bluuebunny/crossref_metadata_2025 huggingface dataset:
Non-invasive thoracoabdominal mapping of post-oesophagectomy conduit function
Authors: Wang Tim Hsu-Han , Tokhi Ashraf , Gharibans Armen , Evennett Nicholas , Beban Grant , Schamberg Gabriel , Varghese Chris , Calder Stefan , Duong Cuong , O’Grady Greg
Published: January 2023

Introduction

Oesophagectomy is a complex procedure performed for malignant and benign conditions. Post-oesophagectomy conduit dysfunction is common, which can occur for several reasons including conduit dysmotility. However, reliable tools for evaluating conduit motility are lacking. A non-invasive device for gastric electrical mapping was recently developed to evaluate gastric electrical activity and function. This study aimed to assess the feasibility of BSGM in the post-oesophagectomy stomach.

Methods

Oesophagectomy patients from Auckland, New Zealand, were recruited. The Gastric Alimetry System® (New Zealand) was employed, comprising a stretchable array (8×8 electrodes), a wearable Reader, and validated iOS app for symptom logging. The protocol comprised a 30-minute baseline, a meal challenge, then 4 hours of post-prandial recordings. Analysis encompassed Principal Gastric Frequency, BMI-adjusted amplitude, Gastric Alimetry Rhythm Index (indicating rhythm stability), meal response, and symptoms. Adverse events were recorded.

Results

6 patients were recruited and gastric activity was successfully captured in all except one with the colonic interposition (negative control). Four patients showed abnormalities indicating post-operative gastric hypofunction: four with low or abnormal frequency (<2.65 cycles/min), three with low amplitude (<22μV), two with low GA-RI (<0.25) and one with a reduced meal response. One patient had significant symptoms (nausea, early satiation) who demonstrated marked hypomotility in all four of these domains. No adverse events occurred.

Conclusion

Gastric Alimetry is a safe and feasible technique to non-invasively assess gastric conduit motility following oesophagectomy. Parameters may need adjustment for post-surgical anatomy. Clinical studies assessing the role in diagnosis and therapy can be advanced.
A human stomach cell type transcriptome atlas
Authors: Öling S , Struck E , Thorsen MN , Zwahlen M , Feilitzen K von , Odeberg J , Pontén F , Lindskog C , Uhlén M , Dusart P , Butler LM
Published: January 2023

The identification of cell type-specific genes and their modification under different conditions is central to our understanding of human health and disease. The stomach, a hollow organ in the upper gastrointestinal tract, provides an acidic environment that contributes to microbial defence and facilitates the activity of secreted digestive enzymes to process food and nutrients into chyme. In contrast to other sections of the gastrointestinal tract, detailed descriptions of cell type gene enrichment profiles in the stomach are absent from the major single cell sequencing-based atlases. Here, we use an integrative correlation analysis method to predict human stomach cell type transcriptome signatures using unfractionated stomach RNAseq data from 359 individuals. We profile parietal, chief, gastric mucous, gastric enteroendocrine, mitotic, endothelial, fibroblast, macrophage, neutrophil, T-cell and plasma cells, identifying over 1600 cell type-enriched genes. We uncover the cell type expression profile of several non-coding genes strongly associated with the progression of gastric cancer and, using a sex-based subset analysis, uncover a panel of male-only chief cell-enriched genes. This study provides a roadmap to further understand human stomach biology.
Simple, low-cost, and well-performing method, the outgrowth technique, for the isolation of epithelial cells from nasal polyps
Authors: Kim Jonghui , Hegener Karla , Hagedorn Claudia , Jameel Kaschin Jamal , Weidinger Daniel , Seuthe Inga Marte Charlott , Eichhorn Sabine , Kreppel Florian , Park Jonas Jae-Hyun , Knobloch Jürgen
Published: January 2023

Objectives

Epithelial cells are an important part of the pathomechanism in chronic rhinosinusitis with nasal polyps. It is therefore essential to establish a robust method for the isolation and culture of epithelial cells from nasal polyps to enable further research. In this study, the feasibility of the outgrowth technique for the isolation of the epithelial cells from the nasal polyps was evaluated.

Methods

The outgrowth technique was performed to isolate the epithelial cells. Proliferation was evaluated up to the 3rd passage. Epithelial cells were identified and differentiation and proliferation were evaluated using flow cytometry with anti-cytokeratin, anti-p63, and anti-Ki-67. A functionality test was assessed by determining type 2–relevant proteins using ELISA, representatively, interleukin-33 and periostin.

Results

Using the outgrowth technique, epithelial cells could be isolated from all tissue samples. Isolated epithelial cells showed a proliferation rate of approximately 7- to 23-fold every 6 days up to the 3rd passage. Over 97% of isolated cells were shown to be cytokeratin- and p63-positive, and over 86% of them were Ki-67–positive in flow cytometry. Interleukin-33 and periostin were detectable in the supernatant.

Conclusions

We introduce a simple, low-cost, and well-performing method for isolating epithelial cells from nasal polyps with the outgrowth technique.
Modelling drug responses and evolutionary dynamics using triple negative breast cancer patient-derived xenografts
Authors: Shea Abigail , Eyal-Lubling Yaniv , Guerrero-Romero Daniel , Garcia Raquel Manzano , Greenwood Wendy , O’Reilly Martin , Georgopoulou Dimitra , Callari Maurizio , Lerda Giulia , Wix Sophia , Giovannetti Agnese , Masina Riccardo , Esmaeilishirazifard Elham , Martin Alistair G. , Nagano Ai , Young Lisa , Kupczak Steven , Cheng Yi , Bardwell Helen , Provenzano Elena , Kane Justine , Lay Jonny , Grybowicz Louise , McAdam Karen , Caldas Carlos , Abraham Jean , Rueda Oscar M , Bruna Alejandra
Published: January 2023

Triple negative breast cancers (TNBC) exhibit inter- and intra-tumour heterogeneity, which is reflected in diverse drug responses and interplays with tumour evolution. Here, we use TNBC patient-derived tumour xenografts (PDTX) as a platform for co-clinical trials to test their predictive value and explore the molecular features of drug response and resistance. Patients and their matched PDTX exhibited mirrored drug responses to neoadjuvant therapy in a clinical trial. In parallel, additional clinically-relevant treatments were tested in PDTXsin vivoto identify alternative effective therapies for each PDTX model. This framework establishes the foundation for anticipatory personalised therapies for those patients with resistant or relapsed tumours. The PDTXs were further explored to model PDTX- and treatment-specific behaviours. The dynamics of drug response were characterised at single-cell resolution revealing a novel mechanism of response to olaparib. Upon olaparib treatment PDTXs showed phenotypic plasticity, including transient activation of the immediate-early response and irreversible sequential phenotypic switches: from epithelial to epithelial-mesenchymal-hybrid states, and then to mesenchymal states. This molecular mechanism was exploitedex vivoby combining olaparib and salinomycin (an inhibitor of mesenchymal-transduced cells) to reveal synergistic effects. In summary, TNBC PDTXs have the potential to help design individualised treatment strategies derived from model-specific evolutionary insights.
Adult stem cell characterization from theMedial GastrocnemiusandSemitendinosusmuscles in early development of cerebral palsy pathology
Authors: Corvelyn M , Meirlevede J , Deschrevel J , Huyghe E , De Wachter E , Gayan-Ramirez G , Sampaolesi M , Van Campenhout A , Desloovere K , Costamagna D
Published: January 2023

Cerebral palsy (CP) is one of the most common lifelong conditions leading to childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle.

In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from theMedial Gastrocnemius(MG) muscle of patients with CP (n=16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n=13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from theSemitendinosus(ST) compared to the MG. Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity. Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle.

In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.
Isogenic lines of rainbow trout (Oncorhynchus mykiss)as a tool to assess how growth and feeding behaviour are correlated to feed efficiency in fish
Authors: Pouil Simon , Kernéis Thierry , Quillet Edwige , Lallias Delphine , Labbé Laurent , Phocas Florence , Dupont-Nivet Mathilde
Published: January 2023

Accurately measuring individual feed intake is required to include feed efficiency (FE) as an objective in commercial breeding programs. Phenotyping individual feed intake through direct measurements remains complex in fish reared in groups. One way to overcome this challenge is to find proxies for estimating FE. This study aimed to investigate the correlations between fish FE and potential predictive criteria in rainbow troutOncorhynchus mykiss. As predictive criteria, we considered the variations of body weight assessed as thermal growth coefficients (TGC) and the feeding behaviour assessed as the number of feed demands over a period and the proportion of the demands made before noon. Feed intake was assessed over three different periods in ten isogenic lines allowing a recording for each of the ten genotypes while keeping fish in groups. The protocol consisted of two successive feed deprivation and refeeding phases after initial basal growth periods. Correlations were then calculated between FE, measured either as feed conversion ratio (FCR) or residual feed intake (RFI), and the different indirect criteria. We found positive phenotypic correlations between FCR and RFI over the feed intake measurement periods (r ⩾ 0.79,P< 0.001). Assessment of the relationship between FE traits (FCR and RFI) calculated over the three measurement periods and TGC revealed no significant association. We found significant positive correlations between RFI calculated from the first feed intake measurement period and feeding behaviour, assessed as the number of feed demands (r = 0.42-0.49,P⩽ 0.022). Nevertheless, such correlations were not established for the two other measurement periods following feed deprivation. While we demonstrated that the weight variations during feed deprivation are not a good proxy for FE (FCR or RFI) in rainbow trout, we also highlighted the interest in exploring more the relationships between FE and feeding behaviour in fish.
The great acceleration of island saturation by species introductions in the Anthropocene has altered species-area relationships
Authors: Gleditsch Jason M. , Behm Jocelyn E. , Helmus Matthew R.
Published: January 2023

The species-area relationship (SAR) is a fundamental pattern of island biogeography which is often curvilinear due to reduced accumulation of species on mid-sized island caused by island isolation and the lack of speciation present on larger islands. The curvature of SARs represents lower saturation of species on mid-sized islands and therefore accelerated species accumulation should linearize island SARs. In the Anthropocene, island species accumulation has accelerated from introduced species. We hypothesize three new patterns. First, the saturation of species for the most unsaturated islands should increase more from introduced species than other islands. Second, SARs should become more linear as islands accumulate more species. Third, introduced species should greatly accelerate the island saturation process. We assessed these patterns for the reptile and amphibian of the Caribbean, a global hotspot of biodiversity. Mid-sized Caribbean islands are now more saturated causing a linearization of contemporary herpetofauna SARs resulting from a ca. 30 myr and 40 myr acceleration of island saturation for reptiles and amphibians, respectively. Thus, humans within the last few hundreds of years—starting with European colonization of the Americas—have greatly accelerated the natural process of island saturation by 30 million years within the Caribbean global biodiversity hotspot.
Open Biomedical Network Benchmark A Python Toolkit for Benchmarking Datasets with Biomedical Networks
Authors: Liu Renming , Krishnan Arjun
Published: January 2023

Over the past decades, network biology has been a major driver of computational methods developed to better understand the functional roles of each gene in the human genome in their cellular context. Following the application of traditional semi-supervised and supervised machine learning (ML) techniques, the next wave of advances in network biology will come from leveraging graph neural networks (GNN). However, to test new GNN-based approaches, a systematic and comprehensive benchmarking resource that spans a diverse selection of biomedical networks and gene classification tasks is lacking. Here, we present the Open Biomedical Network Benchmark (OBNB), a collection of benchmarking datasets derived using networks from 15 sources and tasks that include predicting genes associated with a wide range of functions, traits, and diseases. The accompanying Python package,obnb, contains reusable modules that enable researchers to download source data from public databases or archived versions and set up ML-ready datasets that are compatible with popular GNN frameworks such as PyG and DGL. Our work lays the foundation for novel GNN applications in network biology.obobwill also help network biologists easily set-up custom benchmarking datasets for answering new questions of interest and collaboratively engage with graph ML practitioners to enhance our understanding of the human genome. OBNB is released under the MIT license and is freely available on GitHub:https://github.com/krishnanlab/obnb
BMP suppresses WNT to integrate patterning of orthogonal body axes in adult planarians
Authors: Clark Eleanor G. , Petersen Christian P.
Published: January 2023

Adult regeneration restores patterning of orthogonal body axes after damage in a post-embryonic context. Planarians regenerate using distinct body-wide signals primarily regulating each axis dimension: anteroposterior Wnts, dorsoventral BMP, and mediolateral Wnt5 and Slit determinants. How regeneration can consistently form perpendicular tissue axes without symmetry-breaking embryonic events is unknown, and could either occur using fully independent, or alternatively, integrated signals defining each dimension. Here, we report that the planarian dorsoventral regulatorbmp4suppresses the posterior determinantwnt1to pattern the anteroposterior axis. Double-FISH identified distinct anteroposterior domains within dorsal midline muscle that express eitherbmp4orwnt1. Homeostatic inhibitionbmp4andsmad1expanded thewnt1expression anteriorly, while elevation of BMP signaling throughnog1;nog2RNAi reduced thewnt1expression domain. BMP signal perturbation broadly affected anteroposterior identity as measured by expression of posterior Wnt pathway factors, without affecting head regionalization. Therefore, dorsal BMP signals broadly limit posterior identity. Furthermore,bmp4RNAi caused medial expansion of the lateral determinantwnt5and reduced expression of the medial regulatorslit. Double RNAi ofbmp4andwnt5resulted in lateral ectopic eye phenotypes, suggestingbmp4acts upstream ofwnt5to pattern the mediolateral axis. Therefore,bmp4acts at the top of a patterning hierarchy both to control dorsoventral information and also, through suppression of Wnt signals, to regulate anteroposterior and mediolateral identity. These results reveal that adult pattern formation involves integration of signals controlling individual orthogonal axes.

Author Summary

Systems that coordinate long-range communication across axes are likely critical for enabling tissue restoration in regenerative animals. While individual axis pathways have been identified, there is not yet an understanding of how signal integration allows repatterning across 3-dimensions. Here, we report an unanticipated linkage between anteroposterior, dorsoventral, and mediolateral systems in planarians through BMP signaling. We find that dorsally expressed BMP restricts posterior and lateral identity by suppressing distinct Wnt signals in adult planarians. These results demonstrate that orthogonal axis information is not fully independent and suggest a potentially ancient role of integrated axis patterning in generating stable 3-dimensional adult forms.
Effectiveness of second booster compared to first booster and protection conferred by previous SARS CoV-2 infection against symptomatic Omicron BA.2 and BA.4/5 in France
Authors: Tamandjou Cynthia , Auvigne Vincent , Schaeffer Justine , Vaux Sophie , du Châtelet Isabelle Parent
Published: January 2023

In face of evidence of rapid waning of vaccine effectiveness against Omicron and its sub-lineages, a second booster with mRNA vaccines was recommended for the most vulnerable in France. We used a test negative design to estimate the effectiveness of the second booster relative to the first booster and the protection conferred by a previous SARS-CoV-2 infection, against symptomatic Omicron BA.2 or BA.4/5. We included symptomatic ≥60 years old individuals tested for SARS-CoV-2 in March 21-October 30, 2022. Compared to a 181-210 days old first booster, a second booster restored protection with a relative effectiveness of 39% [95%CI: 38% - 41%], 7-30 days post-vaccination This gain in protection was lower than the one observed with the first booster, at equal time points since vaccination. High levels of protection were associated to previous SARS-CoV-2 infection, especially if the infection was recent and occurred when an antigenic-related variant was dominant.

Highlights

A second Wuhan-like mRNA booster brought additional protection against symptomatic Omicron BA.2 or BA.4/5 infections, relative to a first booster given 181 to 210 days ago.

The gain in protection offered by a second booster was lower to the protection observed with a first booster, at equal time points since these booster doses.

Previous infection, in a vaccinated population, offered high levels and long-lasting protection against symptomatic Omicron BA.2 or BA.4/5 infections.
‘It’s about dying, not just a broken leg’ - Qualitative findings on paramedics’ perception of end-of-life situations in rescue scenarios in Germany
Authors: Rieder Nicola , Banse Christian , Schade Franziska , Nauck Friedemann
Published: January 2023

In Germany, paramedics and emergency physicians arrive separately on scene (‘rendez-vous-system’), which aims to save resources when no physician is needed. Usually, paramedics arrive firstly on scene, and are obliged by law to perform all possible action to maintain a patient’s life. Especially in end-of-life (EoL) situations, this can cause conflicts, as those patients may require a decent consideration between ‘saving life’ and ‘allowing to die’. Whereas the emergency physicians’ perspective on this issue is relatively well examined, until today, in Germany, little is known about the (non-physician) paramedics’ perception.

Aim

To explore paramedics’ perception of rescue scenarios involving patients with advanced, incurable, severe diseases facing their EoL and to scientifically classify this cross-sectional field through experts from different research fields.

Method

Seven semi-structured narrative interviews with paramedics and one focus group with representatives from the Center for Medical Law in Goettingen were conducted and analysed using qualitative content analysis.

Results

Six key categories emerged from the data. Rescue scenarios in EoL situations are perceived as highly complex situations that are narrowed down through deviating goals of care (1), limited options for action (2), an emotional overload of all involved actors (3), consequences of a neglected (care) planning in advance (4) and various background structures, such as current societal and demographic changes (5) and systemic challenges (6). Complexity also arises from the multiple influences of the different categories/ their content on one another.

Discussion

Being confronted with patients that do not wish for further life-maintaining treatment marks a significant shift concerning the range of rescue scenarios, resulting from (i.a.) demographic developments and structural dynamics in health care. Therefore, in addition to specific actions restoring paramedics’ ability to act in rescue scenarios in EoL situations, a general discussion of the emergency services’ area of responsibility as well as the (emergency) medical treatment and care of patients with advanced, incurable, severe diseases is required.
Development of a clinical decision-support tool for Management of Adolescent knee Pain (The MAP-Knee Tool)
Authors: Riel Henrik , Bruun Malene Kjær , Djurtoft Chris , Jensen Martin Bach , Kaalund Søren , van Leeuwen Guido , Overgaard Charlotte , Rahbek Ole , Rathleff Michael Skovdal
Published: January 2023

Objective

This study aimed to develop a clinical decision-support tool (The MAP-Knee Tool) to improve the management of adolescents with non-traumatic knee pain.

Methods

This multi-step study consisted of five steps ((1-4) initial development and (5) end-user testing with adolescents with or without non-traumatic knee pain and medical doctors). It ended with the first version of the MAP-Knee Tool for the six most common non-traumatic knee pain conditions. The tool includes four components: 1) tool for diagnosing, 2) credible explanations of the diagnoses based on two systematic literature searches and an Argumentative Delphi process with international experts, 3) prognostic factors based on an individual participant data meta-analysis, and 4) option grid including an unbiased presentation of management options based on the available evidence.

Results

We included seven children/adolescents (8-15 years old) and seven medical doctors for the end-user testing. All four components were revised accordingly, and the text was condensed as the initial draft was too comprehensive.

Conclusion

We developed a clinical decision-support tool for clinicians and adolescents with non-traumatic knee pain to support the consultation in clinical practice.

Practice Implications

The tool targets clinicians and adolescents with four components that may decrease diagnostic uncertainty and increase shared decision-making.
Genetic determinants of severe COVID-19 in young Asian and Middle Eastern patients
Authors: Badla Beshr Abdulaziz , Hanifa Mohamed Samer , Jain Ruchi , El Naofal Maha , Halabi Nour , Yaslam Sawsan , Ramaswamy Sathishkumar , Taylor Alan , Alfalasi Roudha , Shenbagam Shruti , Khansaheb Hamda , Al Suwaidi Hanan , Nowotny Norbert , Popatia Rizwana , Khayat Abdulla Al , Alsheikh-Ali Alawi , Loney Tom , AlDabal Laila Mohamed , Tayoun Ahmad Abou
Published: January 2023

Studies of genetic factors associated with severe COVID-19 in young adults have been limited in non-Caucasian populations. Here, we use whole exome sequencing to characterize the genetic landscape of severe COVID-19 in a well phenotyped cohort of otherwise healthy, young adults (N=55; mean age 34.1 ± SD 5.0 years) representing 16 countries in Asia, the Middle East, and North Africa. Our findings show enrichment of rare, likely deleterious missense and truncating variants in interferon-mediated and bacterial infection-susceptibility genes, when compared to control, mildly affected, or asymptomatic COVID-19 patients (N = 25), or to general populations representing Asia and the Middle East. Genetic variants tended to associate with mortality, intensive care admission, and ventilation support. Our findings confirm the association of interferon pathway genes with severe COVID-19 and highlight the importance of extending genetic studies to diverse populations given implications for pan-ethnic therapeutic and genetic screening options.

Author Summary

Based on the hypothesis that rare monogenic variants contribute to the severity of SARS-CoV-2 infection outcomes, we performed whole exome sequencing in young, previously healthy patients with severe COVID-19 of Asian or Middle Eastern origins. We found an enrichment of rare missense and truncating variants in immune-related genes, mainly associated with interferon pathways and susceptibility to bacterial infections, which can be therapeutic targets. Genetic findings tended to correlate with mortality, intensive care unit (ICU) admission, high dependency unit (HDU) admission, and invasive ventilation.
A cross-sectional survey examining the association of clinician characteristics with perceived changes in cervical cancer screening and colposcopy practice during the COVID-19 pandemic
Authors: Fuzzell Lindsay , Brownstein Naomi C. , Fontenot Holly B. , Lake Paige , Michel Alexandra , Whitmer Ashley , Rossi Sarah L. , McIntyre McKenzie , Vadaparampil Susan T. , Perkins Rebecca
Published: January 2023

Background

The COVID-19 pandemic led to reductions in cervical cancer screening and colposcopy. Therefore, in this mixed method study we explored perceived pandemic-related practice changes to cervical cancer screenings and colposcopies.

Methods

In 2021, a national sample of 1,251 clinicians completed surveys, including 675 clinicians who performed colposcopy; a subset (n=55) of clinicians completed qualitative interviews.

Results

Nearly half of all clinicians reported they were currently performing fewer cervical cancer screenings (47%) and colposcopies (44% of those who perform the procedure) than before the pandemic. About one-fifth (18.6%) of colposcopists reported performing fewer LEEPs than prior to the pandemic. Binomial regression analyses indicated that older, non-White, internal medicine and family medicine clinicians (compared to OB-GYNs), and those practicing in community health centers (compared to private practice) had higher odds of reporting reduced screening. Among colposcopists, males, internal medicine physicians, those practicing in community health centers, and in the South had higher odds of reporting reduced colposcopies. Qualitative interviews highlighted pandemic-related care disruptions and lack of tracking systems to identify overdue screenings.

Conclusions

Reductions in cervical cancer screening and colposcopy among nearly half of clinicians more than one year into the pandemic raise concerns that inadequate screening and follow-up will lead to future increases in preventable cancers.

Funding

This study was funded by the American Cancer Society, who had no role in the study’s design, conduct, or reporting.
Magnetic seizure therapy and electroconvulsive therapy increase aperiodic activity
Authors: Smith Sydney E. , Kosik Eena L. , van Engen Quirine , Kohn Jordan , Hill Aron T. , Zomorrodi Reza , Blumberger Daniel M. , Daskalakis Zafiris J. , Hadas Itay , Voytek Bradley
Published: January 2023

Major depressive disorder (MDD) is a leading cause of disability worldwide. One of the most efficacious treatments for treatment-resistant MDD is electroconvulsive therapy (ECT). Recently, magnetic seizure therapy (MST) was developed as an alternative to ECT due to its more favorable side effect profile. While these approaches have been very successful clinically, the neural mechanisms underlying their therapeutic effects are unknown. For example, clinical “slowing” of the electroencephalogram beginning in the postictal state and extending days to weeks post-treatment has been observed in both treatment modalities. However, a recent longitudinal study of a small cohort of ECT patients revealed that, rather than delta oscillations, clinical slowing was better explained by increases in aperiodic activity, an emerging EEG signal linked to neural inhibition. Here we investigate the role of aperiodic activity in a cohort of patients who received ECT and a cohort of patients who received MST treatment. We find that aperiodic neural activity increases significantly in patients receiving either ECT or MST. Although not directly related to clinical efficacy in this dataset, increased aperiodic activity is linked to greater amounts of neural inhibition, which is suggestive of a potential shared neural mechanism of action across ECT and MST.
Axial regionalization inTiktaalik roseaeand the origin of quadrupedal locomotion
Authors: Stewart T.A. , Lemberg J.B. , Hillan E.J. , Magallanes I. , Daeschler E.B. , Shubin N.H.
Published: January 2023

The origin of quadrupedal locomotion in tetrapods entailed the evolution of a regionalized axial skeleton with sacral ribs. These ribs provide linkage between the pelvis and vertebral column and contribute to body support and propulsion by the hind limb. The closest relatives of limbed vertebrates are not known to possess such a connection and, therefore, have typically been described as primarily supporting their bodies against the substrate with pectoral fins. However, data on the axial skeletons of stem tetrapods are sparce, with key features of specimens potentially concealed by matrix. Here we provide micro-computed tomography data of the axial skeleton ofTiktaalik roseaeand show that its vertebrae and ribs are regionalized along the craniocaudal axis, including expanded and ventrally curved ribs in the sacral region. The sacral ribs would have contacted the expanded iliac blade of the pelvis in a soft tissue connection. No atlas-axis complex is observed, however the basioccipital-exoccipital complex is deconsolidated from the rest of the neurocranium, suggesting increased mobility at occipital-vertebral junction. Thus, axial regionalization that allowed for innovations in head mobility, body support and buttressing the pelvic fin evolved prior to the origin of limbs.
Two RNA-binding proteins mediate the sorting of miR223 from mitochondria into exosomes
Authors: Ma Liang , Singh Jasleen , Schekman Randy
Published: January 2023

Fusion of multivesicular bodies (MVBs) with the plasma membrane results in the secretion of intraluminal vesicles (ILVs), or exosomes. The sorting of one exosomal cargo RNA, miR223, is facilitated by the RNA-binding protein, YBX1 (Shurtleff et al., 2016). We found that miR223 specifically binds a “cold shock” domain (CSD) of YBX1 through a 5’ proximal sequence motif UCAGU that may represent a binding site or structural feature required for sorting. Prior to sorting into exosomes, most of the cytoplasmic miR223 resides in mitochondria. An RNA-binding protein localized to the mitochondrial matrix, YBAP1, appears to serve as a negative regulator of miR223 enrichment into exosomes. miR223 levels decreased in the mitochondria and increased in exosomes after loss of YBAP1. We observed YBX1 shuttle between mitochondria and endosomes in live cells. YBX1 also partitions into P body granules in the cytoplasm (Liu et al., 2021). We propose a model in which miR223 and likely other miRNAs are stored in mitochondria and are then mobilized by YBX1 to cytoplasmic phase condensate granules for capture into invaginations in the endosome that give rise to exosomes.
Protein aggregation in plant mitochondria inhibits translation and induces an NAC017-dependent ethylene-associated unfolded protein response
Authors: Song Ce , Li Yuanyuan , Hou Yuqi , Yang Mengmeng , Li Tiantian , Liu Yinyin , Xu Chang , Liu Jinjian , Millar A. Harvey , Wang Ningning , Li Lei
Published: January 2023

Loss of Lon1 in plant mitochondria led to stunted plant growth and accumulation of nuclear-encoded mitochondrial proteins, including Lon1 substrates, while mitochondrial-encoded proteins typically decreased in abundance. Lon1 mutants contained protein aggregates in the mitochondria matrix which were enriched in PPR-containing proteins and ribosomal subunits of the translation apparatus and were slowed in mitochondrial RNA splicing, editing and general translation rate. Transcriptome analysis showed multiple organellar unfolded protein responses involving ethylene biosynthesis were induced by either Lon1 loss, mitochondrial ribosomal protein loss, translation or respiratory inhibition and most were regulated by the mitochondrial retrograde signaling pathway dependent on the transcription factor NAC017. The short hypocotyl inlon1mutants during skotomorphogenesis was partially rescued by ethylene inhibitors and mutants showed higher ethylene production rates than wildtype. Together this provides multiple steps in the link between loss of Lon1 and its whole plant phenotype.

Single Sentence Summary

Lon1 knockout inhibits mitochondrial-encoded gene translation and induces retrograde signaling involving unfolded protein responses.
Molecular identification of ALDH1A1 and SIRT2 in the astrocytic putrescine-to-GABA metabolic pathway
Authors: Bhalla Mridula , Shin Jeong Im , Ju Yeon Ha , Park Yongmin Mason , Yoo Seonguk , Lee Hyeon Beom , Lee C Justin
Published: January 2023

GABA (γ-aminobutyric acid) is the primary inhibitory neurotransmitter in the CNS. In astrocytes, GABA is synthesized by degradation of putrescine by monoamine oxidase B (MAO-B), a process which is known to mediate tonic inhibition of neuronal excitability. This astrocytic tonic GABA and related enzymes are also reported to be involved in memory impairment in Alzheimer’s Disease, and therefore are potential therapeutic targets to rescue memory in AD patients. However, the enzymes downstream of MAO-B in this pathway have not been elucidated yet. To fill this gap in knowledge, we performed transcriptomic and literature database analysis and identified Aldehyde dehydrogenase 1 family, member A1 (ALDH1A1) and a histone deacetylase enzyme Sirtuin2 (SIRT2) as plausible candidate enzymes in primary cultured astrocytes. Immunostaining, metabolite analyses, and sniffer patch clamp performed in the presence or absence of suitable inhibitors, or with genetic ablation of the candidate enzymes recapitulated their participation in GABA production. We propose ALDH1A1 and SIRT2 as potential therapeutic targets against Alzheimer’s Disease.
Production of β-PheRS fragments correlates with food avoidance and slow growth, and is suppressed by the appetite-inducing hormone CCHa2
Authors: Brunßen Dominique , Suter Beat
Published: January 2023

The housekeeping tRNA synthetases play many non-canonical roles with diverse functions. The phenylalanyl-tRNA synthetase (PheRS/FARS) is an α2β2tetramere. Recently, human patients with mutations inFARSB, the homolog ofβ-PheRSin Drosophila, have been reported to display problems gaining weight. Here, we show in Drosophila that overexpressing the β subunit in the context of the complete PheRS leads to larval roaming, food avoidance, slow growth, and a developmental delay that can last several days and even prevents pupation. Narrowing down the tissue involved in this behavioral and developmental effect revealed that expression in CCHa2+and Pros+cells induced this phenotype. Simultaneous expression of β-PheRS, α-PheRS, and the appetite-inducing CCHa2 peptide rescued these phenotypes, linking thisβ-PheRSactivity to the appetite-controlling pathway. The fragmentation dynamics of the excessive β-PheRS points to a β-PheRS fragment as a likely candidate inducer of these phenotypes. Fragmentation of PheRS (FARS) has also been observed in humans and mutations in humanβ-PheRS (FARSB)can lead to problems in gaining weight. This study, therefore, points to a potential mechanism for the human phenotype and to possible novel approaches to research ways to correct the balance between hunger and satiety signals in the context of obesity.
Not all Notch pathway mutations are equal in the embryonic mouse retina
Authors: Bosze Bernadett , Suarez-Navarro Julissa , Cajias Illiana , Brzezinski Joseph A. , Brown Nadean L
Published: January 2023

In the vertebrate retina, combinations of Notch ligands, receptors, and ternary complex components determine the destiny of retinal progenitor cells by regulatingHeseffector gene activity. Owing to reiterated Notch signaling in numerous tissues throughout development, there are multiple vertebrate paralogues for nearly every node in this pathway. These Notch signaling components can act redundantly or in a compensatory fashion during development. To dissect the complexity of this pathway during retinal development, we used seven germline or conditional mutant mice and two spatiotemporally distinct Cre drivers. We perturbed the Notch ternary complex and multipleHesgenes with two overt goals in mind. First, we wished to determine if Notch signaling is required in the optic stalk/nerve head for Hes1 sustained expression and activity. Second, we aimed to test ifHes1, 3and5genes are functionally redundant during early retinal histogenesis. With our allelic series, we found that disrupting Notch signaling consistently blocked mitotic growth and overproduced ganglion cells, but we also identified two significant branchpoints for this pathway. In the optic stalk/nerve head, sustained Hes1 is regulated independent of Notch signaling, whereas during photoreceptor genesis both Notch-dependent and -independent roles forRbpjandHes1impact photoreceptor genesis in opposing manners.
Vectored Immunoprophylaxis and Treatment of SARS-CoV-2 Infection
Authors: Tada Takuya , Dcosta Belinda M. , Minnee Julia , Landau Nathaniel R.
Published: January 2023

Vectored immunoprophylaxis was first developed as a means to establish engineered immunity to HIV through the use of an adeno-associated viral vector expressing a broadly neutralizing antibody. We have applied this concept to establish long-term prophylaxis against SARS-CoV-2 by adeno-associated and lentiviral vectors expressing a high affinity ACE2 decoy receptor. Administration of decoy-expressing AAV vectors based on AAV2.retro and AAV6.2 by intranasal instillation or intramuscular injection protected mice against high-titered SARS-CoV-2 infection. AAV and lentiviral vectored immunoprophylaxis was durable and active against recent SARS-CoV-2 Omicron subvariants. The AAV vectors were also effective when administered up to 24 hours post-infection. Vectored immunoprophylaxis could be of value for immunocompromised individuals for whom vaccination is not practical and as a means to rapidly establish protection from infection. Unlike monoclonal antibody therapy, the approach is expected to remain active despite continued evolution viral variants.
Independent regulation of Z-lines and M-lines during sarcomere assembly in cardiac myocytes revealed by the automatic image analysis software sarcApp
Authors: Neininger-Castro Abigail C. , Hayes James B. , Sanchez Zachary C. , Taneja Nilay , Fenix Aidan M. , Moparthi Satish , Vassilopoulos Stéphane , Burnette Dylan T.
Published: January 2023

Sarcomeres are the basic contractile units within cardiac myocytes, and the collective shortening of sarcomeres aligned along myofibrils generates the force driving the heartbeat. The alignment of the individual sarcomeres is important for proper force generation, and misaligned sarcomeres are associated with diseases including cardiomyopathies and COVID-19. The actin bundling protein, α-actinin-2, localizes to the “Z-Bodies” of sarcomere precursors and the “Z-Lines” of sarcomeres, and has been used previously to assess sarcomere assembly and maintenance. Previous measurements of α-actinin-2 organization have been largely accomplished manually, which is time-consuming and has hampered research progress. Here, we introduce sarcApp, an image analysis tool that quantifies several components of the cardiac sarcomere and their alignment in muscle cells and tissue. We first developed sarcApp to utilize deep learning-based segmentation and real space quantification to measure α-actinin-2 structures and determine the organization of both precursors and sarcomeres/myofibrils. We then expanded sarcApp to analyze “M-Lines” using the localization of myomesin and a protein that connects the Z-Lines to the M-Line (titin). sarcApp produces 33 distinct measurements per cell and 24 per myofibril that allow for precise quantification of changes in sarcomeres, myofibrils, and their precursors. We validated this system with perturbations to sarcomere assembly. We found perturbations that affected Z-Lines and M-Lines differently, suggesting that they may be regulated independently during sarcomere assembly.
Effectiveness of the offer of theSmoke Freesmartphone application compared with no intervention for smoking cessation: a pragmatic randomised controlled trial
Authors: Jackson Sarah E. , Kale Dimitra , Beard Emma , Perski Olga , West Robert , Brown Jamie
Published: January 2023

Aim

To evaluate the effectiveness of the offer ofSmoke Free– an evidence-informed, widely used app – for smoking cessation versus no support.

Design

Two-arm individually randomised controlled effectiveness trial.

Setting

Online with no restrictions on location.

Participants

3,143 adult smokers (74.7% female; mean[SD] age 49.0 [11.5] years) motivated to make a quit attempt in the next month, recruited between August-2020 and April-2021.

Interventions and comparators

Offer of theSmoke Freeapp plus follow-up (intervention arm) versus no intervention plus follow-up (comparator arm). Both groups were shown a brief message at the end of the baseline questionnaire encouraging them to make a quit attempt.

Main outcome measures

The primary outcome was self-reported 6-month continuous abstinence assessed 7 months after randomisation. Secondary outcomes included quit attempts in the first month post-randomisation, 3-month continuous abstinence assessed at 4 months, and 6-month continuous abstinence at 7 months among those who made a quit attempt. The primary analysis was performed on an intention-to-treat basis, with missing-equals-smoking imputation. Sensitivity analyses included i) restricting the intervention group to those who took up the offer of the app, ii) using complete cases, and iii) using multiple imputation.

Results

The effective follow-up rate for 7 months was 41.9%. The primary analysis showed no evidence of a benefit of the intervention on rates of 6-month continuous abstinence (intervention 6.8% vs. comparator 7.0%; RR=0.97, 95%CI=0.75-1.26). Analyses on all secondary outcomes also showed no evidence of a benefit. Similar results were observed on complete cases and using multiple imputation. When the intervention group was restricted to those who took up the offer of the app (n=395, 25.3%), participants in the intervention group were 80% more likely to report 6-month continuous abstinence (12.7% vs. 7.0%; RR=1.80, 95%CI=1.30-2.45). Equivalent subgroup analyses produced similar results on the secondary outcomes. These differences persisted after adjustment for key baseline characteristics.

Conclusions

Among motivated smokers provided with very brief advice to quit, offer of theSmoke Freeapp did not have a detectable benefit for cessation compared with follow-up only. However, the app increased quit rates when smokers randomised to receive the app downloaded it.
Actin nucleators safeguard replication forks by limiting nascent strand degradation
Authors: Nieminuszczy Jadwiga , Martin Peter R. , Broderick Ronan , Krwawicz Joanna , Kanellou Alexandra , Mocanu Camelia , Bousgouni Vicky , Smith Charlotte , Wen Kuo-Kuang , Woodward Beth L. , Bakal Chris , Shackley Fiona , Aguilera Andres , Stewart Grant S. , Vyas Yatin M. , Niedzwiedz Wojciech
Published: January 2023

Accurate genome replication is essential for all life and a key mechanism of disease prevention, underpinned by the ability of cells to respond to replicative stress (RS) and protect replication forks. These responses rely on the formation of Replication Protein A (RPA)-single stranded (ss) DNA complexes, yet this process remains largely uncharacterized. Here we establish that actin nucleation-promoting factors (NPFs) associate with replication forks, promote efficient DNA replication and facilitate association of RPA with ssDNA at sites of RS. Accordingly, their loss leads to deprotection of ssDNA at perturbed forks, impaired ATR activation, global replication defects and fork collapse. Supplying an excess of RPA restores RPA foci formation and fork protection, suggesting a chaperoning role for actin nucleators (ANs) (i.e., Arp2/3, DIAPH1) and NPFs (i.e, WASp, N-WASp) in regulating RPA availability upon RS. We also discover that β-actin interacts with RPA directlyin vitro, andin vivoa hyper-depolymerizing β-actin mutant displays a heightened association with RPA and the same dysfunctional replication phenotypes as loss of ANs/NPFs, which contrasts with the phenotype of a hyper-polymerizing β-actin mutant. Thus, we identify components of actin polymerization pathways that are essential for preventing ectopic nucleolytic degradation of perturbed forks by modulating RPA activity.
Burden, Causation, and Particularities of long-COVID in African populations: A rapid systematic review
Authors: Nyasulu Peter S. , Tamuzi Jacques L. , Erasmus Rajiv T.
Published: January 2023

Background

The global estimated prevalence of long COVID-19 is 43%, and the most common symptoms found globally are fatigue, confusion, or lack of confusion, and dyspnea, with prevalence rates of 23%, 14%, and 13%, respectively. However, long COVID still lacks an overall review in African populations. The aim of this review was to determine the prevalence of long COVID, its most common symptoms, comorbidities, and pathophysiological mechanisms.

Methods

A systematic review of long COVID in African populations was conducted. The random effects model was used to calculate the pooled prevalence rates (95% CI). If the results could not be pooled, a narrative synthesis was performed.

Results

We included 14 studies from 7 African countries, totaling 6,030 previously SARS-CoV-2 infected participants and 2,954 long COVID patients. Long COVID had a pooled prevalence of 41% [26%-56%]. Fatigue, dyspnea, and confusion or lack of concentration were the most common symptoms, with prevalence rates (95% CI) of 41% [26%-56%], 25% [12%-38%], and 40% [12%-68%], respectively. Long COVID was associated with advanced age, being female, more than three long COVID symptoms in the acute phase, initial fatigue and dyspnea, post-recovery stress, sadness, and sleep disturbances, and loss of appetite at symptoms onset, mild, moderate, and severe, pre-existing obesity, hypertension, diabetes mellitus, and the presence of any chronic illness (P≤0.05). According to our review, high micro clot and platelet poor plasma (PPP) viscosity explain the pathophysiology of long COVID.

Conclusion

Long COVID prevalence in Africa was comparable to the global prevalence. However, the prevalence of the most common symptoms was higher in Africa. Comorbidities associated with long COVID may lead to additional complications in African populations due to hypercoagulation and thrombosis.