the end of 100 cycles of exposure, UV resistance evolved to similar extents in both treatments. Genome analysis showed that mutations in genes involved in DNA repair, cell membrane structure and RNA polymerase were common in both treatments. However, different functional groups were found mutated in populations experiencing lag and exponential UV treatment. In the former, genes involved in transcriptional and translational regulations and cellular transport were mutated, whereas the latter treatment showed mutations in genes involved in signal transduction and cell adhesion. Interestingly, the treatments showed no phenotypic differences in a number of novel environments. Taken together, these results suggest that selection pressures at different physiological stages can lead to differences in the genomic signatures of adaptation, which need not necessarily translate into observable phenotypic differences.
A mRNA-LNP vaccine against Dengue Virus elicits robust, serotype-specific immunity
Authors: Wollner Clayton J. , Richner Michelle , Hassert Mariah A. , Pinto Amelia K. , Brien James D. , Richner Justin M.
Published: January 2021

Dengue virus (DENV) is the most common vector-borne viral disease with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly-neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding for the membrane and envelope structural proteins from DENV serotype 1 encapsulated into lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection with high levels of neutralizing antibody titers and antiviral CD4+and CD8+T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine, or a vaccine with mutations in the immunodominant fusion-loop epitope, elicited equivalent humoral and cell mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype specific immunity with minimal serum cross-reactivity and reduced ADE compared to a live DENV1 viral infection.

IMPORTANCE

With 400 million worldwide infections each year, dengue is the most common vector-born viral disease. 40% of the world’s population is at risk with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing sub optimally, the need for an effective dengue vaccine is urgent. Here we develop and characterize a novel mRNA vaccine encoding for the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement. Importantly our vaccine only induced serotype specific immune responses and did not induce ADE.
Continued need for non-pharmaceutical interventions after COVID-19 vaccination in long-term-care facilities
Authors: Love Jay , Keegan Lindsay T. , Angulo Frederick J. , McLaughlin John , Shea Kimberly M. , Swerdlow David L. , Samore Matthew H. , Toth Damon J.A.
Published: January 2021

Long-term care facilities (LTCFs) bear disproportionate burden of COVID-19 and are prioritized for vaccine deployment. LTCF outbreaks could continue occurring during vaccine rollout due to incomplete population coverage, and the effect of vaccines on viral transmission are currently unknown. Declining adherence to non-pharmaceutical interventions (NPIs) against within-facility transmission could therefore limit the effectiveness of vaccination. We built a stochastic model to simulate outbreaks in LTCF populations with differing vaccination coverage and NPI adherence to evaluate their interacting effects. Vaccination combined with strong NPI adherence produced the least morbidity and mortality. Healthcare worker vaccination improved outcomes in unvaccinated LTCF residents but was less impactful with declining NPI adherence. To prevent further illness and deaths, there is a continued need for NPIs in LTCFs during vaccine rollout.
Neural stem cells alter nucleocytoplasmic partitioning and accumulate nuclear polyadenylated transcripts during quiescence
Authors: Rossi A. , Coum A. , Madelenat M. , Harris L. , Miedzik A. , Strohbuecker S. , Chai A. , Fiaz H. , Chaouni R. , Faull P. , Grey W. , Bonnet D. , Hamid F. , Makeyev E. V. , Snijders A. P. , Kelly G. , Guillemot F. , Sousa-Nunes R.
Published: January 2021

Quiescence is a cellular state characterised by reversible cell-cycle arrest and diminished biosynthetic activity that protects against environmental insults, replicative exhaustion and proliferation-induced mutations1. Entry into and exit from this state controls development, maintenance and repair of tissues plus, in the adult central nervous system, generation of new neurons and thus cognition and mood2–4. Cancer stem cells too can undergo quiescence, which confers them resistance to current therapies5, 6. Despite clinical relevance, quiescence is poorly understood and is defined functionally given lack of molecular markers. Decrease of the most resource-intensive cellular process of protein synthesis is a feature of quiescence, controlled across species and cell types by inhibition of the Target of Rapamycin (TOR) pathway1, 7. Here, we combine Drosophila genetics and a mammalian model to show that altered nucleocytoplasmic partitioning and nuclear accumulation of polyadenylated RNAs are novel evolutionarily conserved hallmarks of quiescence regulation. Furthermore, nuclear accumulation of messenger RNA (mRNA) in quiescent NSCs (qNSCs) largely predicts protein downregulation, accounting for uncoupling between transcriptome and proteome in quiescence. These mechanisms provide a previously unappreciated regulatory layer to reducing protein synthesis in quiescent cells, whilst priming them for reactivation in response to appropriate cues.
The mechanism of full activation of tumor suppressor PTEN at the phosphoinositide-enriched membrane
Authors: Jang Hyunbum , Smith Iris Nira , Eng Charis , Nussinov Ruth
Published: January 2021

Tumor suppressor PTEN, the second most highly mutated protein in cancer, dephosphorylates signaling lipid PIP3produced by PI3Ks. Excess PIP3promotes cell proliferation. The mechanism at the membrane of this pivotal phosphatase is unknown hindering drug discovery. Exploiting explicit solvent simulations, we tracked full-length PTEN trafficking from the cytosol to the membrane. We observed its interaction with membranes composed of zwitterionic phosphatidylcholine, anionic phosphatidylserine, and phosphoinositides, including signaling lipids PIP2and PIP3. We tracked it’s moving away from the zwitterionic and getting absorbed onto anionic membrane that harbors PIP3. We followed it localizing on microdomains enriched in signaling lipids, as PI3K does, and observed PIP3allosterically unfolding the N-terminal PIP2binding domain, positioning it favorably for the polybasic motif interaction with PIP2. Finally, we determined PTEN catalytic action at the membrane, all in line with experimental observations, deciphering the mechanisms of how PTEN anchors to the membrane and restrains cancer.
Metabolite discovery through global annotation of untargeted metabolomics data
Authors: Chen Li , Lu Wenyun , Wang Lin , Xing Xi , Chen Ziyang , Teng Xin , Zeng Xianfeng , Muscarella Antonio D. , Shen Yihui , Cowan Alexis , McReynolds Melanie R. , Kennedy Brandon , Lato Ashley M. , Campagna Shawn R. , Singh Mona , Rabinowitz Joshua
Published: January 2021

Liquid chromatography-high resolution mass spectrometry (LC-MS)-based metabolomics aims to identify and quantitate all metabolites, but most LC-MS peaks remain unidentified. Here, we present a global network optimization approach, NetID, to annotate untargeted LC-MS metabolomics data. The approach aims to generate, for all experimentally observed ion peaks, annotations that match the measured masses, retention times, and (when available) MS/MS fragmentation patterns. Peaks are connected based on mass differences reflecting adducting, fragmentation, isotopes, or feasible biochemical transformations. Global optimization generates a single network linking most observed ion peaks, enhances peak assignment accuracy, and produces chemically-informative peak-peak relationships, including for peaks lacking MS/MS spectra. Applying this approach to yeast and mouse data, we identified five novel metabolites (thiamine derivatives and N-glucosyl-taurine). Isotope tracer studies indicate active flux through these metabolites. Thus, NetID applies existing metabolomic knowledge and global optimization to annotate untargeted metabolomics data, revealing novel metabolites.
HarnessingEscherichia colifor bio-based production of formate under pressurized H2and CO2gases
Authors: Roger Magali , Reed Tom C. , Sargent Frank
Published: January 2021

ABSRACT

Escherichia coliis gram-negative bacterium that is a workhorse of the biotechnology industry. The organism has a flexible metabolism and can perform a mixed-acid fermentation under anaerobic conditions. Under these conditionsE. colisynthesises a formate hydrogenlyase isoenzyme (FHL-1) that can generate molecular hydrogen and carbon dioxide from formic acid. The reverse reaction is hydrogen-dependent carbon dioxide reduction (HDCR), which has exciting possibilities in bio-based carbon capture and storage if it can be harnessed. In this study, anE. colihost strain was optimised for the production of formate from H2and CO2during bacterial growth in a pressurised batch bioreactor. A host strain was engineered that constitutively produced the FHL-1 enzyme and incorporation of tungsten in to the enzyme, in place of molybdenum, helped poise the reaction in the HDCR direction. The engineeredE. colistrain showed an ability to grow under fermentative conditions while simultaneously producing formate from gaseous H2and CO2supplied in the bioreactor. However, while a sustained pressure of 10 bar N2had no adverse effect on cell growth, when the culture was placed at or above 4 bar pressure of a H2:CO2mixture then a clear growth deficiency was observed. Taken together, this work demonstrates that growing cells can be harnessed to hydrogenate carbon dioxide and provides fresh evidence that the FHL-1 enzyme may be intimately linked with bacterial energy metabolism.
Britain and Hong Kong: the 2019 protests and their aftermath
Authors: Summers Tim
Published: January 2021

Purpose

The purpose of this paper is to examine British policy towards Hong Kong from the protests of 2019 through political controversies in 2020.

Design/methodology/approach

The paper offers a foreign policy analysis based on a chronological account of the public interventions made by London from April 2019 to the passage of the national security law in the middle of 2020. It discusses the factors which contributed to the UK's positions and looks in more detail at an issue which relates to the British colonial legacy: the status of British National (Overseas) passport holders.

Findings

The paper argues that the UK's policy was influenced by a combination of factors: developments in Hong Kong, the implications of and perceptions about its historical position as the former colonial power, the growing influence of lobby groups in the UK and Hong Kong (especially in agenda setting), and (to a lesser extent) the UK's wider relations with China. In trying to balance these, British policy tended to be reactive rather than strategic. London generally took positions sympathetic to the protest movement and political opposition, characterised in the paper as “soft partisanship”, shifting to clear opposition to Beijing's approach when the National Security Law was announced.

Social implications

The paper helps to understand international policy towards Hong Kong.

Originality/value

The paper offers the first account of British policy towards Hong Kong during this period and adds to the limited existing literature on the UK's Hong Kong policy over recent years. This case study sheds light on wider questions of international perceptions of developments in Hong Kong during a tumultuous period in the city's history and informs broader studies of foreign policymaking.
Environmental risk, FDI and tax reforms: why we must worry
Authors: Boachie Yiadom Eric , Mensah Lord
Published: January 2021

Purpose

In this paper, we use empirical models to examine the main channel through which FDI escalates environmental risk. We explore whether countries with “weak” or better still low tax rate attract “dirty” FDI to deteriorate their environment

Design/methodology/approach

The analysis uses a 40-year panel to show that foreign direct investment (FDI) and tax policy matter in accounting for cross-country environmental risk.

Findings

Our sample finds support that the tax channel is the main medium through which FDI worsens environmental risk. By discomposing tax policy into low and high regimes, we report that countries that deliberately reform tax policy to bait FDI have higher environmental risk.

Social implications

A useful lesson from here is that using tax policy to lure FDI amounts to shortchanging capital risk for environmental risk.

Originality/value

The paper is unique because it identifies tax policy as a channel through which FDI affects the environment in Africa. Other studies overly simplifies the relationship between FDI and its impact on the environment, and it makes it difficult and ambiguous in offering specific policy direction.
Challenges and potential solutions to utilization of carrot rejects and waste in food processing
Authors: Kaur Gagan Jyot , Orsat Valerie , Singh Ashutosh
Published: January 2021

Purpose

Of the global carrot production, 20–30% is outgraded as carrot rejects and waste (CRW) at the primary processing level, which is partially used toward animal feed and the remaining ends in the landfills. This study was undertaken to identify the hurdles and seek potential solutions for using CRW in food processing.

Design/methodology/approach

CRW were procured from the processing unit in Ontario, Canada, as (1) outgraded carrots (OGCs) and (2) processed discards (PDs). The physical parameters of CRW, imperfections responsible for their separation from the graded carrots and shelf-life studies were recorded.

Findings

A significant difference with p ≤ 0.05 was recorded for both the physical parameters and the nature of imperfections in CRW. Discolored carrots (42.37 ± 3.59%) and the presence of vertical splits (52.71 ± 3.18%) were among the top defects in the OGCs. In contrast, the presence of broken tips (54.83 ± 2.52%) and vertical splits (40.56 ± 2.65%) were among the primary cause for the generation of PDs. In total, five percent of CRW were initially infected, which later increased to 30% during the seven days storage period.

Research limitations/implications

The limitation of the study was that only two varieties of carrots were considered and these were procured from one processor (the authors’ industry partner) at different time intervals of the year. Microbiological analysis could not be completed and reported due to prevailing coronavirus disease 2019 (COVID-19) situation but is included for future studies.

Practical implications

Development of specialized post-harvest packaging and handling protocols and separation of infected fragments are essential before suggesting the use of CRW in food processing.

Originality/value

Numerous studies report on the post-harvest management and processing of graded carrots, but limited to no studies are published on the usage of CRW in food processing.
Development and application of a service design-based process for improvement of human resource management service quality
Authors: Mashhady Arash , Khalili Hamidreza , Sameti Ardalan
Published: January 2021

Purpose

This research approaches human resource management (HRM) as a service and aims to develop and test a process for improving perceived HRM service quality.

Design/methodology/approach

A three-step process was developed by incorporating concepts and tools from service design approach. Based on the literature, it was hypothesized that applying this process could improve perception of HRM service quality, perceived HRM service value, level of leader–member exchanges along with perceived organizational support, role clarity and role ambiguity. A case study was conducted and these variables were measured and compared, before and after testing the process for a test group and a control group within an organization.

Findings

The main findings suggest the effectiveness of the presented process in improving the perceived HRM service quality and social exchanges (in terms of perceived organizational support and leader–member exchanges), while reducing role conflict and role ambiguity in employees and supervisors.

Practical implications

In a general sense, the obtained result implies that leveraging holistic and collaborative service design tools and concepts in (re)designing internal services, such as HRM, could improve perception of quality in organizational services, which in turn may lead to several important benefits for organizations, particularly in terms of HRM as per the context of this study.

Originality/value

This paper demonstrates development of an employee-centered method by borrowing from service design concepts and tools, to improve the perception of HRM service quality.