bluuebunny/crossref_metadata_2025 huggingface dataset:
The TH1 cell lineage-determining transcription factor T-bet suppresses TH2 gene expression by redistributing GATA3 away from TH2 genes
Authors: Hertweck Arnulf , Vila de Mucha Maria , Barber Paul R , Dagil Robert , Porter Hayley , Ramos Andres , Lord Graham M , Jenner Richard G
Published: April 2022

Lineage-determining transcription factors (LD-TFs) drive the differentiation of progenitor cells into a specific lineage. In CD4+ T cells, T-bet dictates differentiation of the TH1 lineage, whereas GATA3 drives differentiation of the alternative TH2 lineage. However, LD-TFs, including T-bet and GATA3, are frequently co-expressed but how this affects LD-TF function is not known. By expressing T-bet and GATA3 separately or together in mouse T cells, we show that T-bet sequesters GATA3 at its target sites, thereby removing GATA3 from TH2 genes. This redistribution of GATA3 is independent of GATA3 DNA binding activity and is instead mediated by the T-bet DNA binding domain, which interacts with the GATA3 DNA binding domain and changes GATA3′s sequence binding preference. This mechanism allows T-bet to drive the TH1 gene expression program in the presence of GATA3. We propose that redistribution of one LD-TF by another may be a common mechanism that could explain how specific cell fate choices can be made even in the presence of other transcription factors driving alternative differentiation pathways.
Nuclear and cytoplasmic poly(A) binding proteins (PABPs) favor distinct transcripts and isoforms
Authors: Nicholson-Shaw Angela L , Kofman Eric R , Yeo Gene W , Pasquinelli Amy E
Published: April 2022

The poly(A)-tail appended to the 3′-end of most eukaryotic transcripts plays a key role in their stability, nuclear transport, and translation. These roles are largely mediated by Poly(A) Binding Proteins (PABPs) that coat poly(A)-tails and interact with various proteins involved in the biogenesis and function of RNA. While it is well-established that the nuclear PABP (PABPN) binds newly synthesized poly(A)-tails and is replaced by the cytoplasmic PABP (PABPC) on transcripts exported to the cytoplasm, the distribution of transcripts for different genes or isoforms of the same gene on these PABPs has not been investigated on a genome-wide scale. Here, we analyzed the identity, splicing status, poly(A)-tail size, and translation status of RNAs co-immunoprecipitated with endogenous PABPN or PABPC in human cells. At steady state, many protein-coding and non-coding RNAs exhibit strong bias for association with PABPN or PABPC. While PABPN-enriched transcripts more often were incompletely spliced and harbored longer poly(A)-tails and PABPC-enriched RNAs had longer half-lives and higher translation efficiency, there are curious outliers. Overall, our study reveals the landscape of RNAs bound by PABPN and PABPC, providing new details that support and advance the current understanding of the roles these proteins play in poly(A)-tail synthesis, maintenance, and function.
Exonic splicing code and protein binding sites for calcium
Authors: Pengelly Reuben J , Bakhtiar Dara , Borovská Ivana , Královičová Jana , Vořechovský Igor
Published: April 2022

Auxilliary splicing sequences in exons, known as enhancers (ESEs) and silencers (ESSs), have been subject to strong selection pressures at the RNA and protein level. The protein component of this splicing code is substantial, recently estimated at ∼50% of the total information within ESEs, but remains poorly understood. The ESE/ESS profiles were previously associated with the Irving-Williams (I-W) stability series for divalent metals, suggesting that the ESE/ESS evolution was shaped by metal binding sites. Here, we have examined splicing activities of exonic sequences that encode protein binding sites for Ca2+, a weak binder in the I-W affinity order. We found that predicted exon inclusion levels for the EF-hand motifs and for Ca2+-binding residues in nonEF-hand proteins were higher than for average exons. For canonical EF-hands, the increase was centred on the EF-hand chelation loop and, in particular, on Ca2+-coordinating residues, with a 1>12>3∼5>9 hierarchy in the 12-codon loop consensus and usage bias at codons 1 and 12. The same hierarchy but a lower increase was observed for noncanonical EF-hands, except for S100 proteins. EF-hand loops preferentially accumulated exon splits in two clusters, one located in their N-terminal halves and the other around codon 12. Using splicing assays and published crosslinking and immunoprecipitation data, we identify candidate trans-acting factors that preferentially bind conserved GA-rich motifs encoding negatively charged amino acids in the loops. Together, these data provide evidence for the high capacity of codons for Ca2+-coordinating residues to be retained in mature transcripts, facilitating their exon-level expansion during eukaryotic evolution.
DEPhT: a novel approach for efficient prophage discovery and precise extraction
Authors: Gauthier Christian H , Abad Lawrence , Venbakkam Ananya K , Malnak Julia , Russell Daniel A , Hatfull Graham F
Published: April 2022

Advances in genome sequencing have produced hundreds of thousands of bacterial genome sequences, many of which have integrated prophages derived from temperate bacteriophages. These prophages play key roles by influencing bacterial metabolism, pathogenicity, antibiotic resistance, and defense against viral attack. However, they vary considerably even among related bacterial strains, and they are challenging to identify computationally and to extract precisely for comparative genomic analyses. Here, we describe DEPhT, a multimodal tool for prophage discovery and extraction. It has three run modes that facilitate rapid screening of large numbers of bacterial genomes, precise extraction of prophage sequences, and prophage annotation. DEPhT uses genomic architectural features that discriminate between phage and bacterial sequences for efficient prophage discovery, and targeted homology searches for precise prophage extraction. DEPhT is designed for prophage discovery in Mycobacterium genomes but can be adapted broadly to other bacteria. We deploy DEPhT to demonstrate that prophages are prevalent in Mycobacterium strains but are absent not only from the few well-characterized Mycobacterium tuberculosis strains, but also are absent from all ∼30 000 sequenced M. tuberculosis strains.
A rationalized definition of general tumor suppressor microRNAs excludes miR-34a
Authors: Mockly Sophie , Houbron Élisabeth , Seitz Hervé
Published: April 2022

While several microRNAs (miRNAs) have been proposed to act as tumor suppressors, a consensual definition of tumor suppressing miRNAs is still missing. Similarly to coding genes, we propose that tumor suppressor miRNAs must show evidence of genetic or epigenetic inactivation in cancers, and exhibit an anti-tumorigenic (e.g., anti-proliferative) activity under endogenous expression levels. Here we observe that this definition excludes the most extensively studied tumor suppressor candidate miRNA, miR-34a. In analyzable cancer types, miR-34a does not appear to be down-regulated in primary tumors relatively to normal adjacent tissues. Deletion of miR-34a is occasionally found in human cancers, but it does not seem to be driven by an anti-tumorigenic activity of the miRNA, since it is not observed upon smaller, miR-34a-specific alterations. Its anti-proliferative action was observed upon large, supra-physiological transfection of synthetic miR-34a in cultured cells, and our data indicates that endogenous miR-34a levels do not have such an effect. Our results therefore argue against a general tumor suppressive function for miR-34a, providing an explanation to the lack of efficiency of synthetic miR-34a administration against solid tumors.
Fragment screening and structural analyses highlight the ATP-assisted ligand binding for inhibitor discovery against type 1 methionyl-tRNA synthetase
Authors: Yi Jia , Cai Zhengjun , Qiu Haipeng , Lu Feihu , Luo Zhiteng , Chen Bingyi , Gu Qiong , Xu Jun , Zhou Huihao
Published: April 2022

Methionyl-tRNA synthetase (MetRS) charges tRNAMet with l-methionine (L-Met) to decode the ATG codon for protein translation, making it indispensable for all cellular lives. Many gram-positive bacteria use a type 1 MetRS (MetRS1), which is considered a promising antimicrobial drug target due to its low sequence identity with human cytosolic MetRS (HcMetRS, which belongs to MetRS2). Here, we report crystal structures of a representative MetRS1 from Staphylococcus aureus (SaMetRS) in its apo and substrate-binding forms. The connecting peptide (CP) domain of SaMetRS differs from HcMetRS in structural organization and dynamic movement. We screened 1049 chemical fragments against SaMetRS preincubated with or without substrate ATP, and ten hits were identified. Four cocrystal structures revealed that the fragments bound to either the L-Met binding site or an auxiliary pocket near the tRNA CCA end binding site of SaMetRS. Interestingly, fragment binding was enhanced by ATP in most cases, suggesting a potential ATP-assisted ligand binding mechanism in MetRS1. Moreover, co-binding with ATP was also observed in our cocrystal structure of SaMetRS with a class of newly reported inhibitors that simultaneously occupied the auxiliary pocket, tRNA site and L-Met site. Our findings will inspire the development of new MetRS1 inhibitors for fighting microbial infections.
Pre-mRNA splicing factor U2AF2 recognizes distinct conformations of nucleotide variants at the center of the pre-mRNA splice site signal
Authors: Glasser Eliezra , Maji Debanjana , Biancon Giulia , Puthenpeedikakkal Anees Mohammed Keedakkatt , Cavender Chapin E , Tebaldi Toma , Jenkins Jermaine L , Mathews David H , Halene Stephanie , Kielkopf Clara L
Published: April 2022

The essential pre-mRNA splicing factor U2AF2 (also called U2AF65) identifies polypyrimidine (Py) tract signals of nascent transcripts, despite length and sequence variations. Previous studies have shown that the U2AF2 RNA recognition motifs (RRM1 and RRM2) preferentially bind uridine-rich RNAs. Nonetheless, the specificity of the RRM1/RRM2 interface for the central Py tract nucleotide has yet to be investigated. We addressed this question by determining crystal structures of U2AF2 bound to a cytidine, guanosine, or adenosine at the central position of the Py tract, and compared U2AF2-bound uridine structures. Local movements of the RNA site accommodated the different nucleotides, whereas the polypeptide backbone remained similar among the structures. Accordingly, molecular dynamics simulations revealed flexible conformations of the central, U2AF2-bound nucleotide. The RNA binding affinities and splicing efficiencies of structure-guided mutants demonstrated that U2AF2 tolerates nucleotide substitutions at the central position of the Py tract. Moreover, enhanced UV-crosslinking and immunoprecipitation of endogenous U2AF2 in human erythroleukemia cells showed uridine-sensitive binding sites, with lower sequence conservation at the central nucleotide positions of otherwise uridine-rich, U2AF2-bound splice sites. Altogether, these results highlight the importance of RNA flexibility for protein recognition and take a step towards relating splice site motifs to pre-mRNA splicing efficiencies.
ExPheWas: a platform forcis-Mendelian randomization and gene-based association scans
Authors: Legault Marc-André , Perreault Louis-Philippe Lemieux , Tardif Jean-Claude , Dubé Marie-Pierre
Published: April 2022

Establishing the relationship between protein-coding genes and phenotypes has the potential to inform on the molecular etiology of diseases. Here, we describe ExPheWas (exphewas.ca), a gene-based phenome-wide association study browser and platform that enables the conduct of gene-based Mendelian randomization. The ExPheWas data repository includes sex-stratified and sex-combined gene-based association results from 26 616 genes with 1746 phenotypes measured in up to 413 133 individuals from the UK Biobank. Interactive visualizations are provided through a browser to facilitate data exploration supported by false discovery rate control, and it includes tools for enrichment analysis. The interactive Mendelian randomization module in ExPheWas allows the estimation of causal effects of a genetically predicted exposure on an outcome by using genetic variation in a single gene as the instrumental variable.
Effect on Tobacco Use and Subjective Measures of Including E-cigarettes in a Simulated Ban of Menthol in Combustible Cigarettes
Authors: Kotlyar Michael , Shanley Ryan , Dufresne Sheena R , Corcoran Gretchen A , Hatsukami Dorothy K
Published: April 2022

Introduction

Bans of menthol characterizing flavor in tobacco products have been proposed; however, there is limited data regarding the impact on current menthol cigarette smokers of including e-cigarettes in such bans.

Methods

In this six-week pilot study, 47 menthol smokers were randomized to receive all tobacco products from an experimental marketplace simulating either no menthol ban, a menthol ban for cigarettes but not e-cigarettes, or a ban for both (“total menthol ban”).

Results

At the first visit, all but one participant selected cigarettes with e-cigarettes selected by 38%, 69%, and 40% of participants in the no ban, menthol cigarette ban, and total menthol ban groups, respectively. Over the study period, the total menthol ban group smoked more than the menthol cigarette ban group (estimated mean ratio [EMR] in cigarettes per day = 1.38; 95% CI: 1.1, 1.75; p = .006). Compared to the no ban condition, the menthol cigarette ban group smoked slightly fewer (EMR = 0.87; 95% CI: .68, 1.11) and the total menthol ban group smoked slightly more (EMR = 1.20; 95% CI: 1.00, 1.45) although neither difference reached statistical significance. In both menthol ban conditions, ratings were lower (vs. no ban) on several measures of craving and cigarette effects and liking.

Conclusions

Menthol bans that include e-cigarettes may result in different patterns of tobacco use than if only combustible cigarettes are included, although e-cigarettes were not extensively used in any group. Larger studies are needed to determine policies most likely to provide the largest public health benefit.

Implications

Bans of menthol characterizing flavor have been proposed, however, the effects on menthol cigarette smokers of including e-cigarettes in such bans are not clear. This study found that smokers randomized to a simulated ban on menthol in both cigarettes and e-cigarettes smoked more cigarettes per day over the 6-week study period than those randomized to a simulated ban on menthol in only cigarettes suggesting that smoking patterns among current menthol smokers differ depending on which products are included in a menthol ban. Larger studies are needed to determine the policies most likely to provide the largest public health benefit.
Road accidents: unexpected costs of stock market movements
Authors: Fry Jane M , Farrell Lisa
Published: April 2022

Recent interest has grown in the link between stock market returns and health conditions. We extend this literature to road accidents as changes in returns may affect anxiety and stress, leading to driver fatigue and distraction, resulting in road accidents. Using Stats19 administrative data on accidents, we investigate the relationship between FTSE100 returns and accidents in British regions from 2008 to 2019. Accidents respond positively to decreases and increases in returns with effects up to 1.2%. Daily returns can be large, having substantial effect on accidents when returns are large. Compared with US results, we find no effects for fatal accidents. This could result from the UK’s very low fraction of fatalities and differences in road infrastructure, speed, and congestion. Unanticipated changes in returns represent an exogenous shock to individuals which may causally affect driving behaviour, and this is important to road safety stakeholders and for health promotion and policy.
Reaching Hard-to-Reach People Who Use Drugs: A Community-Based Strategy for the Elimination of Hepatitis C
Authors: Nagot Nicolas , D’Ottavi Morgana , Quillet Catherine , Debellefontaine Anne , Castellani Joëlle , Langendorfer Nicolas , Hanslik Bertrand , Guichard Sylvain , Baglioni René , Faucherre Vincent , Tuaillon Edouard , Pageaux Georges-Philippe , Laureillard Didier , Donnadieu-Rigole Hélène
Published: April 2022

Background

Elimination of hepatitis C virus (HCV) among people who use drugs (PWUD) remains a challenge even in countries in which HCV care is provided free of cost. We assessed whether an innovative community-based, respondent-driven sampling (RDS) survey, coupled with HCV screening and immediate treatment, could be efficient to detect and cure current PWUD with chronic HCV in a large city of Southern France.

Methods

At a community site with peers, PWUD (cannabis not included) were enrolled after confirmation by a urine drug test. Participants were then screened for hepatitis B virus, HCV, and human immunodeficiency virus and benefited from onsite HCV treatment evaluation and prescription. Peer support was provided during treatment, and a systematic visit was scheduled 12 weeks after the end of treatment. The cost of the intervention was estimated.

Results

Five hundred fifty-four participants were enrolled. Most were male (78.8%) with a median age of 39 years (interquartile range, 33–46). Cocaine (73.1%) and heroine (46.8%) were the main drugs consumed. Overall, 32.6% of PWUD (N = 181) were HCV seropositive, 49 (27.1%) of which had detectable HCV ribonucleic acid and were thus eligible for treatment. Ten of these patients had severe fibrosis. Hepatitis C virus treatment was initiated for 37 (75.5%) patients, 30 (81.1%) of whom completed their treatment and 27 (73.0%) achieved sustained viral response at week 12. The total cost was 161 euros € per screened patient and 1816€ per patient needing treatment.

Conclusions

A community-based RDS survey approach, involving peers, proved efficient and cost-effective to reach and cure PWUD for HCV. This innovative strategy could be key for the final step of HCV elimination.

Clinical trial registration. ClinicalTrials.gov, NCT04008927.
Phase I Trial of Regorafenib, Hydroxychloroquine, and Entinostat in Metastatic Colorectal Cancer
Authors: Karasic Thomas B , Brown Timothy J , Schneider Charles , Teitelbaum Ursina R , Reiss Kim A , Mitchell Tara C , Massa Ryan C , O’Hara Mark H , DiCicco Lisa , Garcia-Marcano Luis , Amaravadi Ravi K , O’Dwyer Peter J
Published: April 2022

Background

The antiangiogenic tyrosine kinase inhibitor regorafenib provides a survival benefit in patients with previously treated metastatic colorectal cancer (CRC). Antiangiogenic therapy causes hypoxic stress within tumor cells, which activates autophagy as a survival mechanism. The histone deacetylase inhibitor (HDAC) entinostat increases dependence on autophagy through epigenetic mechanisms. Hydroxychloroquine (HCQ) blocks autophagy by blunting lysosomal acidification. We hypothesized that HCQ and entinostat would be tolerable with regorafenib and potentiate the antitumor response.

Methods

This was a 3+3 phase I trial of HCQ and entinostat with regorafenib in patients with metastatic CRC. The primary objective was safety, and the secondary objective was clinical efficacy.

Results

Twenty patients received study therapy. Six evaluable patients were enrolled at each of the three planned dose levels, one patient at an intermediate dose level, and one additional patient withdrew consent after 4 days to receive treatment closer to home. One dose-limiting toxicity was noted in the study at dose level 2 (grade 3 fatigue). Seven patients discontinued therapy due to related toxicities; rapid weight loss was near universal, with a median weight loss of 4.4 kg (range 1.5-12.2 kg) in the first 2 weeks of treatment. No objective responses were observed.

Conclusion

The combination of regorafenib, HCQ, and entinostat was poorly tolerated without evident activity in metastatic CRC.

ClinicalTrials.gov Identifier

NCT03215264
Phase II Study of Cabozantinib in Patients With Bone Metastasis
Authors: Choy Edwin , Cote Gregory M , Michaelson M Dror , Wirth Lori , Gainor Justin F , Muzikansky Alona , Sequist Lecia V , Sullivan Ryan J , Fidias Panagiotis M , Shaw Alice , Heist Rebecca S
Published: April 2022

Bone metastases are often difficult to manage as they can be symptomatic and skeletal-related events (SREs) can contribute to significant morbidity and declines in performance status. We sought to identify a novel medical treatment for bone metastasis by testing the safety and efficacy of cabozantinib in patients with bone metastasis arising from non-breast, non-prostate, malignant solid tumors. Patients were administered cabozantinib as an oral drug starting at 60 mg per day and radiologic measurements were performed at baseline and every 8 weeks. Thirty-seven patients were enrolled. No SREs were observed throughout the study. Twenty patients had disease measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Four of 20 had a partial response by RECIST. An additional 12 patients had some decrease in tumor burden with nine of these having a decrease in tumor burden of at least 10% by RECIST. Six of the patients with at least a minor response had sarcoma. Sixteen patients had biomarkers of bone turnover measured before and after treatment. Most of these patients demonstrated decrease in urine and serum N-telopeptide and serum C-telopeptide. However, these changes in biomarkers of bone turnover did not correlate with radiographic changes measured by RECIST. This study demonstrates clinical activity and safety for cabozantinib in heavily pretreated patients with bone metastasis and shows activity for cabozantinib in patients with metastatic sarcoma.
The past, Present and Future of Parliamentary and Legislative Studies
Authors: Bhattacharya Caroline , Hart Gavin , Haughey Sean , Holden Bates Stephen , Meakin Alexandra
Published: April 2022

This special section emanates from the roundtable on the past, present and future of parliamentary and legislative studies, held as part of the PSA Parliaments specialist group’s 2020 annual conference.
ThePastof Parliamentary and Legislative Studies
Authors: Martin Shane , Taylor-Robinson Michelle M , Crewe Emma
Published: April 2022

In this article, Shane Martin, Michelle M. Taylor-Robinson and Emma Crewe discuss the past of parliamentary and legislative studies. The exchange is based on a Roundtable on the past, present and future of parliamentary studies, which was held online on 9 June 2021 as part of the Annual Conference of the UK Political Studies Association’s Parliaments Specialist Group.
Servile Migration and Gender in Late Medieval England: The Evidence of Manorial Court Rolls
Authors: Bailey Mark
Published: April 2022

Migration in medieval England was substantial, essential and mainly over short distances. Beyond this confident generalization, we know little about either the direction, life-histories or gendered patterns of rural migrants, and have no quantitative data. Yet, despite this, assumptions about peasant migration comprise central elements in two major debates about differential trajectories of social change in late-medieval Europe. The decline of serfdom and the emergence of the European Marriage Pattern in parts of northwest Europe — and by extension its superior economic performance to other regions of the Continent in the age of the Black Death — are attributed mainly to the preference of serfs and rural women to migrate disproportionately to towns.

This article uses the most abundant and unambiguous source of peasant migration — the record of flown serfs in English manorial court rolls — to provide the first quantitative dataset for the proportion of serfs and women moving to towns. It also reassesses the importance of circular migration through qualitative life-histories. Hitherto, no comparable rural material from medieval Europe has been published. It argues that historians have under-utilized this material because of ill-founded doubts about its reliability and quality, while remaining cautious about its typicality. It deploys information gleaned from thousands of court rolls for twenty-six manors across Midland and eastern England to reveal that 33 per cent of serfs headed for towns, and explores subtle differences in regional and gendered patterns of migration. The implications of the findings for the wider debates are discussed.
On Number-Set Identity: A Study
Authors: Ebels-Duggan Sean C
Published: April 2022

Benacerraf’s 1965 multiple-reductions argument depends on what I call ‘deferential logicism’: his necessary condition for number-set identity is most plausible against a background Quineanism that allows autonomy of the natural number concept. (This explains his neglect of ‘theoretical-virtue’ arguments.) Steinhart’s ‘folkist’ sufficient condition on number-set identity, by contrast, puts that autonomy at the center — but fails for not taking the folk perspective seriously enough. Learning from both sides, we explore new conditions on number-set identity, elaborating a 1983 suggestion from Wright.
AUXIN RESPONSE FACTOR7 integrates gibberellin and auxin signaling via interactions between DELLA and AUX/IAA proteins to regulate cambial activity in poplar
Authors: Hu Jian , Su Huili , Cao Hui , Wei Hongbin , Fu Xiaokang , Jiang Xuemei , Song Qin , He Xinhua , Xu Changzheng , Luo Keming
Published: April 2022

Cambial development in the stems of perennial woody species is rigorously regulated by phytohormones. Auxin and gibberellin (GA) play crucial roles in stimulating cambial activity in poplar (Populus spp.). In this study, we show that the DELLA protein REPRESSOR of ga1-3 Like 1 (RGL1), AUXIN RESPONSE FACTOR 7 (ARF7), and Aux/INDOLE-3-ACETIC ACID 9 (IAA9) form a ternary complex that mediates crosstalk between the auxin and GA signaling pathways in poplar stems during cambial development. Biochemical analysis revealed that ARF7 physically interacts with RGL1 and IAA9 through distinct domains. The arf7 loss-of-function mutant showed markedly attenuated responses to auxin and GA, whereas transgenic poplar plants overexpressing ARF7 displayed strongly improved cambial activity. ARF7 directly binds to the promoter region of the cambial stem cell regulator WOX4 to modulate its expression, thus integrating auxin and GA signaling to regulate cambial activity. Furthermore, the direct activation of PIN-FORMED 1 expression by ARF7 in the RGL1–ARF7–IAA9 module increased GA-dependent cambial activity via polar auxin transport. Collectively, these findings reveal that the crosstalk between auxin and GA signaling mediated by the RGL1–ARF7–IAA9 module is crucial for the precise regulation of cambial development in poplar.
Effects of Neural Mobilization on Pain Intensity, Disability, and Mechanosensitivity: An Umbrella Review With Meta–Meta-Analysis
Authors: Cuenca-Martínez Ferran , La Touche Roy , Varangot-Reille Clovis , Sardinoux Maëva , Bahier Jade , Suso-Martí Luis , Fernández-Carnero Josué
Published: April 2022

Objective

The purpose of this study was to assess the current evidence for the effects of neural mobilization (NM) treatments.

Methods

Three umbrella reviews with meta–meta-analyses were conducted to determine the effects of NM on pain intensity and disability in people with musculoskeletal disorders and on mechanosensitivity in participants who were asymptomatic. The study used the grading criteria proposed by the Physical Activity Guidelines Advisory Committee to assess the quality of evidence.

Results

One meta–meta-analysis revealed a statistically significant moderate effect on pain intensity (standardized mean difference [SMD] = −0.75, 95% CI = −1.12 to −0.38) but with evidence of heterogeneity (Q = 14.13; I2 = 65%). The study found a significantly large effect of NM on disability (SMD = −1.22, 95% CI = −2.19 to −0.26), again with evidence of heterogeneity (Q = 31.57; I2 = 87%). The third meta–meta-analysis showed a statistically significant moderate effect of NM on mechanosensitivity (SMD = 0.96, 95% CI = 0.35 to 1.57), with no evidence of heterogeneity (Q = 2.73; I2 = 63%). For all examined outcomes, the quality of evidence was limited.

Conclusion

Overall, the results indicated that although NM treatment had a moderate to large beneficial clinical effect on pain intensity and disability in people with musculoskeletal disorders and on mechanosensitivity in individuals who were asymptomatic, the quality of evidence was limited.

Impact

Neural mobilization treatments showed positive results on the pain intensity and disability in individuals with musculoskeletal conditions. Neural mobilization could be integrated into the physical therapy management, although more research is needed.
Trends in carbon monoxide poisoning deaths in high frequency hurricane states from 2014–19: the need for prevention intervention strategies
Authors: Alfaro Sophie , Sen-Crowe Brendon , Autrey Cody , Elkbuli Adel
Published: April 2022

Introduction

Hurricanes often result in power outages, which increase generator usage and carbon monoxide (CO) deaths. We aim to identify states with the highest frequency of hurricanes and evaluate the number of unintentional CO poisoning deaths by region, age, race and metropolitan distribution.

Methods

The number of hurricanes was determined using the FEMA database, and the number of unintentional CO poisoning deaths was determined using the CDC WONDER database from 2014–19. Hurricane-associated consumer outages were obtained from the Department of Energy.

Results

The number of unintentional CO poisoning deaths was as follows: Florida, South Carolina, North Carolina, Georgia and Alabama. Adults displayed a significantly higher number of unintentional CO poisoning deaths than pediatrics (P < 0.001). The total number of unintentional CO poisoning deaths was highest in the White population (P < 0.001); however, unintentional CO poisoning death rates were nearly two times higher among Black population in adults (0.5 versus 0.3) and pediatrics (0.2 versus 0.1). Medium metropolitan areas exhibited significantly more unintentional CO poisoning deaths (P < 0.001).

Conclusions

Hurricanes and unintentional CO poisoning deaths were most common in Florida. Death rates were higher among Black individuals. Medium metropolitan areas displayed significantly more unintentional CO poisoning deaths than all other areas.
PHANTOM STUDY OF THE ENTRANCE SURFACE DOSE OF A NEW CT SCOUT ACQUISITION THAT ALSO SERVES AS A TUBE WARM-UP
Authors: Ota Joji , Yokota Hajime , Higashida Reona , Komiya Ryota , Kawakami Yuya , Chida Koichi , Masuda Yoshitada , Uno Takashi
Published: April 2022

We determined the effect of a new scout image acquisition technique (‘smart scout’), which also serves as a tube warm-up, on radiation dose and automatic exposure control (AEC) mA settings. The entrance surface dose (ESD) of a chest phantom with and without the smart scout was measured. A conical AEC phantom was scanned in the setting for abdominal CT, and AEC curves were generated. ESD when the smart scout was not used was 0.75 mGy at 120 kV, 50 mA. ESD when using the smart scout was 0.24 mGy for a body habitus setting of ‘Less’, 0.54 mGy for ‘Moderate’ and 0.95 mGy for ‘More’. When the diameter of the subject was ≥32 cm, the mA setting became lower in ‘Less’. The smart scout reduced exposure at the ‘Less’ and Moderate’ settings compared to the conventional scout scan.
CORRELATION BETWEEN ROUTINE PERSONAL DOSIMETRY READING AND THE DOSE TO THE BRAIN OF INTERVENTIONAL STAFF
Authors: Smeulders Jelle , da Silva Edilaine Honorio , Struelens Lara , Vanhavere Filip , De Mey Johan , Martin Colin J , Buls Nico
Published: April 2022

This study aimed to evaluate the relationship between the brain absorbed dose and personal dosimetry readings in interventional cardiologists. Interventional procedures were replicated using Monte Carlo simulations (MCNP 6) with anthropomorphic phantoms representing both operator and patient. Absorbed doses were evaluated for 10 predefined regions of the operator’s brain as well as for dosemeters at chest and neck level. One beam quality (HVL = 6.2 mm Al) and nine beam projections were considered. A significant bias in the laterality of brain dose was found with doses at the left side of the brain being up to 2.8 times higher compared with the right. The correlation between brain dose and dosemeter reading was found to be dependent on beam projection. Yet, a generalized conversion factor (brain dose normalized by Hp(10)), averaged over all considered beam projections, could be proposed for (retrospective) brain dose estimation from routinely measured dosimetry data.
ASSESSMENT OF OCCUPATIONAL EXPOSURE IN THE MAIN PAEDIATRIC INTERVENTIONAL RADIOLOGY PROCEDURES
Authors: Morcillo Ana B , Huerga Carlos , Bayón José , López Antonio , Corredoira Eva , Hernández Teresa , Novo Joan R , Ponce María D , Fernández Lucía , Rodríguez Ricardo , Garzón Gonzalo , Vañó Eliseo , Guibelalde Eduardo , Alejo Luis
Published: April 2022

The aim of this study is to evaluate the personal dose equivalent Hp(10) in the most frequent (non-cardiac) paediatric interventional radiology (PIR) procedures: central venous catheters (CVC), hepatic/biliary and sclerotherapy interventions. i2 active solid-state dosemeters placed over the lead apron were used to monitor the exposure of three interventional radiologists over 18 months. A database was created to register all procedures performed by each radiologist (including the type of procedure and the kerma-area product, PKA). The mean Hp(10) per procedure for CVC, sclerotherapy and hepatic/biliary interventions was respectively 0.01 ± 0.01 mSv, 0.18 ± 0.13 mSv and 0.12 ± 0.06 mSv (k = 2). A similar value of Hp(10)/PKA was found despite the type of procedure or the patient weight (~10 μSv/Gy·cm2). There was high variability among individual interventions, probably due to the variable level of complexity, which led to uncertainties in the measurements’ mean higher than those associated with the dosemeter’s angular and energy dependence. i2 therefore proved suitable for monitoring Hp(10) in PIR procedures.
“Syria is Our Mom, UK is Like Aunty”: The Psychosocial Experiences of Acculturation in Syrian Refugees
Authors: Asmal-Lee Mujahid , Liebling Helen , Goodman Simon
Published: April 2022

In response to the Syrian Civil War, the British Government pledged to resettle 20,000 Syrian refugees by 2020. However, refugee integration can be traumatic. Existing literature has gaps encompassing the ‘lived experiences’ of Syrian refugees specifically. This study used semi-structured interviews and Interpretative Phenomenological Analysis to explore six Syrian refugees’ acculturation in the UK. Three superordinate themes were developed: Living with Loss, Experiencing a New Life, and The Dissonance of Integration: Belonging and Not Belonging. Syrian refugees’ losses impacted their integration. Arrival was experienced as an overwhelming re-birth for some, yet despite their new life, refugees’ integration could not escape past traumas. Syrian refugees’ integration encompassed degrees of belonging, racism, and Islamophobia. Experiences were affected by nurture, support, and connection with state structures, the host society and other refugees. Services and professionals would benefit from understanding refugees’ needs through cultural curiosity, sensitivity, and trust, to avoid exacerbating trauma. Policy recommendations include supporting refugees into meaningful employment and legal support for family reunification. Refugee voices and expertise should be considered in all aspects of integration. Findings have implications for models of integration particularly regarding the role of identity, employment, and how refugees’ experiences relate to what models view as ‘integration’.
The impacts of Centers for AIDS Research program and its enlargement on HIV/AIDS research collaboration
Authors: Xie Ruiyao , He Chaocheng , Qiao Shan , Li Xiaoming , Wu Jiang , Tang Weiming , Cui Wentian , Zhang Qingpeng
Published: April 2022

The Centers for AIDS Research (CFAR) is a large-scale and important program designed to enhance and coordinate high-quality human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) research. This paper explores the long-term (1985–2019) causal impacts of the CFAR program and its enlargement (three enlargement waves when new centers were recruited) on HIV/AIDS research collaboration. The dataset consists of HIV/AIDS-related research article publications collected from the Web of Science. First, the study applies the propensity score matching method combined with difference-in-difference (DiD) models to test the overall causal impact of the CFAR program on HIV/AIDS research collaboration. Then, by categorizing institutions into different groups based on recruitment stages and defining ten intra-/inter-group collaborations, the study constructs time-varying DiD models to explore the causal impacts of three enlargement waves of CFAR for the ten collaborations. The results show that CFAR and its enlargements have positive impacts on HIV/AIDS research collaboration, although the enlargements’ impacts are heterogeneous and specifically vary over time and across collaborations.
Supporting health researchers to realize meaningful patient involvement in research: Exploring researchers’ experiences and needs
Authors: Harmsen Simone , Pittens Carina A C M , Vroonland Eva , van Rensen Annemiek J M L , Broerse Jacqueline E W
Published: April 2022

Involving patients in health research requires a new way of working for all stakeholders involved, including researchers. This research aimed (1) to gain deeper insight into the experiences and needs of researchers regarding meaningful patient involvement and (2) to incorporate these insights into an online tool. This was done in a transdisciplinary research process, including three focus group discussions and three test sessions. We used the Social Cognitive Theory in the analysis process to reflect on how the tool addresses the complex personal, behavioural, and environmental factors that shape researchers’ experiences and needs. Identified factors were categorized into three themes: added value, perceived difficulty and patient-researcher role patterns. A tool was developed that addresses these factors, aiming to stimulate meaningful involvement by encouraging (self)reflection, experimentation, and learning-by-doing. It provides one element in a bigger systems approach to further stimulate patient involvement.
Vulnerability and Pathways to Precarity: How COVID-19 Has Affected Japan’s Nepali Immigrants
Authors: KHAREL Dipesh
Published: April 2022

This article explores the impact of COVID-19 on Nepali immigrants working as cooks in Nepali-owned Indian curry restaurants, one of the largest ethnic entrepreneurships in Japan. The COVID pandemic disproportionally affected the socio-economic situation of the restaurants’ owners and their cooks based on structural (dis)advantages. Many Nepali cooks have lost their jobs, and those who have stayed employed have seen their salaries reduced by 30–50%. As a result, cooks, who were already a vulnerable group, have been pushed into a more precarious situation, struggling to merely survive. However, surprisingly, more than 90% of Nepali restaurant owners have maintained their business operations and are still better positioned to weather this crisis than the cooks in their restaurants. This raises an important question: why are Nepali restaurant owners able to cope with the economic fall-out of the pandemic when Nepali restaurant cooks fell into destitution due to the coronavirus pandemic? Based on in-depth research in Japan and Nepal conducted from March 2020 to June 2021, and supplemented by my long-term research before the pandemic, this article will examine Nepali cooks’ social, economic, and structural vulnerabilities by emphasizing their responses to the pandemic and its outcome. Through the voices of the cooks, their families, and Nepali restaurants owners, I demonstrate how the vulnerability and the unequal effects of the pandemic, compounded by preexisting social inequality, exploitation, and socio-economic hierarchies are reverberating throughout the Nepali restaurant industry. Furthermore, by analyzing the relationship between the cooks and the owners, I argue that social networks at meso level not only increase migrants’ ‘resilience’, as suggested by vulnerabilities scholars but conversely involve a measure of exploitation and produce vulnerabilities.
Optogenetic Reporters Delivered as mRNA Facilitate Repeatable Action Potential and Calcium Handling Assessment in Human iPSC-Derived Cardiomyocytes
Authors: Yiangou Loukia , Blanch-Asensio Albert , de Korte Tessa , Miller Duncan C , van Meer Berend J , Mol Mervyn P H , van den Brink Lettine , Brandão Karina O , Mummery Christine L , Davis Richard P
Published: April 2022

Electrical activity and intracellular Ca2+ transients are key features of cardiomyocytes. They can be measured using organic voltage- and Ca2+-sensitive dyes but their photostability and phototoxicity mean they are unsuitable for long-term measurements. Here, we investigated whether genetically encoded voltage and Ca2+ indicators (GEVIs and GECIs) delivered as modified mRNA (modRNA) into human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) would be accurate alternatives allowing measurements over long periods. These indicators were detected in hiPSC-CMs for up to 7 days after transfection and did not affect responses to proarrhythmic compounds. Furthermore, using the GEVI ASAP2f we observed action potential prolongation in long QT syndrome models, while the GECI jRCaMP1b facilitated the repeated evaluation of Ca2+ handling responses for various tyrosine kinase inhibitors. This study demonstrated that modRNAs encoding optogenetic constructs report cardiac physiology in hiPSC-CMs without toxicity or the need for stable integration, illustrating their value as alternatives to organic dyes or other gene delivery methods for expressing transgenes.
A Linear Time Solution to the Labeled Robinson–Foulds Distance Problem
Authors: Briand Samuel , Dessimoz Christophe , El-Mabrouk Nadia , Nevers Yannis
Published: April 2022

A large variety of pairwise measures of similarity or dissimilarity have been developed for comparing phylogenetic trees, for example, species trees or gene trees. Due to its intuitive definition in terms of tree clades and bipartitions and its computational efficiency, the Robinson–Foulds (RF) distance is the most widely used for trees with unweighted edges and labels restricted to leaves (representing the genetic elements being compared). However, in the case of gene trees, an important information revealing the nature of the homologous relation between gene pairs (orthologs, paralogs, and xenologs) is the type of event associated to each internal node of the tree, typically speciations or duplications, but other types of events may also be considered, such as horizontal gene transfers. This labeling of internal nodes is usually inferred from a gene tree/species tree reconciliation method. Here, we address the problem of comparing such event-labeled trees. The problem differs from the classical problem of comparing uniformly labeled trees (all labels belonging to the same alphabet) that may be done using the Tree Edit Distance (TED) mainly due to the fact that, in our case, two different alphabets are considered for the leaves and internal nodes of the tree, and leaves are not affected by edit operations. We propose an extension of the RF distance to event-labeled trees, based on edit operations comparable to those considered for TED: node insertion, node deletion, and label substitution. We show that this new Labeled Robinson–Foulds (LRF) distance can be computed in linear time, in addition of maintaining other desirable properties: being a metric, reducing to RF for trees with no labels on internal nodes and maintaining an intuitive interpretation. The algorithm for computing the LRF distance enables novel analyses on event-label trees such as reconciled gene trees. Here, we use it to study the impact of taxon sampling on labeled gene tree inference and conclude that denser taxon sampling yields trees with better topology but worse labeling. [Algorithms; combinatorics; gene trees; phylogenetics; Robinson–Foulds; tree distance.]
The new regulation of professional trustees in Switzerland
Authors: Grisel Guillaume
Published: April 2022

The Swiss federal legislator adopted a new federal act on financial institutions (FinIA).1 This legislation came into force on 1 January 2020. It subjects professional trustees and wealth managers to a new licensing and supervisory regime. This law affects not only Swiss institutions, but also foreign institutions operating in Switzerland, whether through a subsidiary, a branch or a representative office. We are approaching the end of the three-year transitional period (from 1 January 2020 to 31 December 2022) during which the institutions concerned must comply with the new legal requirements. This article analyses the scope of the new authorisation and supervision regime, the obligations of professional trustees under the new regulation, the new system of supervision of trustees, the specific rules applying to Swiss branches or representative offices of foreign trustees, the sanctions in case of infringement of obligations and the transitional provisions. This article is mainly addressed to trustees, but the new regulation also applies to professional wealth managers.
The arbitration of trust disputes in New Zealand—a new frontier?
Authors: Anson-Holland James
Published: April 2022

Several provisions in New Zealand’s Trust Act seek to create a regime for the determination of trust disputes through alternative dispute resolution processes. At first blush, the regime seems to resolve the question of whether trust disputes are amenable to resolution through arbitration. However, on closer inspection, the regime gives rise to some real concerns about the recognition and enforceability of some awards, especially when those awards are rendered without the consent of all otherwise interested parties. This article discusses the regime and explores those concerns to highlight the perceived shortcomings.
Sham trusts and the requirement that a shamming intent be shared: Administrators of the Estate of Hanson v O’Leary and Ors
Authors: Arnull Thomas
Published: April 2022

In the recent case of Hanson, the Royal Court considered at length the principles applicable to claims that a trust is a sham and as such is void. The Court traced the case law through a number of recent developments. It reaffirmed the principle that, whereas a trustee's recklessness as to the terms of an apparent trust will constitute an intention that the assets would not be held on those apparent terms, recklessness will not suffice for the required intention to mislead third parties.