bluuebunny/crossref_metadata_2025 huggingface dataset:
Conceptualizing Family Caregivers’ Use of Community Support Services: A Scoping Review
Authors: Choi Hyojin , Reblin Maija , Litzelman Kristin
Published: April 2023

Background and Objectives

Only a fraction of the 53 million caregivers in the United States use available formal community services. This scoping review synthesized the literature on the barriers and facilitators of community support service utilization by adult caregivers of a family member or friend with an illness, disability, or other limitation.

Research Design and Methods

We searched PubMed, CINAHL, PsycInfo, and Web of Science for quantitative and qualitative articles assessing barriers and facilitators of caregivers’ access to and utilization of resources, following Preferred Reporting Items for Systematic Review and Meta-Analysis scoping review guidelines. Thematic analysis, drawing on an initial conceptualization, informed key insights around caregivers’ resource navigation process.

Results

The review provides support for individual factors affecting service use. Notably, some factors—such as time restrictions and increased caregiving demands—appear to function as barriers to accessing services even as they increase caregivers’ need for support. Additionally, contextual barriers including cultural factors and support of friends/family can affect caregivers’ access to resources. Finally, experience with health systems and structures and the intersection with other factors can affect service utilization.

Discussion and Implications

Suboptimal access to and utilization of community support services can be addressed at both the person and system level to mitigate potential inequities. Ensuring that caregivers are aware of, eligible for, and have the capacity and support to access the appropriate resources at the right time is essential for improving caregiver outcomes, reducing burnout, and supporting continued care.
In the thicket of fears, doubts, and murky facts: some reflections on treatment modalities for endometriosis-associated pain
Authors: Canis Michel , Guo Sun-Wei
Published: April 2023

Endometriosis-associated pain can be managed by either surgery or hormonal therapy. The final decision as to which treatment modality to take is based on efficacy and possible complications of different treatment modalities, risk of recurrence, and the patient’s wishes and preferences. But in the thicket of fears, doubts, and murky facts, the choice may ultimately be the trade-off between irrational fears and ignorance versus scientific evidence. We elaborate some pros and cons of the two treatment modalities and highlight some notable downsides of hormonal therapy, in particular the possible yet unquantified risk of long-term hormonal therapy for malignant transformation, perhaps with the only exception of combined oral contraceptives. Thus, when discussing with patients, we advocate the approach of discussing the advantages and disadvantages of all treatment options in detail, accounting for the known pros and cons with a full understanding of the predictive irrationality of human beings. For endometriosis-associated pain, surgery is definitely not a failure of medicine but, rather, a viable option, especially given the recently surfaced undercurrent of wariness and dissatisfaction with the current hormonal drugs among patients with endometriosis. Above all, there is a pressing need to fill the knowledge gap of perioperative interventions intended to reduce the risk of recurrence and to fulfill the demand for the development of safe and efficacious non-hormonal therapeutics.
The first mitotic division: a perilous bridge connecting the zygote and the early embryo
Authors: Coticchio Giovanni , Cimadomo Danilo , Cermisoni Greta Chiara , Rienzi Laura , Papaleo Enrico , Ubaldi Filippo Maria , Borini Andrea , De Santis Lucia
Published: April 2023

Human embryos are very frequently affected by maternally inherited aneuploidies, which in the vast majority of cases determine developmental failure at pre- or post-implantation stages. However, recent evidence, generated by the alliance between diverse technologies now routinely employed in the IVF laboratory, has revealed a broader, more complex scenario. Aberrant patterns occurring at the cellular or molecular level can impact at multiple stages of the trajectory of development to blastocyst. In this context, fertilization is an extremely delicate phase, as it marks the transition between gametic and embryonic life. Centrosomes, essential for mitosis, are assembled ex novo from components of both parents. Very large and initially distant nuclei (the pronuclei) are brought together and positioned centrally. The overall cell arrangement is converted from being asymmetric to symmetric. The maternal and paternal chromosome sets, initially separate and scattered within their respective pronuclei, become clustered where the pronuclei juxtapose, to facilitate their assembly in the mitotic spindle. The meiotic spindle is replaced by a segregation machinery that may form as a transient or persistent dual mitotic spindle. Maternal proteins assist the decay of maternal mRNAs to allow the translation of newly synthesized zygotic transcripts. The diversity and complexity of these events, regulated in a precise temporal order and occurring in narrow time windows, make fertilization a highly error-prone process. As a consequence, at the first mitotic division, cellular or genomic integrity may be lost, with fatal consequences for embryonic development.
A comparison of quasi-experimental methods with data before and after an intervention: an introduction for epidemiologists and a simulation study
Authors: Nianogo Roch A , Benmarhnia Tarik , O’Neill Stephen
Published: April 2023

Background

As the interest in and use of quasi-experimental methods to evaluate impacts of health policies have dramatically increased in the epidemiological literature, we set out this study to (i) systematically compare several quasi-experimental methods that use data before and after an intervention and contrast their performance within a simulation framework while providing a brief overview of the methods; and (ii) discuss challenges that could arise from using these methods as well as directions for future research in the context of epidemiological applications.

Methods

We considered single-group designs [pre-post and interrupted time series (ITS)] and multiple-group designs [controlled interrupted time series/difference-in-differences, synthetic control methods (SCMs): traditional SCMs and generalized SCMs]. We assessed performance based on bias and root mean squared error.

Results

We identified settings in which each method failed to provide unbiased estimates. We found that, among the methods investigated, when data for multiple time points and for multiple control groups are available (multiple-group designs), data-adaptive methods such as the generalized SCM were generally less biased than other methods evaluated in our study. In addition, when all of the included units have been exposed to treatment (single-group designs) and data for a sufficiently long pre-intervention period are available, then the ITS performs very well, provided the underlying model is correctly specified.

Conclusions

When using a quasi-experimental method using data before and after an intervention, epidemiologists should strive to use, whenever feasible, data-adaptive methods that nest alternative identifying assumptions including relaxing the parallel trend assumption (e.g. generalized SCMs).
Association of maternal serum magnesium with pre-eclampsia in African pregnant women: a systematic review and meta-analysis
Authors: Tesfa Endalamaw , Munshea Abaineh , Nibret Endalkachew , Gizaw Solomon Tebeje
Published: April 2023

Pre-eclampsia (PE) is a pregnancy-related disorder characterized by hypertension and proteinuria occurring after 20 weeks of gestation. Several studies have been performed to determine the serum magnesium (Mg) level in PE, but most report inconclusive results. Consequently, this study was designed to resolve this controversy among African women. PubMed, Hinari, Google Scholar and African Journals Online electronic databases were searched for studies published in English. The qualities of included articles were appraised using the Newcastle–Ottawa quality assessment tool. Stata 14 software was utilized for analysis and serum Mg levels in cases and normotensive controls were compared through mean and standardized mean difference (SMD) at the 95% confidence interval (CI). In this review, we found that the mean serum Mg level was significantly reduced in cases (0.910±0.762 mmol/L) vs controls (1.167±1.060 mmol/L). The pooled SMD of serum Mg was significantly lower in cases (−1.20 [95% CI −1.64 to −0.75]). Therefore, since serum Mg is reduced in cases vs controls, we propose that Mg is involved in the pathophysiology of PE. Nevertheless, to know the exact mechanisms of Mg in PE development will require large-scale prospective studies.
Management of postharvest blue mould of apple caused by Penicillium fuscoglaucum using a gel formulation containing Monarda citriodora essential oil and linalool
Authors: Rani Pragya , Sharma Mohini , Poovathumkadavil Thambi Nidhin , Katoch Meenu
Published: April 2023

Aims

This study aimed to develop essential oil-containing biopolymer-based vapor gel formulations for the postharvest management of blue mould of apples. Apples are one of the widely cultivated fruits. They are susceptible to a wide range of fungus leading to high losses in overall production. Many research articles have highlighted the applications of essential oil-biopolymer coatings in the postharvest storage of fruits. However, no studies have yet tried to explore the potential of a vapour gel formulation for postharvest applications.

Methods and results

Contaminated apples were collected from the local market. The causative fungus was isolated and identified. Minimum fungicidal concentrations of Monarda citriodora essential oil (MEO) and hexanal/linalool in the vapour phase were determined in vitro. In vitro and in vivo, checkerboard assays were used to demonstrate the synergistic activity between MEO and hexanal/linalool vapours against the isolated pathogen. MEO and linalool (M + L) combinatorial treatment indicated synergy in vivo and in vitro. In vivo treatment of M + L on apples by direct fumigation showed phytotoxicity. Gel formulations (carrageenan-guar gum, carbopol gel, and soft gel) were developed and evaluated to address phytotoxicity. M + L combination synergistically remediated the phytotoxicity in both carbopol (FICI = 0.625) and soft gels (FICI = 0.5625). The physicochemical parameters (pH, weight loss, TSS, and ascorbic acid (AsAC) of the treated apples were analysed. Reduction in weight loss and increase in AsAC were observed for treated fruits when compared to control, and no change in pH and TSS was observed.

Conclusions

Biopolymer vapour gel formulations containing M + L vapours effectively protect apples from the postharvest blue mould for extended storage.
A New JECFA Method for GC-MS Determination of Propylene Chlorohydrine Residues in Hydroxypropylated Starches
Authors: van der Ark Menko , Hopman Johan , Mijland Paul , Mulder Wubbo , Asdarci Fatma , O’Connell Xavier , Medic Jelena , Wei Qian , Brunt Kommer
Published: April 2023

Background

Propylene chlorohydrins (PCHs) are formed as byproducts in the reaction between starch and propylene oxide (PO). For hydroxypropylated (HP) starch applications in food, Joint FAO/WHO Expert Committee on Food additives (JECFA) set the maximum allowed total propylene chlorohydrin (PHC-t) residues level at 1 mg/kg.

Objective

To develop an improved analytical method for the determination of the PCH-t content in starches in the low mg/kg range to replace the outdated JECFA method.

Methods

A new GC–MS method that utilizes aqueous methanol as extraction medium for PCH. The GC–MS system is equipped with a programmable temperature vaporization injector and Stabilwax-DA column and uses helium as carrier gas. Quantitative detection is achieved in selected ion monitoring mode.

Results

This single-laboratory validation (SLV) study showed good linear calibrations for both 1-chloro-2-propanol (PCH-1) and 2-chloro-1-propanol (PCH-2) in the concentration range of 0.5–4 mg/kg in dry starch. The lower LOQ of PCH-1 and PCH-2 was 0.2–0.3 mg/kg in dry starch, the reproducibility RSD (RSDR) at the concentration level of 1–2 mg/kg in dry starch was 3–5%, and the recovery values for both PCH-1 and PCH-2 were in the range of 78–112% at a concentration level of about 0.6 mg/kg in dry starch. Compared with the current, outdated JECFA method, the new GC–MS method is more sustainable, less laborious, and therefore more economical. The analytical capacity of the new method is 4–5 times higher than the analytical capacity of the old JECFA method.

Conclusion

The GC–MS method is fit for a multi-laboratory trial (MLT).

Highlights

Based on the results of this SLV and the MLT (will be published in a second paper), the Joint FAO/WHO Expert Committee on Food Additives has recently decided to replace the outdated GC–FID JECFA method with the new GC–MS method for the determination of PCH-t content in starches.
Patient or Prisoner?: Acute Burn Injuries in Prisoners—The Birmingham Burns Centre Experience
Authors: Rafie Arash , Kankam Hadyn K N , Sandhu Amritpal , Chipp Elizabeth
Published: April 2023

Increased risk of violence and self-harm means prisoners are a vulnerable population with complex health needs. They account for a small proportion of patients with burn injuries; however, present a unique set of challenges. This study investigates the incidence, pattern and outcomes of burn injuries in prison population. Prisoners referred from 2010 to 2021 were identified using the International Burn Injury Database (iBID). Patient demographics, burn injury characteristics and outcomes were collected. Patients were then stratified based on mechanism of injury, treatment modality (surgery/conservative), hospital admission (inpatient/outpatient), and compliance with outpatient follow-up, for subgroup analyses.

Sixty-eight prisoners sustained burns during the study period, with a median age of 28.5 years and TBSA of 3%. The majority were male (98.5%) and required hospital admission (75%). Scalds were the most common injury type (77.9%) and assault the most frequent cause of burns (63.2%). Eighteen patients (26.5%) underwent a surgical procedure and there were two mortalities. Of patients for whom follow-up was planned, 22% attended no appointments, with a further 49% of prisoners missing at least one appointment. Relative to patients managed nonoperatively, prisoners undergoing surgery had a longer stay and all attended outpatient follow-up appointments. Prisoners represent a unique population with exceptional challenges. Attention should be given to protecting vulnerable patients at risk of assault, education of prison staff around burn prevention and first aid, and ensuring that prisoners are able to access burns follow-up to minimize long-term sequelae. Opportunities exist to aid this such as the adoption of telemedicine.
“Taking Time”: Exploring Music Therapy Student Self-Care Definitions and Practices
Authors: Wilhelm Lindsey A , Moore Carolyn
Published: April 2023

The concept of self-care for music therapists is not a new topic in the literature, yet music therapy students’ perspectives have largely been excluded from formal discussions and research studies. For this reason, this study aimed to examine music therapy students’ conceptualizations of self-care and identify practices that students frequently engage in for self-care. As part of a national survey, music therapy students currently enrolled in an academic degree program for music therapy within the United States defined self-care and identified up to three of their most frequent self-care practices. We analyzed the student self-care definitions and self-care practices using inductive content analysis. Two primary categories emerged from the student definitions—the Act of Self-Care and the Desired Outcomes of Self-Care—with several more detailed subcategories. Additionally, we grouped participants’ most common self-care practices into 10 categories and identified two emergent areas for exploration: self-care practices done with others/done alone and engaging in self-care practices that intentionally do not involve anything related to academics/coursework/clinical work. Together, these findings indicate that students’ conceptualizations of self-care and their self-care practices have similarities and differences with music therapy professionals’ perspectives and practices. We discuss these findings in depth and provide recommendations for future self-care discussions that emphasize the need to prioritize students’ perspectives and to expand conceptualizations of self-care to include contextual and systemic impacts and factors that influence the individual self-care experience.
Presentations and outcomes of people with unexplained symptoms in acute general surgery: protocol for a mixed-methods study
Authors: Romeu Daniel , Taylor Anna K , Guthrie Elspeth , Peckham-Cooper Adam , Henderson Max , Toogood Giles
Published: April 2023

Introduction

Unexplained symptoms are common across healthcare settings and are associated with increased mental and physical morbidity and healthcare expenditure. Improving the identification, explanation and management of unexplained symptoms will be helpful to patientsand healthcare systems. Limited data exists exploring unexplained acute abdominal pain in the surgical setting.

Objectives

This protocol describes three interlinked studies. Study one will determine the prevalence of anxiety and depression in patients presenting with explained and unexplained abdominal pain in an acute surgical setting. Study two will explore how the explanation and management of unexplained symptoms is conveyed to patients. Study three will explore how patients with unexplained symptoms understand these explanations.

Methods and analysis

Patients aged ≥18 years who present to a surgical same day emergency care unit with acute abdominal pain will be eligible. In study one, participants will be asked to complete a questionnaire, including validated self-report measures, at the time of presentation and six months later. They will be divided into explained and unexplained symptom groups based on clinical presentation and investigation outcomes. The proportion in each group meeting diagnostic thresholds for anxiety and depression will be compared and baseline predictors of pain and quality of life six months later will be determined. In study two, recordings of consultations between patients and surgeons involving the explanation and management of unexplained abdominal pain will be analysed. In study three, participants will be interviewed to explore their experiences and understanding of their symptoms.
Fifty years of sperm cell isolations: from structural to omic studies
Authors: Flores-Tornero María , Becker Jörg D
Published: April 2023

The fusion of male and female gametes is a fundamental process in the perpetuation and diversification of species. During the last 50 years, significant efforts have been made to isolate and characterize sperm cells from flowering plants, and to identify how these cells interact with female gametes to achieve double fertilization. The first techniques and analytical approaches not only provided structural and biochemical characterizations of plant sperm cells but also paved the way for in vitro fertilization studies. Further technological advances then led to unique insights into sperm biology at the transcriptomic, proteomic, and epigenetic level. Starting with a historical overview of sperm cell isolation techniques, we provide examples of how these contributed to create our current knowledge of sperm cell biology, and point out remaining challenges.
Sagas and genre: A case for application of network analysis to manuscripts preserving Old Norse-Icelandic saga literature
Authors: Kapitan Katarzyna Anna , Wills Tarrin
Published: April 2023

This study applies statistical approaches to the analysis of the genre relationships of Old Norse-Icelandic literature in order to expand our understanding of the relationships between works, their transmission, and their possible modes of reception, as manifested in the extant manuscripts. This article contributes to the ongoing discussion of the genre boundaries of Old Norse-Icelandic literature and presents an alternative method of engaging with this material in the form of computer-assisted analysis, i.e. data visualization and network analysis. Using data collected from major online databases of Old Norse-Icelandic manuscripts, we present the most complete to date network of co-occurrences in manuscripts of works belonging to a number of literary genres. The present study empirically demonstrates the manifoldness of the connections between the Old Norse-Icelandic works which transcend traditional scholarly genre boundaries. The study identifies two main communities within the network: a community of romances, or works of narrative fiction, which includes mainly legendary sagas (fornaldarsögur) and chivalric sagas (riddarasögur), and a community of historicizing narratives, or pseudo-history, which includes mainly sagas of Icelanders (Íslendingasögur) and kings’ sagas (konungasögur).
Abundances of CNO elements in z ∼ 0.3–0.4 Lyman continuum leaking galaxies
Authors: Izotov Y I , Schaerer D , Worseck G , Berg D , Chisholm J , Ravindranath S , Thuan T X
Published: April 2023

We present observations with the Space Telescope Imaging Spectrograph onboard the Hubble Space Telescope (HST) of 11 Lyman continuum (LyC) leaking galaxies at redshifts, z, in the range 0.29–0.43, with oxygen abundances 12+log(O/H) = 7.64–8.16, stellar masses M⋆ ∼ 107.8–109.8 M⊙, and O32 = [O iii] λ5007/[O ii] λ3727 of ∼ 5–20 aiming to detect the C iii] λ1908 emission line. We combine these observations with the optical Sloan Digital Sky Survey (SDSS) spectra for the determination of carbon, nitrogen, and oxygen abundances. Our sample was supplemented by 31 galaxies from the literature, for which carbon, nitrogen, and oxygen abundances can be derived from the HST and SDSS spectra. These additional galaxies, however, do not have LyC observations. We find that log(C/O) for the entire sample at 12+log(O/H) < 8.1 does not depend on metallicity, with a small dispersion of ∼0.13 dex around the average value of ∼−0.75 dex. On the other hand, the log(N/O) in galaxies at z > 0.1, including LyC leakers, is systematically higher compared to the rest of the sample with lower metallicity. We find that log(C/O) slightly decreases with increasing M⋆ from ∼ −0.65 at M⋆ = 106 M⊙ to ∼ −0.80 at M⋆ = 109–1010 M⊙, whereas log(N/O) is considerably enhanced at M⋆ > 108 M⊙. The origin of these trends remains basically unknown. A possible solution would be to assume that the upper mass limit of the stellar initial mass function in more massive galaxies is higher. This would result in a higher production of oxygen and a larger fraction of massive stars with stellar wind polluting the interstellar medium with nitrogen.
Gas distribution in ODISEA sources from ALMA long-baseline observations in 12CO(2-1)
Authors: Antilen Juanita , Casassus Simon , Cieza Lucas A , González-Ruilova Camilo
Published: April 2023

The 12CO rotational lines in protoplanetary discs are good tracers of the total spatial extension of the gas component, and potentially planet–disc interactions. We present ALMA long baseline observations of the 12CO(2-1) line of 10 protoplanetary discs from the Ophiuchus DIsc Survey Employing ALMA (ODISEA) project, aiming to set constraints on the gas distribution of these sources. The position angle of the gaseous disc can be inferred for five sources using high-velocity channels, which trace the gas in the inner part of the disc. We compare the high-velocity PAs to the orientations inferred from the continuum, representative of the orientation over ∼53 to 256 au in these resolved discs. We find a significant difference in orientation for DoAr 44, which is evidence of a tilted inner disc. Eight discs show evidence of gas inside inner dust cavities or gaps, and the disc of ISO-Oph 196 is not detected in 12CO(2-1), except for the compact signal located inside its dust cavity. Our observations also point out a possible outflow in WLY 2-63.
Esearch3D: propagating gene expression in chromatin networks to illuminate active enhancers
Authors: Heer Maninder , Giudice Luca , Mengoni Claudia , Giugno Rosalba , Rico Daniel
Published: April 2023

Most cell type-specific genes are regulated by the interaction of enhancers with their promoters. The identification of enhancers is not trivial as enhancers are diverse in their characteristics and dynamic in their interaction partners. We present Esearch3D, a new method that exploits network theory approaches to identify active enhancers. Our work is based on the fact that enhancers act as a source of regulatory information to increase the rate of transcription of their target genes and that the flow of this information is mediated by the folding of chromatin in the three-dimensional (3D) nuclear space between the enhancer and the target gene promoter. Esearch3D reverse engineers this flow of information to calculate the likelihood of enhancer activity in intergenic regions by propagating the transcription levels of genes across 3D genome networks. Regions predicted to have high enhancer activity are shown to be enriched in annotations indicative of enhancer activity. These include: enhancer-associated histone marks, bidirectional CAGE-seq, STARR-seq, P300, RNA polymerase II and expression quantitative trait loci (eQTLs). Esearch3D leverages the relationship between chromatin architecture and transcription, allowing the prediction of active enhancers and an understanding of the complex underpinnings of regulatory networks. The method is available at: https://github.com/InfOmics/Esearch3D and https://doi.org/10.5281/zenodo.7737123.
AFM-based force spectroscopy unravels stepwise formation of the DNA transposition complex in the widespread Tn3 family mobile genetic elements
Authors: Fernandez Maricruz , Shkumatov Alexander V , Liu Yun , Stulemeijer Claire , Derclaye Sylvie , Efremov Rouslan G , Hallet Bernard , Alsteens David
Published: April 2023

Transposon Tn4430 belongs to a widespread family of bacterial transposons, the Tn3 family, which plays a prevalent role in the dissemination of antibiotic resistance among pathogens. Despite recent data on the structural architecture of the transposition complex, the molecular mechanisms underlying the replicative transposition of these elements are still poorly understood. Here, we use force-distance curve-based atomic force microscopy to probe the binding of the TnpA transposase of Tn4430 to DNA molecules containing one or two transposon ends and to extract the thermodynamic and kinetic parameters of transposition complex assembly. Comparing wild-type TnpA with previously isolated deregulated TnpA mutants supports a stepwise pathway for transposition complex formation and activation during which TnpA first binds as a dimer to a single transposon end and then undergoes a structural transition that enables it to bind the second end cooperatively and to become activated for transposition catalysis, the latter step occurring at a much faster rate for the TnpA mutants. Our study thus provides an unprecedented approach to probe the dynamic of a complex DNA processing machinery at the single-particle level.
Insplico: effective computational tool for studying splicing order of adjacent introns genome-wide with short and long RNA-seq reads
Authors: Gohr André , Iñiguez Luis P , Torres-Méndez Antonio , Bonnal Sophie , Irimia Manuel
Published: April 2023

Although splicing occurs largely co-transcriptionally, the order by which introns are removed does not necessarily follow the order in which they are transcribed. Whereas several genomic features are known to influence whether or not an intron is spliced before its downstream neighbor, multiple questions related to adjacent introns' splicing order (AISO) remain unanswered. Here, we present Insplico, the first standalone software for quantifying AISO that works with both short and long read sequencing technologies. We first demonstrate its applicability and effectiveness using simulated reads and by recapitulating previously reported AISO patterns, which unveiled overlooked biases associated with long read sequencing. We next show that AISO around individual exons is remarkably constant across cell and tissue types and even upon major spliceosomal disruption, and it is evolutionarily conserved between human and mouse brains. We also establish a set of universal features associated with AISO patterns across various animal and plant species. Finally, we used Insplico to investigate AISO in the context of tissue-specific exons, particularly focusing on SRRM4-dependent microexons. We found that the majority of such microexons have non-canonical AISO, in which the downstream intron is spliced first, and we suggest two potential modes of SRRM4 regulation of microexons related to their AISO and various splicing-related features. Insplico is available on gitlab.com/aghr/insplico.
Novel mechanisms for the removal of strong replication-blocking HMCES- and thiazolidine-DNA adducts in humans
Authors: Sugimoto Yohei , Masuda Yuji , Iwai Shigenori , Miyake Yumi , Kanao Rie , Masutani Chikahide
Published: April 2023

Apurinic/apyrimidinic (AP) sites are DNA lesions created under normal growth conditions that result in cytotoxicity, replication-blocks, and mutations. AP sites are susceptible to β-elimination and are liable to be converted to DNA strand breaks. HMCES (5-hydroxymethylcytosine binding, ES cell specific) protein interacts with AP sites in single stranded (ss) DNA exposed at DNA replication forks to generate a stable thiazolidine protein-DNA crosslink and protect cells against AP site toxicity. The crosslinked HMCES is resolved by proteasome-mediated degradation; however, it is unclear how HMCES-crosslinked ssDNA and the resulting proteasome-degraded HMCES adducts are processed and repaired. Here, we describe methods for the preparation of thiazolidine adduct-containing oligonucleotides and determination of their structure. We demonstrate that the HMCES-crosslink is a strong replication blocking adduct and that protease-digested HMCES adducts block DNA replication to a similar extent as AP sites. Moreover, we show that the human AP endonuclease APE1 incises DNA 5′ to the protease-digested HMCES adduct. Interestingly, while HMCES-ssDNA crosslinks are stable, the crosslink is reversed upon the formation of dsDNA, possibly due to a catalytic reverse reaction. Our results shed new light on damage tolerance and repair pathways for HMCES-DNA crosslinks in human cells.
The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms
Authors: Kleinova Renata , Rajendra Vinod , Leuchtenberger Alina F , Lo Giudice Claudio , Vesely Cornelia , Kapoor Utkarsh , Tanzer Andrea , Derdak Sophia , Picardi Ernesto , Jantsch Michael F
Published: April 2023

Adenosine deaminase acting on RNA ADAR1 promotes A-to-I conversion in double-stranded and structured RNAs. ADAR1 has two isoforms transcribed from different promoters: cytoplasmic ADAR1p150 is interferon-inducible while ADAR1p110 is constitutively expressed and primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease associated with aberrant IFN production. In mice, deletion of ADAR1 or the p150 isoform leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype is rescued by deletion of the cytoplasmic dsRNA-sensor MDA5 indicating that the p150 isoform is indispensable and cannot be rescued by ADAR1p110. Nevertheless, editing sites uniquely targeted by ADAR1p150 remain elusive. Here, by transfection of ADAR1 isoforms into ADAR-less mouse cells we detect isoform-specific editing patterns. Using mutated ADAR variants, we test how intracellular localization and the presence of a Z-DNA binding domain-α affect editing preferences. These data show that ZBDα only minimally contributes to p150 editing-specificity while isoform-specific editing is primarily directed by the intracellular localization of ADAR1 isoforms. Our study is complemented by RIP-seq on human cells ectopically expressing tagged-ADAR1 isoforms. Both datasets reveal enrichment of intronic editing and binding by ADAR1p110 while ADAR1p150 preferentially binds and edits 3’UTRs.
BRAF
V600E/RAS Mutations and Lynch Syndrome in Patients With MSI-H/dMMR Metastatic Colorectal Cancer Treated With Immune Checkpoint Inhibitors
Authors: Colle Raphael , Lonardi Sara , Cachanado Marine , Overman Michael J , Elez Elena , Fakih Marwan , Corti Francesca , Jayachandran Priya , Svrcek Magali , Dardenne Antoine , Cervantes Baptiste , Duval Alex , Cohen Romain , Pietrantonio Filippo , André Thierry
Published: April 2023

Background

We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS).

Patients and Methods

Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events.

Results

Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity.

Conclusion

In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.
Association Between Immune-Related Adverse Events and Survival in Patients with Hepatocellular Carcinoma Treated With Atezolizumab Plus Bevacizumab
Authors: Fukushima Taito , Morimoto Manabu , Kobayashi Satoshi , Ueno Makoto , Uojima Haruki , Hidaka Hisashi , Kusano Chika , Chuma Makoto , Numata Kazushi , Tsuruya Kota , Arase Yoshitaka , Kagawa Tatehiro , Hattori Nobuhiro , Ikeda Hiroki , Watanabe Tsunamasa , Tanaka Katsuaki , Maeda Shin
Published: April 2023

Background

Immune checkpoint inhibitors (ICIs) are effective for advanced hepatocellular carcinoma (HCC). However, there are few reports on the correlation between the clinical efficacy of ICIs and the development of immune-related adverse events (irAEs) in patients with HCC. The aim of this study was to investigate the association between irAE development and survival in patients with HCC treated with atezolizumab plus bevacizumab.

Patients and Methods

We enrolled 150 patients with advanced HCC treated with atezolizumab plus bevacizumab between October 2020 and October 2021 at 5 territorial institutions. We compared the efficacy of atezolizumab plus bevacizumab between patients who experienced irAEs (irAE group) and those who did not (non-irAE group).

Results

Thirty-two patients (21.3%) developed irAEs of any grade. Grade 3/4 irAEs were observed in 9 patients (6.0%). The median progression-free survivals (PFS) in the irAE and non-irAE groups were 273 and 189 days, respectively (P = .055). The median overall survivals (OS) in the irAE and non-irAE groups were not reached and 458 days, respectively (P = .036). Grade 1/2 irAEs significantly prolonged PFS (P = .014) and OS (P = .003). Grade 1/2 irAEs were significantly associated with PFS (hazard ratio [HR], 0.339; 95% confidence interval [CI], 0.166-0.691; P = .003) and OS (HR, 0.086; 95% CI, 0.012-0.641; P = .017) on multivariate analysis.

Conclusion

The development of irAEs was associated with increased survival in a real-world population of patients with advanced HCC treated with atezolizumab plus bevacizumab. Grade 1/2 irAEs were strongly correlated with PFS and OS.
Investigation of mid-infrared long-term variability of dusty AGB stars using multi-epoch scan data of AKARI and WISE
Authors: Tachibana Kengo , Miyata Takashi , Kamizuka Takafumi , Ohsawa Ryou , Takita Satoshi , Nakagawa Akiharu , Ita Yoshifusa , Uchiyama Mizuho
Published: April 2023

Asymptotic giant branch (AGB) stars are one of the main sources of dust in the Universe. They form and supply dust triggered by stellar pulsations, but the details of the mechanism are still unknown. Among all AGB stars, dusty AGB stars are the most important in terms of dust supply because they contain the star with a high mass-loss rate. To investigate the relationship between the pulsation and the dust supply for such dusty AGB stars, long-term mid-infrared monitoring is necessary. In this study, we combine data from a infrared astronomical satellites AKARI and WISE to generate mid-infrared long-term observation data. This collected data enables us to investigate the variability of dusty AGB stars with a variability period of more than several hundred days (>250 d). Furthermore, we determine the mid-infrared variability amplitudes of 169 O-rich AGB stars and 28 OH/IR stars in our Galaxy, as well as data at other wavelengths. This study is the largest study on mid-infrared variability. Additionally, we discover a positive correlation between the variability amplitude A18μm in the 18μm band and the $\mathit {W3}-\mathit {W4}$ infrared color which is the measure of the dust supply. Also, we find that this relationship is independent of the variability period and mode. Finally, we calculate the radiative transfer of circumstellar dust from AGB stars. The result of our calculations showed that $A_{18\mu \rm {m}}$ is strongly affected by the luminosity change ratio of the central star. These experimental results imply that the luminosity change ratio has a strong influence on the dust supply of AGB star.
Loss of Chloroplast GNAT Acetyltransferases Results in Distinct Metabolic Phenotypes in Arabidopsis
Authors: Ivanauskaite Aiste , Rantala Marjaana , Laihonen Laura , Konert Minna M , Schwenner Naike , Mühlenbeck Jens S , Finkemeier Iris , Mulo Paula
Published: April 2023

Acetylation is one of the most common chemical modifications found on a variety of molecules ranging from metabolites to proteins. Although numerous chloroplast proteins have been shown to be acetylated, the role of acetylation in the regulation of chloroplast functions has remained mainly enigmatic. The chloroplast acetylation machinery in Arabidopsis thaliana consists of eight General control non-repressible 5 (GCN5)-related N-acetyltransferase (GNAT)–family enzymes that catalyze both N-terminal and lysine acetylation of proteins. Additionally, two plastid GNATs have also been reported to be involved in the biosynthesis of melatonin. Here, we have characterized six plastid GNATs (GNAT1, GNAT2, GNAT4, GNAT6, GNAT7 and GNAT10) using a reverse genetics approach with an emphasis on the metabolomes and photosynthesis of the knock-out plants. Our results reveal the impact of GNAT enzymes on the accumulation of chloroplast-related compounds, such as oxylipins and ascorbate, and the GNAT enzymes also affect the accumulation of amino acids and their derivatives. Specifically, the amount of acetylated arginine and proline was significantly decreased in the gnat2 and gnat7 mutants, respectively, as compared to the wild-type Col-0 plants. Additionally, our results show that the loss of the GNAT enzymes results in increased accumulation of Rubisco and Rubisco activase (RCA) at the thylakoids. Nevertheless, the reallocation of Rubisco and RCA did not have consequent effects on carbon assimilation under the studied conditions. Taken together, our results show that chloroplast GNATs affect diverse aspects of plant metabolism and pave way for future research into the role of protein acetylation.
The benefits of making peace with pain: chronic pain acceptance moderates the indirect effect of perceived burdensomeness between pain severity and suicidal cognitions
Authors: Hale Willie , Vacek Sarah , Crabtree Meghan , Grelle Kaitlin , Bryan Craig J , McGeary Donald D , Kanzler Kathryn E
Published: April 2023

Objective

The purpose of this study was (1) to examine the degree to which perceived burdensomeness mediates the relationship between pain severity and suicidal cognitions and (2) to determine whether this mediated relationship was moderated by pain acceptance. We predicted that high levels of pain acceptance would buffer relationships on both paths of the indirect effect.

Methods

Two-hundred seven patients with chronic pain completed an anonymous self-report battery of measures, including the Chronic Pain Acceptance Questionnaire, the Interpersonal Needs Questionnaire, the Suicidal Cognitions Scale, and the pain severity subscale of the West Haven–Yale Multidimensional Pain Inventory. Conditional process models were examined with Mplus.

Results

Chronic pain acceptance significantly moderated both paths of the mediation model. Results from the conditional indirect effect model indicated that the indirect effect was significant for those with low (b = 2.50, P = .004) and medium (b = 0.99, P = .01) but not high (b = 0.08, P = .68) levels of pain acceptance and became progressively stronger as pain acceptance scores decreased. The nonlinear indirect effect became nonsignificant at acceptance scores 0.38 standard deviation above the mean—a clinically attainable treatment target.

Conclusions

Higher acceptance mitigated the relationship between pain severity and perceived burdensomeness and the relationship between perceived burdensomeness and suicidal cognitions in this clinical sample of patients experiencing chronic pain. Findings indicate that any improvement in pain acceptance can be beneficial, and they provide clinicians with a clinical cut-point that might indicate lower vs higher suicide risk.
Managing Diversity in Nigeria’s Fourth Republic National Assembly: Integrated Parties versus Ethno-Regional Balancing
Authors: Demarest Leila , Langer Arnim
Published: April 2023

Since independence, Nigeria has adopted federalism to manage the country’s deep ethno-regional divisions, but federalism has not averted instability and return to military rule in the past. This highlights the need for additional factors and mechanisms to secure and stabilize civilian rule in Nigeria. The country’s ethnic party ban ensures that parties in power have a broad basis across the territory. Theoretically, these “integrated” parties are often argued to foster intergroup compromise and political stability. Yet in our case study of intergroup relations in Nigeria’s National Assembly, we demonstrate that the country’s broad-based parties do not play a strong role in organizing intergroup cooperation. Despite this, the Assembly has not experienced substantial policy gridlock. We argue that instead of integrated parties, ethno-regional balancing (i.e., a practice whereby key positions in parliament are allocated to different groupings) is a much more important stabilizing factor in Nigeria’s federal parliament.
Expert Consideration on Regulatory Aspects for Perinatal Derivatives in Clinical Settings
Authors: Hofmann Nicola , Lafarge Xavier , Antica Mariastefania , Ferry Nicolas , Girandon Lenart , Gramignoli Roberto , Jurga Marcin , Kerdjoudj Halima , Navakauskiene Ruta , Schiavi Jessica , Shablii Volodymyr , Nicolás Francisco J , Gindraux Florelle
Published: April 2023

Perinatal derivatives (PnD) are drawing growing interest among the scientific community as an unrestricted source of multipotent stem cells, secretome, and biological matrices. They are useful for the treatment of diseases that currently have limited or no effective therapeutic options, but they require the development of regenerative approaches. With this development, the question of regulation of donation, processing, and distribution has therefore become more important. Within the European Cooperation in Science and Technology (COST) community, we compiled a group of international experts on PnD technologies, who revised and compared existing EU national regulations. Notably, despite clear European directives, each EU Country has developed their own implementation and standard levels for cell- and tissue-based therapies. To enable extended applications of PnD treatments within the EU community and worldwide, harmonization is highly recommended. This paper aims to provide an overview of the various options available to introduce PnD into clinical practice. For this purpose, the different aspects resulting from (1) the type of PnD, (2) the amount of available data, (3) the degree of manipulation, and (4) the intended application and the process toward a possible commercialization will be presented. In the future, it will be important to find a balance between regulatory requirements and the best medical quality of the PnD product.
SAA1 deficiency alleviates cardiac remodeling by inhibiting NF‐κB/p38/JNK and TGFβ/Smad pathways
Authors: Xiao Yusha , Ni Lihua , Shi Hongjie , Yang Kang , Yang Jianguo , Zhao Jinping , Liu Jinping , Luo Pengcheng
Published: April 2023

Heart failure (HF) is the end stage of the progression of many cardiovascular diseases. Cardiac remodeling is the main pathophysiological process of cardiac function deterioration in HF patients. Inflammation is a key factor that stimulates cardiomyocyte hypertrophy, fibroblast proliferation, and transformation leading to myocardial remodeling, which severity is significantly related to the prognosis of patients. SAA1 (Serum amyloid A1) is a lipid‐binding protein that was an important regulator involved in inflammation, whose biological functions in the heart remain rarely known. In this research, we intended to test the role of SAA1 in SAA1‐deficient (SAA1−/−), and wild‐type mice were exposed to transverse aortic banding surgery to establish the model of cardiac remodeling. Besides, we assessed the functional effects of SAA1 on cardiac hypertrophy and fibrosis. The expression of SAA1 was increased in the mice transverse aortic banding model induced by pressure overload. After 8 weeks of transverse aortic banding, SAA1−/− mice displayed a lower level of cardiac fibrosis than wild‐type mice, but did not significantly influence the cardiomyocyte hypertrophy. In addition, there was also no significant difference in cardiac fibrosis severity between wild‐type‐sham and knockout‐sham mice. These findings are the first to reveal SAA1 absence hinders cardiac fibrosis after 8 weeks of transverse aortic banding. Furthermore, SAA1 deficiency had no significant effect on cardiac fibrosis and hypertrophy in the sham group in this study.