bluuebunny/crossref_metadata_2025 huggingface dataset:
CscoreTool-M infers 3D sub-compartment probabilities within cell population
Authors: Zheng Xiaobin , Tran Joseph R , Zheng Yixian
Published: May 2023

Motivation

Computational inference of genome organization based on Hi-C sequencing has greatly aided the understanding of chromatin and nuclear organization in three dimensions (3D). However, existing computational methods fail to address the cell population heterogeneity. Here we describe a probabilistic-modeling-based method called CscoreTool-M that infers multiple 3D genome sub-compartments from Hi-C data.

Results

The compartment scores inferred using CscoreTool-M represents the probability of a genomic region locating in a specific sub-compartment. Compared to published methods, CscoreTool-M is more accurate in inferring sub-compartments corresponding to both active and repressed chromatin. The compartment scores calculated by CscoreTool-M also help to quantify the levels of heterogeneity in sub-compartment localization within cell populations. By comparing proliferating cells and terminally differentiated non-proliferating cells, we show that the proliferating cells have higher genome organization heterogeneity, which is likely caused by cells at different cell-cycle stages. By analyzing 10 sub-compartments, we found a sub-compartment containing chromatin potentially related to the early-G1 chromatin regions proximal to the nuclear lamina in HCT116 cells, suggesting the method can deconvolve cell cycle stage-specific genome organization among asynchronously dividing cells. Finally, we show that CscoreTool-M can identify sub-compartments that contain genes enriched in housekeeping or cell-type-specific functions.

Availability and implementation

https://github.com/scoutzxb/CscoreTool-M.
O019 Studying telomere biology and genomic instability in gliomas
Authors: Bhatt H , Norris K , Cleal K , Kurian K , Gray W , Baird D
Published: May 2023

Introduction

Glioblastoma (GBM) is the most aggressive primary brain cancer. Identifying novel markers which stratify patients and predict response to targeted therapies is a priority. Telomeres are caps on chromosome ends protecting them from aberrant DNA damage response. Telomere length (TL) alterations and fusions are key markers for genomic instability and high-resolution telomere analysis provides powerful prognostic and predictive information in several tumour types. We therefore studied telomeric profiles and fusions in GBM patients and related this to clinical outcome.

Methods

Tumours from 151 adults with isocitrate dehydrogenase-wildtype GBMs were analysed for TL using the precision High-Throughput Single Telomere Length Analysis technique. 67 patients underwent further multiplex long-range polymerase chain reaction to identify fusions via Southern hybridisation using telomere-adjacent 33P radioisotope-labelled probes. Telomere fusions from 10 tumours that exhibited the highest frequency of fusions were characterised with long-read Nanopore sequencing.

Results

GBMs display short telomeres with a median length of 4.0kb. Shorter TLs in patients with unmethylated O6-methylguanine DNA methyltransferase status (commonest current biomarker) conferred worse survival (HR 2.13, p = 0.002). 66/67 (98.5%) patients analysed revealed telomeric fusions. Nanopore sequencing validated these events, while confirming the presence of microhomology and telomeric deletion. This mutational spectrum is consistent with utilisation of specific DNA repair pathways in mediating telomere fusion.

Conclusion

This study provides the first mechanistic evidence of dysfunctional telomeres in adult GBMs and suggests TL analysis may provide independent prognostic information. The presence of telomere fusions indicates significant genomic instability and may favour targeted therapies for patients exhibiting this signature.
O020 Comparison of indices of deprivation and screening uptake within a local AAA screening programme
Authors: Musto L , Olalobo A , Bown M
Published: May 2023

Introduction

The NHS Abdominal Aortic Aneurysm Screening Programme (NAAASP) was established nationally to reduce the number of deaths caused by ruptured AAA. NAAASP invites all men in their 65th year for a simple abdominal ultrasound scan. Across the country uptake to the programme varies greatly. The aim of this study is to determine the impact of deprivation on local screening programme attendance.

Methods

The attendance for patients invited to screening within the Leicester, Leicestershire and Rutland screening NAAASP programme between the years 2016 and 2021 was compared to indices of multiple deprivation (IMD) (derived from their Lower Layer Super Output Area (LSOA) for each patient). Multiple logistic regression was used to determine the most significant component contributing to the IMD score.

Results

28,730 men in total were invited to attend. Mean IMD for those that attended screening was 15.6 versus 20.6 for non-attenders (P value <0.001). Multiple regression revealed the IMD domains most associated with non-attendance to screening to be; Health Deprivation and Disability domain (P<0.001), Outdoor living environment domain (P<0.001) and Adult skills and English language proficiency domain (P<0.001). Barriers to housing and service domain including ‘geographical barriers’ which relate to the physical proximity of local services and employment domains did not show any association with attendance.

Conclusion

In line with the contemporary medical literature, social deprivation affects the uptake of the local National Abdominal Aortic Aneurysm Screening Programme (NAAASP). Health deprivation and disability, Outdoor living environment and adult education domains are most contributory to non-attendance.
O043 Evaluation of minimal factor H therapy administered to kidneys during ex vivo normothermic perfusion as a treatment to improve ischaemia reperfusion injury
Authors: Connelly C , Gibson B , Mahendran B , Tingle S J , Bates L , Cooper M , Thompson E , Wilson C , Sheerin N , Marchbank K
Published: May 2023

Introduction

Complement activation is a key mechanism of Ischaemia reperfusion injury, with the alternative pathway driving damage in particular. The main regulator of the alternative pathway is factor H. We hypothesised that homodimeric mini-factor H (HDM-FH; PMID:29588430) may protect transplanted kidneys from complement mediated damage when administered during normothermic perfusion machine perfusion.

Methods

Kidneys were retrieved from female white landrace pigs following an optimised protocol. One kidney from each pair was randomised to receive 5mg of HDM-FH (∼8μg/mL). Kidneys were perfused at 37°C with autologous blood for 6 hours. HDM-FH binding was measured using ELISA and immunofluorescence. Complement activation was measured by quantifying Bb deposition in tissue. The ability of HDM-FH to inhibit complement in serum was measured using haemolytic assays.

Results

4mgs of HDM-FH bound from perfusate during perfusion, with <10% lost in urine suggesting saturation was achieved. HDM-FH binding within the kidneys was confirmed using immunofluorescence. HDM-FH localised to glomeruli with deposition increasing over the time of the perfusion. Alternative pathway activation was reduced in kidneys receiving HDM-FH as demonstrated by reduced Bb deposition. Fibrinogen deposition was also reduced and found to colocalise with C3 in glomeruli. HDM-FH inhibits complement activity in serum in a dose-dependent manor.

Conclusion

Infusion with HDM-FH prior to simulated kidney transplant conditions reduced complement activation and other secondary negative outcomes to the organ. Therefore, organ perfusion with HDM-FH is highly likely to help prolong graft survival after transplant and this will be assessed in future studies.
O108 Racial discrimination in surgical practice: a 5 year global review
Authors: El Boghdady M , Ewalds-Kvist B M
Published: May 2023

Introduction

Racial discrimination indicates the unkind conduct towards other persons based on their race or skin colour. We aimed to systematically review racial discrimination in surgery and answer the following questions:1) Does racial/ethnic discrimination in surgery exist in the last 5 years. 2) If yes, are ways suggested to reduce racial/ethnic discrimination in surgery?

Methods

The systematic review was performed in compliance with the PRISMA guidelines along AMSTAR 2. A 5-year literature search was carried out on PubMed for articles published from 1/1/2017 to 01/11/2022. The retrieved citations were quality assessed by MERSQI and evidence graded by GRADE.

Results

A total of 9116 participants responded with a mean of 1013 (SD=2408) responses per citations reported in 9 studies from a final list of 10 included citations. Nine studies were from USA and 1 from South Africa. The evidence of racial discrimination was justified on strong scientific evidence constituting the basis for grade I. The second question's answer was ‘yes’ which was defendable on moderate scientific recommendation and thereby establishing the basis for evidence grade II.

Conclusion

There is sufficient evidence for the presence of racial discrimination in surgical practice in the last 5 years in the US. Ways to decrease racial discrimination in surgery exist. Healthcare and training systems must increase the awareness of these issues to eliminate the harmful effect on the individual and on the surgical team's performance. The existence of the discussed problems needs to be managed in more countries with diverse healthcare systems.
Spectrum and frequency of genetic variants in sporadic amyotrophic lateral sclerosis
Authors: Ruf Wolfgang P , Boros Matej , Freischmidt Axel , Brenner David , Grozdanov Veselin , de Meirelles Joao , Meyer Thomas , Grehl Torsten , Petri Susanne , Grosskreutz Julian , Weyen Ute , Guenther Rene , Regensburger Martin , Hagenacker Tim , Koch Jan C , Emmer Alexander , Roediger Annekathrin , Steinbach Robert , Wolf Joachim , Weishaupt Jochen H , Lingor Paul , Deschauer Marcus , Cordts Isabell , Klopstock Thomas , Reilich Peter , Schoeberl Florian , Schrank Berthold , Zeller Daniel , Hermann Andreas , Knehr Antje , Günther Kornelia , Dorst Johannes , Schuster Joachim , Siebert Reiner , Ludolph Albert C , Müller Kathrin
Published: May 2023

Therapy of motoneuron diseases entered a new phase with the use of intrathecal antisense oligonucleotide therapies treating patients with specific gene mutations predominantly in the context of familial amyotrophic lateral sclerosis. With the majority of cases being sporadic, we conducted a cohort study to describe the mutational landscape of sporadic amyotrophic lateral sclerosis. We analysed genetic variants in amyotrophic lateral sclerosis-associated genes to assess and potentially increase the number of patients eligible for gene-specific therapies. We screened 2340 sporadic amyotrophic lateral sclerosis patients from the German Network for motor neuron diseases for variants in 36 amyotrophic lateral sclerosis-associated genes using targeted next-generation sequencing and for the C9orf72 hexanucleotide repeat expansion. The genetic analysis could be completed on 2267 patients. Clinical data included age at onset, disease progression rate and survival. In this study, we found 79 likely pathogenic Class 4 variants and 10 pathogenic Class 5 variants (without the C9orf72 hexanucleotide repeat expansion) according to the American College of Medical Genetics and Genomics guidelines, of which 31 variants are novel. Thus, including C9orf72 hexanucleotide repeat expansion, Class 4, and Class 5 variants, 296 patients, corresponding to ∼13% of our cohort, could be genetically resolved. We detected 437 variants of unknown significance of which 103 are novel. Corroborating the theory of oligogenic causation in amyotrophic lateral sclerosis, we found a co-occurrence of pathogenic variants in 10 patients (0.4%) with 7 being C9orf72 hexanucleotide repeat expansion carriers. In a gene-wise survival analysis, we found a higher hazard ratio of 1.47 (95% confidence interval 1.02–2.1) for death from any cause for patients with the C9orf72 hexanucleotide repeat expansion and a lower hazard ratio of 0.33 (95% confidence interval 0.12–0.9) for patients with pathogenic SOD1 variants than for patients without a causal gene mutation.

In summary, the high yield of 296 patients (∼13%) harbouring a pathogenic variant and oncoming gene-specific therapies for SOD1/FUS/C9orf72, which would apply to 227 patients (∼10%) in this cohort, corroborates that genetic testing should be made available to all sporadic amyotrophic lateral sclerosis patients after respective counselling.
The Problem of ‘Uncertainty’ in International Criminal Law and the Common Law ‘Method’
Authors: Akhavan Payam , Mégret Frédéric
Published: May 2023

International criminal law has evolved from abstract ideas of an international criminal jurisdiction in the early twentieth century to encompass a comprehensive set of tribunals, rules, and methods. This article explores the contribution of the common law to the development of international criminal law, drawing on two key historical episodes – the Nuremberg and Tokyo tribunals, and the ad hoc International Criminal Tribunal for the former Yugoslavia (ICTY) and International Criminal Tribunal for Rwanda (ICTR) – to consider the common law’s historic influence over, and relationship to, uncertainty within the system of international criminal law. First, the article highlights how British jurists framed the normative uncertainty vis-à-vis the idea of international criminal justice in their contributions to this Yearbook. Second, it examines the characteristics shared between common law and international criminal law, with a view to appraising the potential relationship of both ‘systems’. Finally, it interrogates the differing treatments of the common law throughout the development of substantive international criminal law over time, considering how judges utilized the common law as they navigated the complex dialectic between ‘statutory’ and ‘judge-made’ law.
Strategic control of location and ordinal context in visual working memory
Authors: Fulvio Jacqueline M , Yu Qing , Postle Bradley R
Published: May 2023

Working memory (WM) requires encoding stimulus identity and context (e.g. where or when stimuli were encountered). To explore the neural bases of the strategic control of context binding in WM, we acquired fMRI while subjects performed delayed recognition of 3 orientation patches presented serially and at different locations. The recognition probe was an orientation patch with a superimposed digit, and pretrial instructions directed subjects to respond according to its location (“location-relevant”), to the ordinal position corresponding to its digit (“order-relevant”), or to just its orientation (relative to all three samples; “context-irrelevant”). Delay period signal in PPC was greater for context-relevant than for “context-irrelevant” trials, and multivariate decoding revealed strong sensitivity to context binding requirements (relevant vs. “irrelevant”) and to context domain (“location-” vs. “order-relevant”) in both occipital cortex and PPC. At recognition, multivariate inverted encoding modeling revealed markedly different patterns in these 2 regions, suggesting different context-processing functions. In occipital cortex, an active representation of the location of each of the 3 samples was reinstated regardless of the trial type. The pattern in PPC, by contrast, suggested a trial type-dependent filtering of sample information. These results indicate that PPC exerts strategic control over the representation of stimulus context in visual WM.
SyntenyViewer: a comparative genomics-driven translational research tool
Authors: Flores Raphael , Huneau Cécile , Burlot Laura , Lainé Mathilde , Kimmel Erik , Pommier Cyril , Alaux Michael , Adam-Blondon Anne-Françoise , Pont Caroline , Quesneville Hadi , Salse Jerome
Published: May 2023

SyntenyViewer is a public web-based tool relying on a relational database available at https://urgi.versailles.inrae.fr/synteny delivering comparative genomics data and associated reservoir of conserved genes between angiosperm species for both fundamental (evolutionary studies) and applied (translational research) applications. SyntenyViewer is made available for (i) providing comparative genomics data for seven major botanical families of flowering plants, (ii) delivering a robust catalog of 103 465 conserved genes between 44 species and inferred ancestral genomes, (iii) allowing us to investigate the evolutionary fate of ancestral genes and genomic regions in modern species through duplications, inversions, deletions, fusions, fissions and translocations, (iv) use as a tool to conduct translational research of key trait-related genes from model species to crops and (v) offering to host any comparative genomics data following simplified procedures and formats

Database URL https://urgi.versailles.inrae.fr/synteny
Female and Male Fertility after Colectomy and Reconstructive Surgery in Inflammatory Bowel Disease: A National Cohort Study from Sweden
Authors: Druvefors Emma , Myrelid Pär , Andersson Roland E , Landerholm Kalle
Published: May 2023

Background and Aims

Colectomy and reconstruction in patients with inflammatory bowel disease [IBD] may adversely affect fertility, but few population-based studies on this subject are available.

Methods

Fertility was assessed in 2989 women and 3771 men with IBD and prior colectomy during 1964–2014, identified from the Swedish National Patient Register, and in 35 092 matched individuals.

Results

Reconstruction with ileoanal pouch anastomosis [IPAA] was as common as ileorectal anastomosis [IRA] in ulcerative colitis [UC] and IBD-unclassified [IBD-U] but rare in Crohn’s disease [CD]. Compared with the matched reference cohort, women with IBD had lower fertility overall after colectomy (hazard ratio [HR] 0.65, confidence interval [CI] 0.61–0.69), with least impact with leaving the rectum intact [HR 0.79, CI 0.70–0.90]. Compared with colectomy only, fertility in female patients remained unaffected after IRA [HR 0.86, CI 0.63–1.17 for UC, 0.86, CI 0.68–1.08 for IBD-U and 1.07, CI 0.70–1.63 for CD], but was impaired after IPAA, especially in UC [HR 0.67, CI 0.50–0.88], and after completion proctectomy [HR 0.65, CI 0.49–0.85 for UC, 0.68, CI 0.55–0.85 for IBD-U and 0.61, CI 0.38–0.96 for CD]. In men, fertility was marginally reduced following colectomy [HR 0.89, CI 0.85–0.94], regardless of reconstruction.

Conclusions

Fertility was reduced in women after colectomy for IBD. The least impact was seen when a deviated rectum was left intact. IRA was associated with no further reduction in fertility, whereas proctectomy and IPAA were associated with the strongest impairment. IRA therefore seems to be the preferred reconstruction to preserve fertility in selected female patients. Fertility in men was only moderately reduced after colectomy.
Sex and age-specific interactions of coronary atherosclerotic plaque onset and prognosis from coronary computed tomography
Authors: van Rosendael Sophie E , Bax A Maxim , Lin Fay Y , Achenbach Stephan , Al-Mallah Mouaz H , Andreini Daniele , Budoff Matthew J , Cademartiri Filippo , Callister Tracy Q , Chinnaiyan Kavitha , Chow Benjamin J W , Cury Ricardo C , DeLago Augustin J , Feuchtner Gudrun , Hadamitzky Martin , Hausleiter Joerg , Kaufmann Philipp A , Kim Yong-Jin , Leipsic Jonathon A , Maffei Erica , Marques Hugo , de Araújo Gonçalves Pedro , Pontone Gianluca , Raff Gilbert L , Rubinshtein Ronen , Villines Todd C , Chang Hyuk-Jae , Berman Daniel S , Min James K , Bax Jeroen J , Shaw Leslee J , van Rosendael Alexander R
Published: May 2023

Aims

The totality of atherosclerotic plaque derived from coronary computed tomography angiography (CCTA) emerges as a comprehensive measure to assess the intensity of medical treatment that patients need. This study examines the differences in age onset and prognostic significance of atherosclerotic plaque burden between sexes.

Methods and results

From a large multi-center CCTA registry the Leiden CCTA score was calculated in 24 950 individuals. A total of 11 678 women (58.5 ± 12.4 years) and 13 272 men (55.6 ± 12.5 years) were followed for 3.7 years for major adverse cardiovascular events (MACE) (death or myocardial infarction). The age where the median risk score was above zero was 12 years higher in women vs. men (64–68 years vs. 52–56 years, respectively, P < 0.001). The Leiden CCTA risk score was independently associated with MACE: score 6–20: HR 2.29 (1.69–3.10); score > 20: HR 6.71 (4.36–10.32) in women, and score 6–20: HR 1.64 (1.29–2.08); score > 20: HR 2.38 (1.73–3.29) in men. The risk was significantly higher for women within the highest score group (adjusted P-interaction = 0.003). In pre-menopausal women, the risk score was equally predictive and comparable with men. In post-menopausal women, the prognostic value was higher for women [score 6–20: HR 2.21 (1.57–3.11); score > 20: HR 6.11 (3.84–9.70) in women; score 6–20: HR 1.57 (1.19–2.09); score > 20: HR 2.25 (1.58–3.22) in men], with a significant interaction for the highest risk group (adjusted P-interaction = 0.004).

Conclusion

Women developed coronary atherosclerosis approximately 12 years later than men. Post-menopausal women within the highest atherosclerotic burden group were at significantly higher risk for MACE than their male counterparts, which may have implications for the medical treatment intensity.
Prognostic impact of artificial intelligence-based fully automated global circumferential strain in patients undergoing stress CMR
Authors: Pezel Théo , Garot Philippe , Toupin Solenn , Hovasse Thomas , Sanguineti Francesca , Champagne Stéphane , Morisset Stéphane , Chitiboi Teodora , Jacob Athira J , Sharma Puneet , Unterseeh Thierry , Garot Jérôme
Published: May 2023

Aims

To determine whether fully automated artificial intelligence-based global circumferential strain (GCS) assessed during vasodilator stress cardiovascular (CV) magnetic resonance (CMR) can provide incremental prognostic value.

Methods and results

Between 2016 and 2018, a longitudinal study included all consecutive patients with abnormal stress CMR defined by the presence of inducible ischaemia and/or late gadolinium enhancement. Control subjects with normal stress CMR were selected using a propensity score-matching. Stress-GCS was assessed using a fully automatic machine-learning algorithm based on featured-tracking imaging from short-axis cine images. The primary outcome was the occurrence of major adverse clinical events (MACE) defined as CV mortality or nonfatal myocardial infarction. Cox regressions evaluated the association between stress-GCS and the primary outcome after adjustment for traditional prognosticators. In 2152 patients [66 ± 12 years, 77% men, 1:1 matched patients (1076 with normal and 1076 with abnormal CMR)], stress-GCS was associated with MACE [median follow-up 5.2 (4.8–5.5) years] after adjustment for risk factors in the propensity-matched population [adjusted hazard ratio (HR), 1.12 (95% CI, 1.06–1.18)], and patients with normal CMR [adjusted HR, 1.35 (95% CI, 1.19–1.53), both P < 0.001], but not in patients with abnormal CMR (P = 0.058). In patients with normal CMR, an increased stress-GCS showed the best improvement in model discrimination and reclassification above traditional and stress CMR findings (C-statistic improvement: 0.14; NRI = 0.430; IDI = 0.089, all P < 0.001; LR-test P < 0.001).

Conclusion

Stress-GCS is not a predictor of MACE in patients with ischaemia, but has an incremental prognostic value in those with a normal CMR although the absolute event rate remains low.
Fulminant biventricular multivalvular infective endocarditis in complex congenital heart disease: a case report
Authors: Abbate Massimiliana , Fusco Flavia , Columbano Laura , Sarubbi Berardo , Scognamiglio Giancarlo
Published: May 2023

Background

Infective endocarditis (IE) is a major issue during follow-up of adults with congenital heart disease (ACHD), leading to significant mortality.

Case summary

A 37-year-old woman with transposition of great arteries and previous Mustard operation developed a drug-resistant pneumonia shortly after a pacemaker implant procedure performed at a local hospital. After referral to the ACHD centre, the patient was diagnosed with multivalvular IE with biventricular involvement by methicillin-resistant Staphylococcus aureus. On admission, the patient was already in acute respiratory distress and presented both systemic and pulmonary embolization. Despite adequate treatment was promptly started, the patient developed multiorgan failure.

Discussion

This case depicts a particularly aggressive of infective endocarditis forms caused with biventricular involvement and multiple embolization. Patients with congenital heart disease are at high risk of IE with adverse impact on the prognosis. Early recognition and treatment are the keys to improve prognosis. Therefore, suspicion should be high, especially following invasive procedure, which should be preferably performed at ACHD specialized centres.
The effect of micro-osteoperforation on the rate of tooth movement during the alignment stage in patients with mandibular crowding: a randomised controlled trial
Authors: Faik Sahin Mucahid , Baysal Asli
Published: May 2023

Background

Orthodontic treatment is a long process that requires patient cooperation. Risks of side effects such as caries formation, periodontal problems, and root resorption increases as well as problems in patient cooperation arises with longer treatments. Several different techniques were developed that may shorten the treatment time.

Objective

The aim of this study was to evaluate the effectiveness of micro-osteoperforations (MOPs) performed during the alignment stage.

Trial design

Randomized controlled trial.

Methods

Twenty-eight subjects who had crowding in the mandibular arch were included in the study. The first group (4 boys and 10 girls, mean age = 17.21 ± 3.76 years) was treated with MOP (MOP) and the second group (8 boys and 6 girls, mean age = 15.29 ± 1.77 years) was treated without MOP (control). Cephalometric variables, periodontal parameters, Little irregularity index, alignment duration, patient satisfaction, and ease of operation were evaluated. The level of statistical significance was P ≤ 0.05.

Results

Alignment duration was shorter (P = 0.000) in the MOP group (105.57 ± 18.34 days) compared to control group (135.86 ± 15.12 days). Alleviating of the crowding was more in the MOP group, compared to the control group in all time points. The pain level in the MOP group in the first appointment was higher compared to control group (P = 0.002). There was no significant difference between the groups in cephalometric parameters. Higher increases were found for gingival index (P = 0.008) and bleeding index (P = 0.039) in the control group compared to MOP group at the end of treatment

Limitations

The study was a single-centre study.

Conclusion

Alignment stage was shortened with MOP application. There was no difference between groups for patient satisfaction and pain level except for the first appointment. No difference was observed between the groups regarding cephalometric values. Clinically insignificant inflammation was observed in periodontal tissues for both groups.

Registration

This study was registered at the Clinical Trials Registry (ClinicalTrials.gov NCT03652454).
The Evolution of the Discrete Multirenculate Kidney in Mammals from Ecological and Molecular Perspectives
Authors: Zhou Xu , Rong Wenqi , Guo Boxiong , He Xiaofang , Cao Li , Zheng Yu , Xu Shixia , Yang Guang , Ren Wenhua
Published: May 2023

Mammals have developed different kinds of renal structures during evolution, yet the origin of the renal structural phenotypes and the molecular mechanisms underlying their adaptive evolution remains unclear. Here, we reconstructed the ancestral state of the renal structures across mammals and found that the unilobar kidney was the ancestral character in mammals. The subsequent correlation analyses between renal phenotypes and life history traits revealed that species with a larger body or in aquatic habitats tend to have evolved discrete multirenculate kidneys (DMKs). To explore the molecular convergent mechanisms among mammals with this most distinct renal structure, the DMK, we used 45 genes related to duplex/multiplex kidney diseases to compare the evolutions of species with DMKs and with other renal phenotypes. Twelve rapidly evolving genes that were functionally enriched in cilium assembly and centrosome were identified in species with DMKs, suggesting that these genes played key roles in the evolution of DMKs. In addition, positive selection was detected in six crucial genes which are mainly involved in epithelial tube morphogenesis and the regulation of neurogenesis. Finally, 12 convergent amino acid substitutions, 6 of which are in crucial domain of proteins, were shared by 2 or more lineages with DMKs. These findings could provide some novel insights into the origin and evolution of renal structures across mammals and the pathogenesis of renal diseases in humans.
Continuity of maternal and infant care through integrated health service delivery networks in Latin America: a scoping review
Authors: Panjwani Sonya , Garney Whitney R , Wilson Kelly , Goodson Patricia , Hamie Silva
Published: May 2023

Latin America has experienced substantial development over the last three decades; however, development has been uneven with persistent inequalities, especially in the areas of maternal and child health. Since the early 1990s, most Latin American health-care systems have undergone a series of reforms to improve access to services, with the most recent being the implementation of integrated health service delivery networks (IHSDNs). This model posits that patients will receive better continuity of care and higher-quality health services and avoid duplicated efforts. While decreased maternal and infant mortality rates have been observed in the region since IHSDN implementation, there is limited evidence on this model’s implications for maternal and infant care. The purpose of this study is to explore how IHSDNs affect access to and continuity of maternal and infant care in Latin America, according to the peer-reviewed literature. A scoping review was conducted systematically to identify peer-reviewed articles published since 2007 on studies that took place in Latin America, include IHSDNs, focus on the antenatal and/or postnatal period, include women and/or infants under 2 years of age and are written in English, Spanish or Portuguese. Seven studies (n = 7) met the inclusion criteria for this review. Barriers identified were related to person-centred care (n = 5) and logistical challenges (n = 5). The most cited facilitator encompassed social support for women when accessing care (n = 3). Potential solutions to improve care access included an improvement in the network structure and a greater focus on care provision, rather than regulations and compliance. Findings from this study suggest that the IHSDN model has the potential to improve care for women during pregnancy and post-birth if the model is implemented to its full extent. However, implementation of the model in Latin America is still weak, creating barriers for women when seeking care, particularly for disparate populations and those residing in rural areas.
Examining the feasibility of a youth advocacy program promoting healthy snacking in New York City: a mixed-methods process evaluation
Authors: Gangrade Navika , Botchwey Nisha , Leak Tashara M
Published: May 2023

Adolescents from urban communities are at risk for unhealthy snacking behaviors. Youth advocacy interventions are shown to improve certain adolescent health behaviors, such as substance use. However, it remains unclear if youth advocacy is a feasible method to promote healthy snacking. As such, the aim of this study was to examine the feasibility of a youth advocacy program promoting healthy snacking among adolescents in New York City by conducting a mixed-methods process evaluation. Adolescents (12–18 years) at a Boys and Girls Club in New York City were recruited to participate in a 12-session adaptation of the Youth Engagement and Action for Health! program to advocate for the promotion of healthy snacks in corner stores. A mixed-methods process evaluation was conducted to assess recruitment, reach (attendance), dose delivered (amount of intervention delivered), fidelity (degree to which intervention was implemented according to curriculum) and dose received (participant engagement/satisfaction). Satisfaction was also evaluated through focus groups. Descriptive statistics were calculated for quantitative data, and focus groups were analyzed using thematic analysis. Participant retention (94.74%), attendance (93.52%), dose delivered (98.94%), fidelity (98.5%), engagement (4.97/5) and program satisfaction (4/5) were high. Focus groups (n = 6; 28 participants) revealed that participants learned about nutrition, enjoyed being advocates and improved snacking behaviors.
Messenger RNA rescues medium-chain acyl-CoA dehydrogenase deficiency in fibroblasts from patients and a murine model
Authors: Zhao Xue-Jun , Mohsen Al-Walid , Mihalik Stephanie , Solo Keaton , Basu Shakuntala , Aliu Ermal , Shi Huifang , Kochersberger Catherine , Karunanidhi Anuradha , Van’t Land Clinton , Coughlan Kimberly A , Siddiqui Summar , Rice Lisa M , Hillier Shawn , Guadagnin Eleonora , DeAntonis Christine , Giangrande Paloma H , Martini Paolo G V , Vockley Jerry
Published: May 2023

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common inherited disorder of mitochondrial fatty acid β-oxidation (FAO) in humans. Patients exhibit clinical episodes often associated with fasting. Symptoms include hypoketotic hypoglycemia and Reye-like episodes. With limited treatment options, we explored the use of human MCAD (hMCAD) mRNA in fibroblasts from patients with MCAD deficiency to provide functional MCAD protein and reverse the metabolic block. Transfection of hMCAD mRNA into MCAD- deficient patient cells resulted in an increased MCAD protein that localized to mitochondria, concomitant with increased enzyme activity in cell extracts. The therapeutic hMCAD mRNA-lipid nanoparticle (LNP) formulation was also tested in vivo in Acadm−/− mice. Administration of multiple intravenous doses of the hMCAD mRNA-LNP complex (LNP-MCAD) into Acadm−/− mice produced a significant level of MCAD protein with increased enzyme activity in liver, heart and skeletal muscle homogenates. Treated Acadm−/− mice were more resistant to cold stress and had decreased plasma levels of medium-chain acylcarnitines compared to untreated animals. Furthermore, hepatic steatosis in the liver from treated Acadm−/− mice was reduced compared to untreated ones. Results from this study support the potential therapeutic value of hMCAD mRNA-LNP complex treatment for MCAD deficiency.
Gallbladder cancer-associated genetic variants rs1003349 and rs1004030 regulate MMP14 expression by altering SOX10- and MYB-binding sites
Authors: J Vinay , Palo Ananya , Besra Kusumbati , Dixit Manjusha
Published: May 2023

The pathogenesis of gallbladder cancer is complex, involving environmental and genetic risk factors. The matrix metallopeptidase 14 (MMP14) alters the tumor microenvironment and promotes tumorigenesis. In this study, we have characterized the role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer pathogenesis. Previously, we have shown the association of rs1004030 and rs1003049 with GBC and allele-specific differential expression of MMP14 in GBC patients. These variants reside within the cis-regulatory element (CRE) with high DNase and H3K4me3 signals, suggesting an active regulatory role in MMP14 expression. The luciferase-based reporter assay showed the role of promoter variants on expression levels in two GBC cell lines. Deleting the 119 bp promoter region surrounding the variants rs1004030 and rs1003049 by CRISPR-Cas9 genome editing resulted in reduced MMP14 expression in G415 cells. Electrophoretic mobility shift assay shows the presence of risk allele ‘C’/‘G’ at rs1004030 and rs1003049 and create binding sites for transcription factors SOX10 and MYB, respectively. Further, stable knockdown of these transcription factors in G415 and TGBC1TKB cells showed reduced expression of MMP14. However, in both GBC cells, ectopic expression of these transcription factors increased the expression of MMP14. Rescue of MYB and SOX10 expression levels showed a significant increase in luciferase activity only in risk allele-carrying constructs. In conclusion, our study unveils a mechanistic role of the MMP14 promoter variants rs1004030 and rs1003049 in gallbladder cancer.
An in vivo functional assay to characterize human STAT5B genetic variants during zebrafish development
Authors: Landi Estefanía , Karabatas Liliana , Rodríguez Gomez Tomás , Salatino Lucía , Scaglia Paula , Ramírez Laura , Keselman Ana , Braslavsky Débora , Sanguineti Nora , Pennisi Patricia , Rey Rodolfo A , Bergadá Ignacio , Jasper Héctor G , Domené Horacio M , Plazas Paola V , Domené Sabina
Published: May 2023

Growth hormone (GH) binding to GH receptor activates janus kinase 2 (JAK2)-signal transducer and activator of transcription 5b (STAT5b) pathway, which stimulates transcription of insulin-like growth factor-1 (IGF1), insulin-like growth factor binding protein 3 (IGFBP3) and insulin-like growth factor acid-labile subunit (IGFALS). Although STAT5B deficiency was established as an autosomal recessive disorder, heterozygous dominant-negative STAT5B variants have been reported in patients with less severe growth deficit and milder immune dysfunction. We developed an in vivo functional assay in zebrafish to characterize the pathogenicity of three human STAT5B variants (p.Ala630Pro, p.Gln474Arg and p.Lys632Asn). Overexpression of human wild-type (WT) STAT5B mRNA and its variants led to a significant reduction of body length together with developmental malformations in zebrafish embryos. Overexpression of p.Ala630Pro, p.Gln474Arg or p.Lys632Asn led to an increased number of embryos with pericardial edema, cyclopia and bent spine compared with WT STAT5B. Although co-injection of WT and p.Gln474Arg and WT and p.Lys632Asn STAT5B mRNA in zebrafish embryos partially or fully rescues the length and the developmental malformations in zebrafish embryos, co-injection of WT and p.Ala630Pro STAT5B mRNA leads to a greater number of embryos with developmental malformations and a reduction in body length of these embryos. These results suggest that these variants could interfere with endogenous stat5.1 signaling through different mechanisms. In situ hybridization of zebrafish embryos overexpressing p.Gln474Arg and p.Lys632Asn STAT5B mRNA shows a reduction in igf1 expression. In conclusion, our study reveals the pathogenicity of the STAT5B variants studied.
Epigenotype–genotype–phenotype correlations in SETD1A and SETD2 chromatin disorders
Authors: Lee Sunwoo , Menzies Lara , Hay Eleanor , Ochoa Eguzkine , Docquier France , Rodger Fay , Deshpande Charu , Foulds Nicola C , Jacquemont Sébastien , Jizi Khadije , Kiep Henriette , Kraus Alison , Löhner Katharina , Morrison Patrick J , Popp Bernt , Richardson Ruth , van Haeringen Arie , Martin Ezequiel , Toribio Ana , Li Fudong , Jones Wendy D , Sansbury Francis H , Maher Eamonn R
Published: May 2023

Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype–genotype–phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
Genome of tetraploid sour cherry (Prunus cerasus L.) ‘Montmorency’ identifies three distinct ancestral Prunus genomes
Authors: Goeckeritz Charity Z , Rhoades Kathleen E , Childs Kevin L , Iezzoni Amy F , VanBuren Robert , Hollender Courtney A
Published: May 2023

Sour cherry (Prunus cerasus L.) is a valuable fruit crop in the Rosaceae family and a hybrid between progenitors closely related to extant Prunus fruticosa (ground cherry) and Prunus avium (sweet cherry). Here we report a chromosome-scale genome assembly for sour cherry cultivar Montmorency, the predominant cultivar grown in the USA. We also generated a draft assembly of P. fruticosa to use alongside a published P. avium sequence for syntelog-based subgenome assignments for ‘Montmorency’ and provide compelling evidence P. fruticosa is also an allotetraploid. Using hierarchal k-mer clustering and phylogenomics, we show ‘Montmorency’ is trigenomic, containing two distinct subgenomes inherited from a P. fruticosa-like ancestor (A and A') and two copies of the same subgenome inherited from a P. avium-like ancestor (BB). The genome composition of ‘Montmorency’ is AA'BB and little-to-no recombination has occurred between progenitor subgenomes (A/A' and B). In Prunus, two known classes of genes are important to breeding strategies: the self-incompatibility loci (S-alleles), which determine compatible crosses, successful fertilization, and fruit set, and the Dormancy Associated MADS-box genes (DAMs), which strongly affect dormancy transitions and flowering time. The S-alleles and DAMs in ‘Montmorency’ and P. fruticosa were manually annotated and support subgenome assignments. Lastly, the hybridization event ‘Montmorency’ is descended from was estimated to have occurred less than 1.61 million years ago, making sour cherry a relatively recent allotetraploid. The ‘Montmorency’ genome highlights the evolutionary complexity of the genus Prunus and will inform future breeding strategies for sour cherry, comparative genomics in the Rosaceae, and questions regarding neopolyploidy.
Metabarcoding Used for the First Time to Identify Prey of Wild Totoaba macdonaldi
Authors: Mroue-Ruiz F H , Pacheco-Sandoval A , Lago-Lestón A , Giffard-Mena I , Abadía-Cardoso A , Chong-Robles J , Schramm Y
Published: May 2023

Synopsis

Totoaba macdonaldi is an endangered endemic fish of the Gulf of California. Overexploitation resulted in the Mexican government banning the fishing of this species in 1975, and it being listed as endangered. However, the species is still subject to illegal fishing. Despite its conservation status, little is known about totoaba biology. The present study aimed to implement, for the first time, a metabarcoding protocol to describe the totoaba diet. Four wild totoaba individuals, seized by Mexican law enforcement agents, were dissected, and their stomach contents were collected. Three representative amplicon libraries were generated for cephalopods, chordates, and eukaryotes. After sequencing, 18 different taxa were identified, of which 11 species were recognized as prey. The totoaba were found to have consumed Pacific anchovy (Cetengraulis mysticetus), flathead grey mullet (Mugil cephalus), bigeye croaker (Micropogonias megalops), northern anchovy (Engraulis mordax), ocean whitefish (Caulolatilus princeps), milkfish (Chanos chanos), and Pacific sardine (Sardinops sagax). Members of the Euphausiidae family (krill) were also identified. This study identified up to four times more species in much fewer samples than previous studies based on morphological recognition, thus confirming metabarcoding as an effective method for studying the feeding habits of this species and one providing the tools required for further analysis of the totoaba diet.
The impact of mitral valve surgery on ventricular arrhythmias in patients with Barlow’s disease: preliminary results of a prospective study
Authors: Ascione Guido , Azzola Guicciardi Nicolò , Lorusso Roberto , Boccellino Antonio , Lapenna Elisabetta , Del Forno Benedetto , Carino Davide , Bisogno Arturo , Palmisano Anna , D’Angelo Giuseppe , Della Bella Paolo , Esposito Antonio , Agricola Eustachio , Alfieri Ottavio , Castiglioni Alessandro , Maisano Francesco , Vergara Pasquale , De Bonis Michele
Published: May 2023

OBJECTIVES

Aim of this study was to evaluate arrhythmic burden of patients with Barlow’s disease and significant mitral regurgitation (MR) and assess the impact of mitral repair on ventricular arrhythmias (VA) in this group of subjects.

METHODS

We prospectively included 88 consecutive patients with Barlow’s disease referred to our Institution from February 2021 to May 2022. All enrolled patients underwent 24-h Holter monitoring before surgery. Sixty-three of them completed 3 months echocardiographic and Holter follow-up. Significant arrhythmic burden was defined as ≥1% premature ventricular beats/24 h or at least one episode of non-sustained ventricular tachycardia (VT), VT or ventricular fibrillation.

RESULTS

At baseline, 29 patients (33%) were arrhythmogenic (AR), while 59 (67%) were not [non-arrhythmogenic (NAR)]. AR subjects tended to be more often females with history of palpitations. Sixty-three patients completed 3-months follow-up. Twenty of them (31.7%) were AR at baseline and 43 (68.3%) were not. Among AR patients, 9 (45%) remained AR after mitral surgery, while 11 (55%) became NAR. Considering NAR subjects at baseline, after mitral valve repair 8 (18.6%) evolved into AR, while 35 (81.4%) remained NAR. A higher prevalence of pre-operative MAD was found among patients experiencing VA reduction if compared with patients who remained arrhythmogenic (63.6% vs 11.1%, P = 0.028).

CONCLUSIONS

In our experience, one-third of Barlow’s patients referred for mitral surgery showed a significant arrhythmic burden. Almost half of the subjects arrhythmogenic at baseline were free from significant VA after mitral repair. However, a minority (18.6%) of subjects without arrhythmic burden at baseline experienced significant VA at follow-up.