bluuebunny/crossref_metadata_2025 huggingface dataset:
Oxidative reactions catalyzed by hydrogen peroxide produced byStreptococcus pneumoniaeand other Streptococci Cause the Release and Degradation of Heme from Hemoglobin
Authors: Alibayov Babek , Scasny Anna , Khan Faidad , Creel Aidan , Smith Perriann , Jop Vidal Ana G. , Fitisemanu Fa’alataitaua M. , Padilla-Benavides Teresita , Weiser Jeffrey , Vidal Jorge E.
Published: August 2022

Streptococcus pneumoniae(Spn) strains cause pneumonia that kills millions every year worldwide. Spn produces Ply, a hemolysin that lyses erythrocytes releasing hemoglobin and also produces the pro-oxidant hydrogen peroxide (Spn-H2O2) during growth. The hallmark of the pathophysiology of hemolytic diseases is the oxidation of hemoglobin but oxidative reactions catalyzed by Spn-H2O2has been poorly studied. We characterized the oxidation of hemoglobin by Spn-H2O2. We prepared a series of single (ΔspxB, or ΔlctO), double mutant (ΔspxBΔlctO) and complemented strains in TIGR4, D39 and EF3030. We then utilized anin vitromodel with oxy-hemoglobin to demonstrate that oxy-hemoglobin was oxidized rapidly, within 30 min of incubation, by Spn-H2O2to met-hemoglobin and that the main source of Spn-H2O2was pyruvate oxidase (SpxB). Moreover, extended incubation caused the release and the degradation of heme. We then assessed oxidation of hemoglobin and heme degradation by other bacteria inhabitants of the respiratory tract. All hydrogen peroxide-producing streptococci tested caused the oxidation of hemoglobin and heme degradation whereas those bacterial species that produce <1 μM H2O2, neither oxidized hemoglobin nor degraded heme. Anex vivobacteremia model confirmed that oxidation of hemoglobin and heme degradation occurred concurrently with hemoglobin that was released from erythrocytes by Ply. Finally, gene expression studies demonstrated that heme, but not red blood cells or hemoglobin induced an upregulated transcription of thespxBgene. Oxidation of hemoglobin may be important for pathogenesis and for the symbiosis of hydrogen peroxide-producing bacteria with other species by providing nutrients such as iron.
Antibacterial Action of Gliotoxin Realized Through Interaction with Tiol-containing Proteins
Authors: Vasilchenko Alexey S. , Gurina Elena V. , Drozdov Konstantin A. , Andreev Dmitry , Lebedev Egor , Vasilchenko Anastasia V.
Published: August 2022

Gliotoxin is a secondary metabolite of various fungi belonging to the class of epipolythiodioxopiperazines. The mechanism of gliotoxin cytotoxic activity on eukaryotes is established, while the precise interaction between gliotoxin and bacteria has not been clarified yet. The aim of this study was evaluating the gliotoxin action on model Gram-positive and Gram-negative bacteria. It was found that gliotoxin uptake rate was higher in S. epidermidis than E.coli. However, for Gram-negative bacteria, the bactericidal effect is achieved at higher doses of gliotoxin (10-100 μg/ml), compared to Gram-positive ones (0.75-6.25 μg/ml). Bactericidal effect had developed in 4 hours, which was the same for both E. coli MG1655 and S. epidermidis. Novel chip-based bioluminescent sensor with gel-immobilized E.coli MG1655 pKatG-lux revealed oxidative stress. However, pre-incubation of bacteria with Trolox did not affect the bactericidal properties of gliotoxin, while 2-merkaptoethanol and reduced glutathione significantly reduced gliotoxin’s bactericidal property. Another bioluminescent sensor E.coli MG1655 pIbpA-lux revealed heat shock stress in bacteria treated with gliotoxin. At the cellular level, exposure bacteria with gliotoxin accompanied by disruption of bacterial membranes.
Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum
Authors: Kümpornsin Krittikorn , Kochakarn Theerarat , Yeo Tomas , Luth Madeline R , Pearson Richard D , Hoshizaki Johanna , Schindler Kyra A , Mok Sachel , Park Heekuk , Uhlemann Anne-Catrin , Cubel Sonia Moliner , Franco Virginia , Gomez-Lorenzo Maria G , Gamo Francisco Javier , Winzeler Elizabeth A , Fidock David A , Chookajorn Thanat , Lee Marcus CS
Published: August 2022

In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays revealed a ∼5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines. When challenged with KAE609, high-level resistance was obtained more rapidly and at lower inoculum than wild-type parasites. Selections were also successful with an “irresistible” compound, MMV665794 that failed to yield resistance with other strains. Mutations in a previously uncharacterized gene, PF3D7_1359900, which we term quinoxaline resistance protein (QRP1), were validated as causal for resistance to MMV665794 and an analog, MMV007224. The increased genetic repertoire available to this “mutator” parasite can be leveraged to drive P. falciparum resistome discovery.
Never in Mitosis Kinase 2 regulation of metabolism is required for neural differentiation
Authors: Spice Danielle M. , Cooper Tyler T. , Lajoie Gilles A. , Kelly Gregory M.
Published: August 2022

1.

Wnt and Hh are known signalling pathways involved in neural differentiation and recent work has shown the cell cycle regulator, Never in Mitosis Kinase 2 (Nek2) is able to regulate both pathways. Despite its known function in pathway regulation, few studies have explored Nek2 within embryonic development. The P19 embryonal carcinoma cell model was used to investigate Nek2 and neural differentiation through CRISPR knockout and overexpression studies. Loss of Nek2 reduced cell proliferation in the undifferentiated state and during directed differentiation, while overexpression increased cell proliferation. Despite these changes in proliferation rates, Nek2 deficient cells maintained pluripotency markers after neural induction while Nek2 overexpressing cells lost these markers in the undifferentiated state. Nek2 deficient cells lost the ability to differentiate into both neurons and astrocytes, although Nek2 overexpressing cells enhanced neuron differentiation at the expense of astrocytes. Hh and Wnt signaling were explored, however there was no clear connection between Nek2 and these pathways causing the observed changes to differentiation phenotypes. Mass spectrometry was also used during wildtype and Nek2 knockout cell differentiation and we identified reduced electron transport chain components in the knockout population. Immunoblotting confirmed the loss of these components and additional studies showed cells lacking Nek2 were exclusively glycolytic. Interestingly, hypoxia inducible factor 1α was stabilized in these Nek2 knockout cells despite culturing them under normoxic conditions. Since neural differentiation requires a metabolic switch from glycolysis to oxidative phosphorylation, we propose a mechanism where Nek2 prevents HIF1α stabilization, thereby allowing cells to use oxidative phosphorylation to facilitate neuron and astrocyte differentiation.
Structural basis of ferroportin inhibition by minihepcidin PR73
Authors: Wilbon Azaan Saalim , Shen Jiemin , Ruchala Piotr , Zhou Ming , Pan Yaping
Published: August 2022

Ferroportin (Fpn) is the only known iron exporter in humans and is essential for maintaining iron homeostasis. Fpn activity is suppressed by hepcidin, an endogenous peptide hormone, which inhibits iron export and promotes endocytosis of Fpn. Hepcidin deficiency leads to hemochromatosis and iron-loading anemia. Previous studies have shown that small peptides that mimic the first few residues of hepcidin, i.e. minihepcidins, are more potent than hepcidin. However, the mechanism of enhanced inhibition by minihepcidins remains unclear. Here, we report the structure of human ferroportin in complex with a minihepcidin, PR73 that mimics the first 9 residues of hepcidin, at 2.7 Å overall resolution. The structure reveals novel interactions that were not present between Fpn and hepcidin. We validate PR73-Fpn interactions through binding and transport assays. These results provide insights into how minihepcidins increase inhibition potency and will guide future developments of Fpn inhibitors.
TnSmu1 is a functional integrative and conjugative element in Streptococcus mutans that when expressed causes growth arrest of host bacteria
Authors: McLellan Lisa K. , Anderson Mary E. , Grossman Alan D.
Published: August 2022

Integrative and conjugative elements (ICEs) are major drivers of horizontal gene transfer in bacteria. They mediate their own transfer from host cells (donors) to recipients and allow bacteria to acquire new phenotypes, including pathogenic and metabolic capabilities and drug resistances. Streptococcus mutans, a major causative agent of dental caries, contains a putative ICE, TnSmu1, integrated at the 3’ end of a leucyl tRNA gene. We found that TnSmu1 is a functional ICE, containing all the genes necessary for ICE function. It excised from the chromosome and excision was stimulated by DNA damage. We identified the DNA junctions generated by excision of TnSmu1, defined the ends of the element, and detected the extrachromosomal circle. We found that TnSmu1 can transfer from S. mutans donors to recipients when co-cultured on solid medium. The presence of TnSmu1 in recipients inhibited successful acquisition of another copy and this inhibition was mediated, at least in part, by the likely transcriptional repressor encoded by the element. Using microscopy to track individual cells, we found that activation TnSmu1 caused an arrest of cell growth. Our results demonstrate that TnSmu1 is a functional ICE that affects the biology of its host cells.
Linear motif specificity in signaling through p38α and ERK2 mitogen-activated protein kinases
Authors: Robles Jaylissa Torres , Shi Guangda , Turk Benjamin E.
Published: August 2022

Mitogen-activated protein kinase (MAPK) cascades are essential for eukaryotic cells to integrate and respond to a wide array of stimuli. Maintaining specificity in signaling through MAPK networks is key to coupling specific inputs to appropriate cellular responses. One way that MAPKs achieve specificity is through transient interactions with docking sites: short linear motifs found in MAPK substrates, regulators, and scaffolds. Docking sites bind to a conserved groove located in the catalytic domain of all MAPKs including the ERK and p38 subfamilies, but how specificity is achieved remains unresolved. To understand the basis of docking selectivity for these two subfamilies, we screened a library of thousands of human proteome-derived sequences for docking to ERK2 and p38α. We discovered a large number of sequences that bound specifically to only one MAPK or promiscuously to both, and that selective and non-selective interactors conformed to distinct sequence motifs. In particular, selective binding to p38α correlated with higher net charge in the docking site, and this phenomenon was driven by enrichment for Lys residues. A pair of acidic residues unique to the docking groove of p38α mediated selectivity for Lys-rich basic motifs. Finally, we validated a set of full-length proteins harboring docking sites selected as hits in our screens to be authentic MAPK interactors and identified ChREBP and TACC1 as cellular MAPK substrates. This study identifies distinguishing features that help define MAPK signaling networks and explains how specific docking motifs promote signaling integrity.
CD73-positive cell spheroid transplantation attenuates colonic atrophy
Authors: Hisamatsu Daisuke , Itakura Natsumi , Mabuchi Yo , Ozaki Rion , Suto Eriko Grace , Naraoka Yuna , Ikeda Akari , Ito Lisa , Akazawa Chihiro
Published: August 2022

The incidence of inflammatory bowel diseases (IBD) is increasing worldwide. Mesenchymal stem/stromal cells (MSCs) have immunomodulatory functions and are a promising source for cell transplantation therapy for IBD. However, owing to their heterogeneous nature, their therapeutic efficacy in colitis is controversial and depends on the delivery route and form of transplanted cells. Cluster of differentiation (CD)73 is widely expressed in MSCs and used to obtain a homogeneous MSC population. Herein, we determined the optimal method for MSC transplantation using CD73+ cells in a colitis model. mRNA sequencing analysis showed that CD73+ cells exhibit downregulation of inflammatory genes and upregulation of extracellular matrix-related genes. Furthermore, three-dimensional CD73+ cell spheroids showed enhanced engraftment at the injured site through the enteral route, facilitated extracellular matrix remodeling, and downregulated inflammatory gene expression in fibroblasts, leading to attenuation of colonic atrophy. Therefore, the interaction between intestinal fibroblasts and exogenous MSCs via tissue remodeling is one mechanism that can be exploited for colitis prevention. Our results highlight that transplantation of homogeneous cell populations with well-characterized properties is beneficial for IBD treatment.
Indexing of superimposed Laue diffraction patterns using a dictionary–branch–bound approach
Authors: Seret Anthony , Gao Wenqiang , Juul Jensen Dorte , Godfrey Andy , Zhang Yubin
Published: August 2022

X-ray Laue diffraction is an important method for characterizing the local crystallographic orientation and elastic strain in polycrystalline materials. Existing analysis methods are designed mainly to index a single or a few Laue diffraction pattern(s) recorded in a detector image. In this work, a novel method called dictionary–branch–bound (DBB) is presented to determine the crystallographic orientations of multiple crystals simultaneously illuminated by a parallel X-ray incident beam, using only the spot positions in a detector image. DBB is validated for simulated X-ray Laue diffraction data. In the simulation, up to 100 crystals with random crystallographic orientations are simultaneously illuminated. Fake spots are randomly added to the detector image to test the robustness of DBB. Additionally, spots are randomly removed to test the resilience of DBB against true spots that are undetected due to background noise and/or spot overlap. Poisson noise is also added to test the sensitivity of DBB to less accurate positions of detected spots. In all cases except the most challenging one, a perfect indexing with a mean angular error below 0.08° is obtained. To demonstrate the potential of DBB further, it is applied to synchrotron microdiffraction data. Finally, guidelines for using DBB in experimental data are provided.
The effect of Generation Z's perceptions of brand activism on brand loyalty: evidence from Vietnam
Authors: Nguyen Dinh Toan , Le Dang Ha Anh , Truong Linh Giang , Truong Ngan Giang , Vu Viet Vinh
Published: August 2022

Purpose

The study was conducted to investigate the impact of Generation Z's perceptions of brand activism on brand loyalty through the mediating role of brand attitude and brand trust.

Design/methodology/approach

The study first reviewed previous research and developed hypotheses related to the research objectives. Structural equation modelling (SEM) was conducted to test the hypotheses with the survey data of 1,133 individuals from Generation Z in Vietnam.

Findings

First, the findings indicated that: perceived argument quality, perceived authenticity, and perceived altruistic motives have a significant positive effect on brand attitude and brand trust. In addition, perceived self-interest motives have a significant positive effect on brand attitude. Brand trust has a significant positive effect on brand attitude. Finally, brand attitude and brand trust have a significant positive effect on brand loyalty. The study's empirical analysis carries implications for brand managers when implementing brand activism campaigns.

Originality/value

There is a paucity of research that investigates customers' perceptions of brand activism through perceived argument quality, perceived authenticity, perceived altruistic motives, and perceived self-interest motives and the influences of these on brand loyalty. The main contribution of this study is to fill this gap.
The disappearance of Bangkok's Artbox: examining the challenges of sustaining a mobile night market during the COVID-19 pandemic
Authors: Chan Steve Kwok-Leung
Published: August 2022

Purpose

This study aims to investigate the reasons for the shutdown of a mobile night market during the COVID-19 pandemic. Lack of tourists was obviously one of the causes but social reasons must also exist. The study investigates territoriality, collectivization and human relations in urban social spaces which are essential for the sustainability of a market than solely short-term profit and unconnected customers.

Design/methodology/approach

In this study qualitative methods are used, including reviewing contents, semi-structured interviews with vendors and customers, and informant interviews.

Findings

Drawing from urban space theories, this paper argues that trendy markets catering for diverse market segments sustain their business. Once the market has shifted away from local Thai customers to main tourists, it loses its base and becomes vulnerable in territoriality negotiation.

Practical implications

The findings and model provide practice information for local authorities, town planners and night market operators in the design of open-air marketplaces. Such knowledge pinpoints the importance of connecting place and people in order to sustain a business.

Originality/value

Studies on mobile marketplaces are rare. The findings address the “detaching” process and consequence from the perspective of place attachment.

Peer review

The peer review history for this article is available at: https://publons.com/publon/10.1108/IJSE-04-2021-0218
Rural cultural wealth: dismantling deficit ideologies of rurality
Authors: Crumb Loni , Chambers Crystal , Azano Amy , Hands Africa , Cuthrell Kristen , Avent Max
Published: August 2022

Purpose

Rural education research has historically been cast in a deficit lens, with rural places characterized by their problems or shortcomings, as if the way of understanding rural itself is to compare it to nonrural locales. These intransigent and narrow perceptions of rurality hinders recognition of the assets and possibilities of rural places. The purpose of this paper is to apply community-empowering, transgressive knowledge to analyses of rural communities to advance rural education research and practice.

Design/methodology/approach

In this conceptual paper, the authors propose an asset-based, conceptual framework to ground rural research and education practices: rural cultural wealth.

Findings

The authors describe and explore the concept of rural cultural wealth within the context of education. Furthermore, the authors discuss the dynamics of rurality and propose four constructs that comprise the rural cultural wealth framework, rural resourcefulness, rural ingenuity, rural familism and rural community unity, and consider implications for future research and practice.

Originality/value

The goal of this paper is to advance a rural cultural wealth framework aimed to interrupt social reproduction of educational inequities that impact rural students.
Thermal aging effects on the properties of the Cu/(SAC0307 powder + Zn-particles)/Cu joint ultrasonic-assisted soldered at low-temperature
Authors: Gan Guisheng , Chen Shiqi , Jiang Liujie , Jiang Zhaoqi , Liu Cong , Ma Peng , Cheng Dayong , Liu Xin
Published: August 2022

Purpose

This study aims to evaluate the effect of thermal aging temperature on the properties of Cu/Cu joints.

Design/methodology/approach

A new method that 1 um Zn-particles and Sn-0.3Ag-0.7Cu (SAC0307) with a particle size of 25–38 µm were mixed to fill the joint and successfully achieved the micro-joining of Cu/Cu under ultrasonic-assisted at low-temperature, and then the effect of thermal aging temperature on the properties of Cu/Cu joints was researched.

Findings

The composition of the intermetallic compounds (IMCs) on the upper and lower interfaces of Cu/SACZ/Cu joints remained unchanged, which was Cu5Zn8 in aging process, and the thickness of the IMCs on the upper and lower interfaces of the Cu/SACZ/Cu joints increased accordingly. Compared with the as-received joints, the thickness of the upper and lower interfaces IMCs of the soldering aged time for 24 h increased by 404.7% and 505.5% at 150ºC, respectively. The IMCs formation tendency and the IMCs growth rate of the lower interface are larger than those of the upper interface because the soldering seam near the IMCs at the upper and lower interfaces of the as-received joints were mostly white SAC0307 balls black Zn-particles, respectively. The growth activation energy of IMCs in the upper and lower interfaces is about 89.21 and 55.11 kJ/mol, respectively. Under the same aging time, with the increase of the aging temperature, the shear strength of Cu/SACZ/Cu joints did not change significantly at first before 150ºC. When the aging temperature reached 150ºC, the shear strength of the joints decreased significantly; the shear strength of the joints was the smallest at 150ºC for 24 h, which was 39.4% lower than that of the as-received joints because the oxidation degree of Zn particles in the joint with the increase of aging temperature and time.

Originality/value

Cu/Cu joints were successfully achieved under ultrasonic-assisted at low-temperature.
Pollination deficits and contributions of pollinators in apple production: A global meta‐analysis
Authors: Olhnuud Aruhan , Liu Yunhui , Makowski David , Tscharntke Teja , Westphal Catrin , Wu Panlong , Wang Meina , van der Werf Wopke
Published: August 2022

Apple is one of the most widely cultivated fruit crops world‐wide, and apple yield benefits from pollination by insects. The global decline in wild pollinator populations raises concern about the adequacy of pollination services in apple production.

Here, we present a global meta‐analysis of pollination in apple. We assembled from the literature a dataset comprising results of 48 studies across five continents on fruit set and seed set in apple with insect pollination, artificial pollination and pollinator exclusion, and analysed the effects of explanatory factors such as variety and continent.

Fruit set was on average 41% lower with open pollination than with artificial pollination, while seed set was 20% lower. These pollination deficits varied across continents and cultivars. Pollination deficits for fruit set were greatest in Asia (63%) followed by Europe (30%), whereas pollination deficits for seed set were greatest in Asia (47%) and South America (40%). Important differences in pollination deficit were also identified between cultivars but these differences were confounded with continent effects.

Fruit set and seed set were 71% and 62% higher, respectively, when insects had open access to flowers than when they were artificially excluded, while results varied among cultivars.

Synthesis and applications. Globally, there are substantial contributions of pollinators to fruit set and seed set in apple, as well as considerable limitations in apple pollination services, particularly in Asia, Europe and South America. Several management strategies could be applied to reduce the pollination deficits in apple production: (1) conserving wild bees and enhancing their abundance and diversity, (2) using managed bees for pollination, (3) using varieties with low pollinator dependency and/or (4) artificial pollination. These strategies should be tailored to the regional situation, considering the potential of landscapes for restoring wild pollinators, the acceptability of cultivated varieties for available pollinators, the acceptance in the market of self‐compatible varieties and the costs of management, such as artificial pollination, pollinator conservation, beekeeping and planting self‐compatible varieties. Conservation of wild pollinators is preferred in regions with sufficient potential for wild pollinators as it contributes to biodiversity conservation and improves pollination in both crops and wild plants.
‘Is Radioactive Iodine Present Equally in the Cream on Milk as in the Milk Itself?’: Lonely Sources and the Gendered history of Cold War Britain
Authors: Douthwaite Jessica
Published: August 2022

This article argues that one way to foreground and privilege women's perspectives on the Cold War is by re‐interpreting their historical experiences of food and drink. The article develops this argument by analysing one letter, from an unknown woman to the BBC, in the context of nuclear health concerns in early Cold War Britain. This article contends that where archival references to food, drink and women are ephemeral, a lonely source can describe historical experience that extends far beyond its singularity. While it would be easy to dismiss this letter as exceptional, it demonstrates one woman's informed and reasonable approach to an unstable and inexplicable topic. The article argues that divesting research from its traditional, masculine Cold War rules of perception contributes to a fairer view of previously ignored ‘feminine’ sources.
ENDURING HARM: Unlikely Comparisons, Slow Violence and the Administration of Urban Injustice
Authors: Anand Nikhil , Wiggin Bethany , Kamath Lalitha , Deekshit Pranjal
Published: August 2022

In this comparative and collaborative collection of essays we work through contemporary and historical practices of governing urban waters in Philadelphia and Mumbai. Taken together, the essays in this collection argue that events of enduring harm visited upon racialized, marginalized citizens are produced through slow bureaucratic processes of aversion, ambiguation and ambivalence, perpetuated in and through regulatory regimes, water quality standards, legal discourses and everyday practices in the city. These practices entangle racialized and poorer populations in situations of durable and everyday harm and are central to the creation, maintenance and reproduction of vulnerable and disposable human and non‐human life in the city.
Prevalence and risk factors of self‐reported psychotic experiences among high school and college students: A systematic review, meta‐analysis, and meta‐regression
Authors: Fekih‐Romdhane Feten , Pandi‐Perumal Seithikurippu R. , Conus Philippe , Krebs Marie‐Odile , Cheour Majda , Seeman Mary V. , Jahrami Haitham A.
Published: August 2022

Background

Adolescents are at high risk of incident psychopathology. Fleeting psychotic experiences (PEs) that emerge in young people in response to stress may be warning signs that are missed by research that fails to study stressed populations, such as late high school and college/university students. Our aim in this systematic review was to conduct a meta‐analysis that estimates prevalence rates of PEs in students, and to assess whether these rates differ by gender, age, culture, and COVID‐19 exposure.

Method

We searched nine electronic databases, from their inception until January 31, 2022 for relevant studies. We pooled the estimates using the DerSimonian–Laird technique and random‐effects meta‐analysis. Our main outcome was the prevalence of self‐reported PEs in high school and college/university students. We subsequently analyzed our data by age, gender, population, country, culture, evaluation tool, and COVID‐19 exposure.

Results

Out of 486 studies retrieved, a total of 59 independent studies met inclusion criteria reporting 210′ 024 students from 21 different countries. Nearly one in four students (23.31%; 95% CI 18.41%–29.05%), reported having experienced PEs (heterogeneity [Q = 22,698.23 (62), p = 0.001] τ2 = 1.4418 [1.0415‐2.1391], τ = 1.2007 [1.0205‐1.4626], I2 = 99.7%, H = 19.13 [18.59‐19.69]). The 95% prediction intervals were 04.01%–68.85%. Subgroup analyses showed that the pooled prevalence differed significantly by population, culture, and COVID‐19 exposure.

Conclusion

This meta‐analysis revealed high prevalence rates of self‐reported PEs among teen and young adult students, which may have significance for mental health screening in school settings. An important realization is that PEs may have very different mental health meaning in different cultures.
A novel splicing variant in GALNS in mucopolysaccharidosis IVA and the necessity of re‐evaluating primer sequences
Authors: Kim Sang‐Mi , Noh Eu Seon , Park Jong‐Ho , Park Hyung‐Doo , Lee Soo‐Youn , Jang Ja‐Hyun , Cho Sung Yoon
Published: August 2022

Mucopolysaccharidosis type IVA (MPS IVA; Morquio syndrome type A) is an autosomal recessive disorder caused by defects in the lysosomal hydrolase N‐acetylgalactosamine‐6‐sulfatase (GALNS) gene, leading to progressive systemic skeletal dysplasia. Early diagnosis and early intervention with enzyme replacement therapy are crucial for improving outcomes in these patients. However, a relatively high number of patients are genetically undiagnosed due to high allelic heterogeneity and the absence of robust functional evidence for most variants of the GALNS gene. Herein, we report a novel intronic variant identified with RNA analysis and an allele dropout (ADO) event caused by a common benign variant in the primer‐binding site in a Korean boy with MPS IVA.

A 28‐month‐old boy presented with pectus carinatum, kyphoscoliosis, and joint hypermobility with multiple skeletal dysplasia involving the vertebrae and hip joint. Total urinary glycosaminoglycans were elevated with a predominant keratan sulfate fraction, and GALNS (EC 3.1.6.4) activity was significantly decreased in leukocytes. Sanger sequencing was performed; however, only one heterozygous intronic variant with uncertain clinical significance, c.566+3A > T (p.(?)), was identified. As the patient exhibited clinical and biochemical features of MPS IVA, we conducted whole genome sequencing (WGS) of the patient and his family to clarify the molecular diagnosis. WGS revealed a compound heterozygous genotype, c.1019G > A (p.(Gly340Asp)) and c.566+3A > T (p.(?)), in the GALNS gene. On mRNA sequencing, c.566+3A > T, was confirmed to cause exon 5 skipping and a premature stop codon. With subsequent investigation, we discovered that the variant, c.1019G > A, was undetected on initial sequencing because of ADO due to a common benign variant (rs3859024:G > C) at the primer annealing location.

We present a novel intronic variant with a splicing defect in the GALNS gene and suggest that clinicians review primer sequences in cases not diagnosed on Sanger sequencing before progressing to diagnostic steps such as WGS.
The Unintended Effects of Stock Pledging: A Perspective on the Shareholder–Creditor Conflict*
Authors: Liu Yuanyuan , Jiu Lili
Published: August 2022

This paper examines whether and how stock pledging by a firm's largest shareholder affects the conflict of interest between shareholders and creditors. We find such stock pledging is negatively associated with corporate risk‐taking. This association is more pronounced for companies with high debt costs before such pledging, with dominant controlling shareholders, and those whose largest shareholders  borrow from small lenders. Further, we find firms subject to such pledging are more likely to be granted new private loans and exhibit greater investment efficiency. Overall, stock pledging by a firm's largest shareholder unintentionally mitigates the shareholder–creditor conflict by reducing corporations' pursuit of risky investments.
Macrophage polarization in placenta accreta and macrophage‐trophoblast interactions
Authors: Che Jia‐hui , Zheng Zi‐meng , Li Ming‐qing , Yao Xiaoying
Published: August 2022

Problem

Placenta accreta (PA) is defined by an abnormal invasion of placental trophoblasts into the myometrium, which can lead to serious postpartum complications. Macrophages play an important role in the regulation of trophoblast function. Both granulocyte colony‐stimulating factor (G‐CSF) and its receptor (granulocyte colony‐stimulating factor receptor, G‐CSFR) have effects on trophoblast invasion. However, the current understanding of G‐CSF secretion, G‐CSFR expression, abnormal polarization of decidual macrophages (dMϕ) in PA and the abnormal invasion of placental trophoblasts into the myometrium are limited.

Method of Study

The polarization of dMϕ in PA was analyzed by flow cytometry (FCM), and the expression of G‐CSFR in placental trophoblasts in PA was evaluated by immunohistochemistry. In an in vitro co‐culture model, we investigated the effects of HTR‐8/SVneo trophoblasts cell line (HTR‐8) on macrophage human monocyte cell line (THP‐1) polarization and G‐CSF secretion, and we also analyzed the effects of THP‐1 cells, especially M2‐like subtype, on primary trophoblasts and HTR‐8 proliferation, invasion, and adhesion. FCM, transwell assays, adhesion assays, and proliferation assays were used in the above model.

Results

Compared with controls (n = 9), dMϕ showed significantly lower levels of M1 markers CD80 and CD86 and higher levels of the M2 markers CD163 and CD206, and G‐CSFR expression of placental trophoblasts was increased in PA (n = 5). In vitro experiments showed that the trophoblast HTR‐8 cell line induced polarization of THP‐1 cells to an M2‐like subtype and increased their secretion of G‐CSF. Furthermore, IL‐4/IL‐13‐induced M2‐like THP‐1 macrophages were able to increase the expression of G‐CSFR, proliferation, invasion and adhesion of both primary trophoblasts and HTR‐8 trophoblasts.

Conclusions

There is an altered immune imbalance at the maternal‐fetal interface in PA, which further may lead to abnormal trophoblast function. G‐CSF and its receptors may play important roles in abnormal polarization of macrophages and abnormal invasion of trophoblasts.
A prospective, randomized clinical trial of emergency treatment of chemotherapy‐induced neutropenia and febrile neutropenia by pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF)
Authors: Huang Xiaofeng , Li Shuo , Shi Wenjie , Wang Ye , Wan Xinyu , He Jinzhi , Xu Yinggang , Zhang Weiwei , Shi Xiaoqing , Chen Rui , Xu Lu , Zha Xiaoming , Wang Jue
Published: August 2022

Aims

As one of the mainstays of breast cancer therapy, chemotherapy inevitably induces neutropenia. In this study, we explored the role of PEG‐rhG‐CSF (pegylated recombinant human granulocyte colony‐stimulating factor) in the emergency treatment of chemotherapy‐induced grades 3–4 neutropenia.

Methods

A total of 100 patients with breast cancer were randomized (1:1) into the study. Fifty patients randomized to the experimental group were treated with PEG‐rhG‐CSF after grades 3–4 neutropenia following the first cycle of chemotherapy, while 50 patients randomized to the control group received a daily injection of rhG‐CSF (recombinant human granulocyte colony‐stimulating factor). The primary endpoint was the recovery time of grades 3–4 neutropenia.

Results

Compared with patients in the control group, the mean ± SD recovery time of grades 3–4 neutropenia and febrile neutropenia (FN) was significantly shorter for patients in the experimental group (grades 3–4, P = .000; grade 4, P = .000; FN, P = .038). There is no significant difference in the incidence of FN for the two groups. In the experimental group, the duration of grades 3–4 neutropenia in patients aged <60 years and ≥60 years was 2.15 and 3.20 days, respectively (P = .037). Adverse events (AEs) of any grade were reported in 37 (75.5%) and 28 (59.6%) patients from the two groups, respectively. No grade ≥3 AEs were reported.

Conclusion

This study supported that the PEG‐rhG‐CSF was more effective and convenient than rhG‐CSF for treating grades 3–4 neutropenia and FN in patients with breast cancer and had manageable toxicity.
A phase 1b/2 clinical study of marstacimab, targeting human tissue factor pathway inhibitor, in haemophilia
Authors: Mahlangu Johnny N. , Lamas Jose Luis , Morales Juan Cristobal , Malan Daniel R. , Šalek Silva Zupančić , Wang Michael , Boggio Lisa N. , Hegemann Inga , Mital Andrzej , Cardinal Matthew , Zhu Tong , Sun Pengling , Arkin Steven
Published: August 2022

A phase 1b/2, three‐month study of marstacimab, a human monoclonal antibody targeting tissue factor pathway inhibitor (TFPI), was conducted in participants with haemophilia A or B, with or without inhibitors. Participants assigned to four cohorts received escalating weekly doses based on inhibitor status (without inhibitors: 300 mg, a single 300‐mg loading dose with subsequent 150‐mg doses, or 450 mg; with inhibitors: 300 mg). Safety outcomes were treatment‐emergent adverse events (TEAEs), injection site reactions, clinical and laboratory parameter changes. Efficacy was assessed by annualised bleeding rates (ABRs). Pharmacokinetics and pharmacodynamics (PD) were also evaluated. Among 26 treated participants [haemophilia A without inhibitor, n = 16 (61.5%); haemophilia A with inhibitor, n = 7 (26.9%); haemophilia B, n = 3 (11.5%)], 24 completed the study. Overall, 80.8% experienced TEAEs. ABR during treatment was significantly reduced versus an external on‐demand control group (p < 0.0001) and versus pretreatment ABR (p < 0.0001), with significant reductions observed across all dose cohorts. Marstacimab exposure generally increased in a dose‐related manner, with steady‐state concentration reached by day 57. Changes in pharmacodynamic biomarkers occurred across all dose cohorts. Marstacimab was safe and well tolerated. Clinically meaningful reductions in ABR and treatment‐related changes for all PD biomarkers indicated effective targeting of TFPI. (Clinicaltrials.gov identifier, NCT02974855).
What do older adults think about when formulating implementation intentions for physical activity? Evidence from a qualitative study
Authors: Bösch Valérie Désirée , Warner Lisa Marie , Nyman Samuel R. , Haftenberger Julius , Clarke Kye , Inauen Jennifer
Published: August 2022

Objectives

Physical activity is an important health behaviour especially for older adults. Forming implementation intentions is an effective strategy to implement physical activity in daily life for young and middle‐aged adults. However, evidence for older adults is inconclusive. This study explored the thoughts of older adults about implementation intentions and potential barriers and facilitators while formulating them.

Methods

Three samples of older adults from the United Kingdom (n = 8), Germany (n = 9) and Switzerland (n = 17) were prompted to think aloud while formulating implementation intentions to be more physically active. After the task, semi‐structured interviews were conducted. Data were analysed thematically.

Results

Participants expressed pre‐established thoughts about implementation intentions (e.g. they feel too restrictive). During the formulation of implementation intentions, several barriers to creating them were reported (e.g. problems with finding cues due to absence of recurring daily routines), but participants also mentioned that forming implementation intentions acted as a facilitator for physical activity (e.g. cues as useful reminders to be active, task itself triggering self‐reflection about physical activity). After the task, participants reflected on circumstances that decrease the likelihood of enacting implementation intentions (e.g. spontaneous alternative activities, weather, health‐related barriers, Covid‐19‐related barriers), which triggered spontaneous coping planning.

Conclusions

The results on barriers and facilitators of implementation intentions and physical activity from older adults' perspectives provide starting points for improving instructions for older adults on how to create implementation intentions for physical activity. Future studies are needed to investigate whether the findings extend to implementation intentions for other behaviours.
Revisiting gender occupational segregation trends in Canada: 1991–2016
Authors: Kaida Lisa , Boyd Monica
Published: August 2022

Despite continued interest in gender (in)equality at work, Canadian research on gender occupational segregation stopped in the early 2000s. We revisit gender occupational segregation trends using newly developed harmonized occupational categories which resolve temporal changes in occupational classifications. Our analysis of the 1991–2016 Canadian Census Masterfiles finds gender occupational segregation, whether measured by the index of dissimilarity or Gini index, has steadily decreased since the 1990s. Yet the pace of its decline has slowed since 2000. This can be explained by the diminishing changes in vertical segregation, measured by inequality in earnings across occupations. Our results contribute to an ongoing debate about a stalled gender revolution. We also suggest new topics for future study.
Longitudinal development of children's sharing behaviour: Only children versus children with siblings from rural China
Authors: Lin Zhumei , Yu Jing , Jiang Yingying , Wang Xiao Tian , Zhu Liqi
Published: August 2022

This study examined the development of children's sharing behaviour towards friends and strangers using dictator games with a longitudinal design in a sample of rural Chinese children (n = 589, 47.0% girls) at 3–4 years old and 2 years later (n = 453, 44.2% girls). Results showed that the willingness to share and the amount of sharing changed over time and were affected by family structure. Only children shared fewer stickers than non‐only children at ages 3–4, but the amount they shared did not differ at ages 5–6. Only children may develop reciprocal friendships at an older age due to their lack of experience with siblings. Children shared more stickers with friends than strangers at ages 3–4, and such ingroup bias became stronger at ages 5–6.
ANAID‐ICH nomogram for predicting unfavorable outcome after intracerebral hemorrhage
Authors: Li Jiawen , Luo Dong , Peng Feifei , Kong Qi , Liu Huawei , Chen Meiyuan , Tong Lusha , Gao Feng
Published: August 2022

Objective

Diffusion‐weighted imaging lesions (DWILs) are associated with unfavorable outcome in intracerebral hemorrhage (ICH). We proposed a novel predictive nomogram incorporating DWILs.

Methods

A total of 738 patients with primary ICH in a tertiary hospital were prospectively enrolled as a training cohort. DWILs were defined as remote focal hyperintensities on DWI corresponding to low intensities on apparent diffusion coefficient images and remote from the focal hematoma. The outcome of interest was modified Rankin Scale scores of 4–6 at 90 days after onset. Multivariate logistic regression was used to construct a nomogram. Model performance was tested in the training cohort and externally validated with respect to discrimination, calibration, and clinical usefulness in another institute. Additionally, the nomogram was compared with the ICH score in terms of predictive ability.

Results

Overall, 153 (20.73%) and 23 (15.54%) patients developed an unfavorable outcome in the training and validation cohorts, respectively. The multivariate analysis revealed that age, National Institutes of Health Stroke Scale (NIHSS) score, anemia, infratentorial location, presence of DWILs, and prior ICH were associated with unfavorable outcome. Our ANAID‐ICH nomogram was constructed according to the aforementioned variables; the area under the receiver operating characteristic curve was 0.842 and 0.831 in the training and validation sets, respectively. With regard to the 90‐day outcome, the nomogram showed a significantly higher predictive value than the ICH score in both cohorts.

Conclusions

The ANAID‐ICH nomogram comprising age, NIHSS score, anemia, infratentorial location, presence of DWILs, and prior ICH may facilitate the identification of patients at higher risk for an unfavorable outcome.
Inequality Interactions: The Dynamics of Multidimensional Inequalities
Authors: Segal Paul
Published: August 2022

This article offers a multidimensional, interdisciplinary and dynamic framework for understanding socio‐economic inequalities. It uses the tools of economic inequality measurement to demonstrate the link between interpersonal and categorical inequalities and to show the effect of progressive redistribution on both. It then presents two new concepts for analysing interactions between varieties of inequality:inequality re‐orderingis defined as a reduction in categorical or group inequalities that leaves interpersonal inequality unchanged, andinequality diversionis defined as a reduction in one form of inequality that increases another form of inequality. The argument that inequality diversion arises across economic and social dimensions is illuminated through two case studies: the transition to increasing meritocracy, and the relationship between professional female labour market participation and domestic service. Exploring these relationships is essential to a joined‐up approach to inequality reduction, enabling us to understand trade‐offs and complementarities in tackling inequalities, and to identify policies required to reduce them.
Capturing complex interactions in disease ecology with simplicial sets
Authors: Silk Matthew J. , Wilber Mark Q. , Fefferman Nina H.
Published: August 2022

Network approaches have revolutionized the study of ecological interactions. Social, movement and ecological networks have all been integral to studying infectious disease ecology. However, conventional (dyadic) network approaches are limited in their ability to capture higher‐order interactions. We present simplicial sets as a tool that addresses this limitation. First, we explain what simplicial sets are. Second, we explain why their use would be beneficial in different subject areas. Third, we detail where these areas are: social, transmission, movement/spatial and ecological networks and when using them would help most in each context. To demonstrate their application, we develop a novel approach to identify how pathogens persist within a host population. Fourth, we provide an overview of how to use simplicial sets, highlighting specific metrics, generative models and software. Finally, we synthesize key research questions simplicial sets will help us answer and draw attention to methodological developments that will facilitate this.
Economic aspects of treating seizure clusters
Authors: Faught Edward
Published: August 2022

Seizure clusters may initiate a chain of events that have economic as well as clinical consequences. The potential economic consequences of seizure clusters must be weighed against the cost of medication to attenuate them. This is true both for individual patients and for society. Data needed for economic analyses include the chance that a cluster will progress to an adverse outcome, such as a need for emergency care, the costs of such an outcome, the cost of a rescue medication (RM), and the effectiveness of the RM. Indirect costs, such as lost employment for patients and caregivers, must also be considered. Several types of economic analyses can be used to determine costs and benefits of a medical intervention. There are studies comparing different RMs from an economic perspective, but there is little direct information on the costs of using an RM versus allowing clusters to run their course. However, the high expense of consequences of seizure clusters makes it likely that effective RMs will make economic as well as medical sense for many patients.