bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Risk Endometrial Cancer Assessed by Immediate Intraoperative Frozen Sections of Sentinel Lymph Nodes – A Retrospective Study
Authors: Miller Sarah E , Tavallaee Mahkam , Renz Malte , Folkins Ann K , Karam Amer
Published: June 2021

While sentinel lymph node (SLN) sampling has been established for low-risk endometrial cancer, few data exists on high-risk histologies. This study aims to measure the accuracy of immediate intraoperative SLN biopsy with frozen section in high-risk endometrial cancer. Patients diagnosed with endometrial cancer of high-grade histology (grade 3 endometrioid, clear cell, serous, carcinosarcoma, de- or undifferentiated histology) between 2014 and 2019 at a single institution who underwent SLN mapping, followed by pelvic lymphadenectomy with or without para-aortic lymphadenectomy were included. SLNs were assessed intraoperatively using multiple frozen sections and H&E staining. Lymph node metastases detected by SLN biopsy were compared with complete lymphadenectomy specimens.

35 patients with high-grade endometrial cancer histology underwent SLN mapping followed by lymphadenectomy. In 34 of 35 (97%) of these patients mapping with at least one SLN was successful. Positive SLNs were identified in 7/34 patients (20.6%). There were no patients who had positive lymph nodes on complete lymphadenectomy without a positive SLN, resulting in 100% sensitivity, and 0% false-negative rate.

SLN mapping using intraoperative frozen sections in high-risk endometrial cancer demonstrated 100% sensitivity and 0% false-negative rate, provides immediate feedback on successful SLN mapping and valuable intraoperative information on the disease status guiding the intraoperative decision for completion lymphadenectomy.

Highlights

Intraoperative SLN assessment in high-grade endometrial cancer by frozen section.

100% sensitivity and 0% false-negative rate compared to complete lymphadenectomy.

Protocol provides immediate intraoperative feedback on successful SLN mapping.

Protocol helps inform surgeon’s decision to proceed with complete lymphadenectomy.
Complexity and Variability Analyses of Motor Activity Distinguish Mood States in Bipolar Disorder
Authors: Jakobsen Petter , Stautland Andrea , Riegler Michael Alexander , Côté-Allard Ulysse , Sepasdar Zahra , Nordgreen Tine , Torresen Jim , Fasmer Ole Bernt , Oedegaard Ketil Joachim
Published: June 2021

Aims

Changes in motor activity are core symptoms of mood episodes in bipolar disorder. The manic state is characterized by increased variance, augmented complexity and irregular circadian rhythmicity when compared to healthy controls. The aim was to characterize differences in motor activity when comparing manic patients to their euthymic selves.

Methods

Motor activity was collected from 14 bipolar inpatients in mania and remission. 24-h recordings and 2-h time series in the morning and evening were analyzed for mean activity, variability and complexity. Lastly, the recordings were analyzed with the similarity graph algorithm and graph theory concepts such as edges, bridges, connected components and cliques.

Results

When compared to euthymia, over the duration of approximately one circadian cycle, the manic state presented reduced variability, displayed by decreased standard deviation (p = 0.013) and augmented complexity shown by increased sample entropy (p = 0.025). During mania there were also fewer edges (p = 0.039) and more bridges (p = 0.026). Similar changes in variability and complexity were observed in the 2-h morning and evening sequences, mainly in the estimates of the similarity graph algorithm. A comparison of morning and evening sequences within states revealed no significant change in estimates for mania. Contrarily, the euthymic state showed significant evening differences in variance and complexity, displayed by fewer edges (p = 0.010) and an increased number of connected components (p = 0.009).

Conclusion

The motor activity of mania is characterized by altered complexity, variability, and circadian rhythms when compared within-subject to euthymia.
Similar costs and outcomes for differentiated service delivery models for HIV treatment in Uganda
Authors: Guthrie Teresa , Muheki Charlotte , Rosen Sydney , Kanoowe Shiba , Lagony Stephen , Greener Ross , Miot Jacqueline , Balidawa Hudson , Kiggundu Josen , Calnan Jacqueline , Dejene Seyoum , Xulu Thembi , Sigwebela Ntombi , Long Lawrence C
Published: June 2021

Background

This study aimed to measure the total annual cost per patient and total cost per patient virally suppressed (defined as <1000 copies/ml) on antiretroviral therapy in Uganda in five differentiated service delivery models (DSDMs), including facility- and community-based models and the standard of care.

Methods

A cost/outcome study was undertaken from the perspective of the service provider, using retrospective patient record review of a cohort of patients over a two-year period, with bottom-up collection of patients’ resource utilization data, top-down collection of above-delivery level and delivery-level providers’ fixed operational costs, and local unit costs.

Results

Forty-seven DSDMs located at facilities or community-based points in four regions of Uganda were included in the study, with 653 adults on ART (>18 years old) enrolled in a DSDM. The study found that retention in care was 98% for the sample as a whole [96-100%], and viral suppression, 91% [86%-93%]. The mean cost to the provider (Ministry of Health or NGO implementers) was $152 per annum per patient treated, ranging from $141 to $166. Differences among the models’ costs were largely due to patients’ ARV regimens and proportions of patients on second line regimens. Service delivery costs, excluding ARVs, other medicines and laboratory tests, were modest, ranging from $9.66-16.43 per patient.

Conclusion

We conclude that differentiated ART service delivery in Uganda achieved excellent treatment outcomes at a cost similar to the standard of care. While large budgetary savings might not be immediately realized, the reallocation of “saved” staff time could improve health system efficiency as facilities and patients gain more experience with DSD models.
Assay-related Differences in SuPAR Levels: Implications for Measurement and Data Interpretation
Authors: Hayek Salim S. , Raffield Laura M. , Gao Yan , Engstrom Gunnar , Quyyumi Arshed A. , Reiner Alexander P. , Reiser Jochen
Published: June 2021

With the growing interest in studying the role of soluble urokinase plasminogen activator receptor (suPAR) in kidney and other diseases, levels are now being measured in major cohorts across the world through various methods, including immunoassays and through proteomics. Reported suPAR values have however varied dramatically depending on which assay is used. Comparing suPAR assays and their ability to discriminate risk is crucial for the Nephrology and overall research community to guide assay choice and inform interpretation of findings. To that end we measured suPAR in 3 different major cohorts (Malmo Diet and Cancer Study, n=4637; Jackson Heart Study, n=1905; and the Emory Cardiovascular Biobank, n=487) using two different methods in each cohort, encompassing the most commonly used approaches (immunoassays and proteomics). We find dramatic differences between assays; with notably poor correlations between immunoassays and proteomic approaches (r=0.2-0.5). Proteomics-based suPAR measures very poor discriminatory ability for cardiovascular and incident kidney disease. Amongst the immunoassays, the suPARnostic assay reported the highest values and had the strongest discriminatory ability.
Reduced neutralisation of the Delta (B.1.617.2) SARS-CoV-2 variant of concern following vaccination
Authors: Davis Chris , Logan Nicola , Tyson Grace , Orton Richard , Harvey William , Haughney John , Perkins Jon ,   The COVID-19 Genomics UK (COG-UK) Consortium, Peacock Thomas P. , Barclay Wendy S. , Cherepanov Peter , Palmarini Massimo , Murcia Pablo R. , Patel Arvind H. , Robertson David L. , Thomson Emma C. , Willett Brian J.
Published: June 2021

Vaccines are proving to be highly effective in controlling hospitalisation and deaths associated with SARS-CoV-2 infection but the emergence of viral variants with novel antigenic profiles threatens to diminish their efficacy. Assessment of the ability of sera from vaccine recipients to neutralise SARS-CoV-2 variants will inform the success of strategies for minimising COVID19 cases and the design of effective antigenic formulations. Here, we examine the sensitivity of variants of concern (VOCs) representative of the B.1.617.1 and B.1.617.2 (first associated with infections in India) and B.1.351 (first associated with infection in South Africa) lineages of SARS-CoV-2 to neutralisation by sera from individuals vaccinated with the BNT162b2 (Pfizer/BioNTech) and ChAdOx1 (Oxford/AstraZeneca) vaccines. Across all vaccinated individuals, the spike glycoproteins from B.1.617.1 and B.1.617.2 conferred reductions in neutralisation of 4.31 and 5.11-fold respectively. The reduction seen with the B.1.617.2 lineage approached that conferred by the glycoprotein from B.1.351 (South African) variant (6.29-fold reduction) that is known to be associated with reduced vaccine efficacy. Neutralising antibody titres elicited by vaccination with two doses of BNT162b2 were significantly higher than those elicited by vaccination with two doses of ChAdOx1. Fold decreases in the magnitude of neutralisation titre following two doses of BNT162b2, conferred reductions in titre of 7.77, 11.30 and 9.56-fold respectively to B.1.617.1, B.1.617.2 and B.1.351 pseudoviruses, the reduction in neutralisation of the delta variant B.1.617.2 surpassing that of B.1.351. Fold changes in those vaccinated with two doses of ChAdOx1 were 0.69, 4.01 and 1.48 respectively. The accumulation of mutations in these VOCs, and others, demonstrate the quantifiable risk of antigenic drift and subsequent reduction in vaccine efficacy. Accordingly, booster vaccines based on updated variants are likely to be required over time to prevent productive infection. This study also suggests that two dose regimes of vaccine are required for maximal BNT162b2 and ChAdOx1-induced immunity.
A Cross-Sectional Survey of the Knowledge, Attitudes & Practices of Antimicrobial Users and Providers in an Area of High-Density Livestock-Human Population in Western Kenya
Authors: Kemp Steven A. , Pinchbeck Gina L. , Fèvre Eric M. , Williams Nicola J.
Published: June 2021

Background

Antimicrobial resistance (AMR) is one of the most important global health crises in recent times and is driven primarily by antimicrobial consumption. In East Africa, there is a paucity of data regarding the knowledge, attitudes and practices related to antimicrobial use (AMU). We investigate the ways in which antimicrobial users in the veterinary sector accessed veterinary antimicrobials, and common behaviours of veterinary antimicrobial users and prescribers associated with AMU and AMR.

Methods

In total, 70 farmers, staff at 49 agricultural-veterinary antimicrobial shops (agrovet staff) and 28 veterinary animal healthcare workers or veterinary surgeons (veterinary professionals) were interviewed in Busia county, western Kenya in 2016 using a standard questionnaire as a framework for structured interviews. Data recorded included participant demographics, level of education, access to and sources of veterinary antimicrobials, prescribing patterns and knowledge of AMR and antimicrobial withdrawal periods.

Results

The majority of antimicrobials were accessed through informal means, purchased from agroveterinary shops; more than half of staff did not hold nationally mandated qualifications to advise on or sell veterinary antimicrobials. Approximately 40% of veterinary antimicrobials were sold without a prescription and it was noted that both price and customer preference were important factors when selling antimicrobials in almost all agrovet shops. Knowledge of the dangers associated with AMR and AMU were mostly superficial. Treatment failure occurred often, and there was a lack of differentiation between AMR and simply treatment failure.

Conclusion

In this study area in East Africa with high-density human and livestock populations, AMU was primarily for maintenance of livestock health. These findings have highlighted several aspects surrounding inappropriate access to antimicrobials, and as such require attention from policy makers concerned with AMR in both livestock and human medicine sectors. Improving prescribing practices and ensuring a minimum level of general education and awareness of prescribers, as well as expanding the role of agrovet staff in antimicrobial stewardship programmes, may help begin to mitigate the maintenance and transmission of AMR, particularly amongst livestock.
Disease Triangle Dynamics of Coccidioidomycosis in Northern Arizona
Authors: Mead Heather L. , Kollath Dan , de Melo Teixeira Marcus , Roe Chandler C. , Keim Paul K. , Plude Carmel , Terriquez Joel , Nandurkar Nivedita , Donohoo Chelsea , O’Connor Brettania L.W. , Barker Bridget M.
Published: June 2021

Coccidioides species are the etiological agent of Valley fever (Vf). Disease ranges from pneumonia to extrapulmonary infection. If diagnosis is delayed or missed, the risk of severe disease increases. We investigate the disease triangle (intersection of pathogen, host, and environment) of Vf in Northern Arizona, where the risk of acquiring the disease is lower but prevalent and rising. We inspect reported and hospitalized cases of VF hosts. Then assess pathogen origin by comparing Northern Arizona clinical isolates to isolates from other regions. Lastly, we survey Northern Arizona soils for evidence of Coccidioides. We found that cases of Vf are increasing some requiring hospitalization. The Northern Arizona Coccidioidies isolates were genetically related to Southern Arizona populations. However, we detected Coccidioides DNA in Northern Arizona soils. We expect that cases will continue to increase and suggest increased awareness and screening for the disease is crucial to limit severe illness in Northern Arizona.

Article Summary Line

Our work is the first description of the Valley fever disease triangle in Northern Arizona, which considers the complex interaction between host, pathogen and environment in the region. Our data suggests that the prevalence of diagnosed cases is rising in the region, some of which are extreme enough to necessitate hospitalization. We present the first evidence of Coccidioides spp. in Northern Arizona soils, suggesting that the pathogen is maintained in the local environment. Until disease prevention is an achievable option via vaccination, we anticipate that incidence of Valley fever will rise in the area. Therefore, enhanced disease awareness and screening for the coccidioidomycosis is vital to the communities of Northern Arizona.
Utility of family history in disease prediction in the era of polygenic scores
Authors: Wolford Brooke N. , Surakka Ida , Graham Sarah E. , Nielsen Jonas B. , Zhou Wei , Gabrielsen Maiken Elvestad , Skogholt Anne Heidi , Brumpton Ben M. , Douville Nicholas , Hornsby Whitney E. , Fritsche Lars G. , Boehnke Michael , Lee Seunggeun , Kang Hyun M. , Hveem Kristian , Willer Cristen J.
Published: June 2021

Clinicians have historically used family history and other risk prediction algorithms to guide patient care and preventive treatment such as statin therapeutics for coronary artery disease. As polygenic scores move towards clinical use, we have begun to consider the interplay of these scores with other predictors for optimal second generation risk prediction. Here, we assess the use of family history and polygenic scores as independent predictors of coronary artery disease and type 2 diabetes. We highlight considerations for use of family history as a predictor of these two diseases after evaluating their effectiveness in the Trøndelag Health Study and the UK Biobank. From these, we advocate for collection of high resolution family history variables in biobanks for future prediction models.
Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: A CAN-BIND-1 Study Report
Authors: Anteraper Sheeba Arnold , Guell Xavier , Lee Yoon Ji , Raya Jovicarole , Demchenko Ilya , Churchill Nathan W. , Frey Benicio N. , Hassel Stefanie , Lam Raymond W. , MacQueen Glenda M. , Milev Roumen , Schweizer Tom A. , Strother Stephen C. , Whitfield-Gabrieli Susan , Kennedy Sidney H. , Bhat Venkat ,   the CAN-BIND Investigator Team
Published: June 2021

Objective

Neuroimaging studies have demonstrated aberrant structure and function of the “cognitive-affective cerebellum” in Major Depressive Disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression.

Methods

A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 Healthy Controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI1 corresponded to default mode network (DMN) / inattentive processing; ROI2 corresponded to attentional networks including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons.

Results

In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3.

Conclusions

These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies.
Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer’s disease
Authors: Levitis Elizabeth , Vogel Jacob W. , Funck Thomas , Halchinski Vladimir , Gauthier Serge , Voglein Jonathan , Levin Johannes , Benzinger Tammie , Iturria-Medina Yasser , Evans Alan C. ,   for the Dominantly Inherited Alzheimer Network,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2021

Amyloid-beta (Aβ) deposition is one of the hallmark pathologies in both sporadic Alzheimer’s disease (sAD) and autosomal dominant Alzheimer’s disease (ADAD), the latter of which is caused by mutations in genes involved in Aβ processing. Despite Aβ deposition being a centerpiece to both sAD and ADAD, some differences between these AD subtypes have been observed with respect to the spatial pattern of Aβ. Previous work has shown that the spatial pattern of Aβ in individuals spanning the sAD spectrum can be reproduced with high accuracy using an epidemic spreading model (ESM), which simulates the diffusion of Aβ across neuronal connections and is constrained by individual rates of Aβ production and clearance. However, it has not been investigated whether Aβ deposition in the rarer ADAD can be modeled in the same way, and if so, how congruent the spreading patterns of Aβ across sAD and ADAD are. We leverage the ESM as a data-driven approach to probe individual-level variation in the spreading patterns of Aβ across three different large-scale imaging datasets (2 SAD, 1 ADAD). We applied the ESM separately to the Alzheimer’s Disease Neuroimaging initiative (N=737), the Open Access Series of Imaging Studies (N=510), and the Dominantly Inherited Alzheimer’s Network (N=249), the latter two of which were processed using an identical pipeline. We assessed inter- and intra-individual model performance in each dataset separately, and further identified the most likely epicenter of Aβ spread for each individual. Using epicenters defined in previous work in sAD, the ESM provided moderate prediction of the regional pattern of Aβ deposition across all three datasets. We further find that, while the most likely epicenter for most Aβ-positive subjects overlaps with the default mode network, 13% of ADAD individuals were best characterized by a striatal origin of Aβ spread. These subjects were also distinguished by being younger than ADAD subjects with a DMN Aβ origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most ADAD patients express Aβ spreading patters similar to those of sAD, but that there may be a subset of ADAD patients with a separate, striatal phenotype.
Metabolic resilience is encoded in genome plasticity
Authors: Agudelo Leandro Z. , Tuyeras Remy , Llinares Claudia , Morcuende Alvaro , Park Yongjin , Sun Na , Linna-Kuosmanen Suvi , Atabaki-Pasdar Naeimeh , Ho Li-Lun , Galani Kyriakitsa , Franks Paul W. , Kutlu Burak , Grove Kevin , Femenia Teresa , Kellis Manolis
Published: June 2021

Metabolism plays a central role in evolution, as resource conservation is a selective pressure for fitness and survival. Resource-driven adaptations offer a good model to study evolutionary innovation more broadly. It remains unknown how resource-driven optimization of genome function integrates chromatin architecture with transcriptional phase transitions. Here we show that tuning of genome architecture and heterotypic transcriptional condensates mediate resilience to nutrient limitation. Network genomic integration of phenotypic, structural, and functional relationships reveals that fat tissue promotes organismal adaptations through metabolic acceleration chromatin domains and heterotypic PGC1A condensates. We find evolutionary adaptations in several dimensions; low conservation of amino acid residues within protein disorder regions, nonrandom chromatin location of metabolic acceleration domains, condensate-chromatin stability through cis-regulatory anchoring and encoding of genome plasticity in radial chromatin organization. We show that environmental tuning of these adaptations leads to fasting endurance, through efficient nuclear compartmentalization of lipid metabolic regions, and, locally, human-specific burst kinetics of lipid cycling genes. This process reduces oxidative stress, and fatty-acid mediated cellular acidification, enabling endurance of condensate chromatin conformations. Comparative genomics of genetic and diet perturbations reveal mammalian convergence of phenotype and structural relationships, along with loss of transcriptional control by diet-induced obesity. Further, we find that radial transcriptional organization is encoded in functional divergence of metabolic disease variant-hubs, heterotypic condensate composition, and protein residues sensing metabolic variation. During fuel restriction, these features license the formation of large heterotypic condensates that buffer proton excess, and shift viscoelasticity for condensate endurance. This mechanism maintains physiological pH, reduces pH-resilient inflammatory gene programs, and enables genome plasticity through transcriptionally driven cell-specific chromatin contacts. In vivo manipulation of this circuit promotes fasting-like adaptations with heterotypic nuclear compartments, metabolic and cell-specific homeostasis. In sum, we uncover here a general principle by which transcription uses environmental fluctuations for genome function, and demonstrate how resource conservation optimizes transcriptional self-organization through robust feedback integrators, highlighting obesity as an inhibitor of genome plasticity relevant for many diseases.
Where there’s smoke, there’s fuel: dynamic vegetation data improve predictions of wildfire hazard in the Great Basin
Authors: Smith Joseph T. , Allred Brady W. , Boyd Chad S. , Davies Kirk W. , Jones Matthew O. , Kleinhesselink Andrew R. , Maestas Jeremy D. , Naugle David E.
Published: June 2021

Wildfires are a growing management concern in western US rangelands, where invasive annual grasses have altered fire regimes and contributed to an increased incidence of catastrophic large wildfires. Fire activity in arid, non-forested ecosystems is thought to be largely controlled by interannual variation in fuel amount, which in turn is controlled by antecedent weather. Thus, long-range forecasting of fire activity in rangelands should be feasible given annual estimates of fuel quantity. Using a 32 yr time series of spatial data, we employed machine learning algorithms to predict the relative probability of large (>405 ha) wildfire in the Great Basin based on fine-scale annual and 16-day estimates of cover and production of vegetation functional groups, weather, and multitemporal scale drought indices. We evaluated the predictive utility of these models with a leave-one-year-out cross-validation, building spatial hindcasts of fire probability for each year that we compared against actual footprints of large wildfires. Herbaceous aboveground biomass production, bare ground cover, and long-term drought indices were the most important predictors of burning. Across 32 fire seasons, 88% of the area burned in large wildfires coincided with the upper 3 deciles of predicted fire probabilities. At the scale of the Great Basin, several metrics of fire activity were moderately to strongly correlated with average fire probability, including total area burned in large wildfires, number of large wildfires, and maximum fire size. Our findings show that recent years of exceptional fire activity in the Great Basin were predictable based on antecedent weather-driven growth of fine fuels and reveal a significant increasing trend in fire probability over the last three decades driven by widespread changes in fine fuel characteristics.
A Reevaluation of the Effect of Dietary Restriction on Different Recombinant Inbred (RI) Lines of Male and Female Mice
Authors: Unnikrishnan Archana , Matyi Stephanie , Garrett Karla , Ranjo-Bishop Michelle , Allison David B , Ejima Keisuke , Chen Xiwei , Dickinson Stephanie , Richardson Arlan
Published: June 2021

Dietary restriction (DR) was reported to either have no effect or reduced the lifespan of the majority of the 41-recombinant inbred (RI)-lines studied (Liao et al., 2010). In an appropriately power longevity study (n > 30 mice/group), we measured the lifespan of the four RI-lines (115-RI, 97-RI, 98-RI, and 107-RI) that were reported to have the greatest decrease in lifespan when fed 40% DR. DR increased the median lifespan of female and male 115-RI mice and female 97-RI and 107-RI mice. DR had little effect (less than 4%) on the median lifespan of female and male 98-RI mice and male 97-RI mice and reduced the lifespan of male 107-RI mice over 20%. While our study was unable to replicate the effect of DR on the lifespan of the RI-mice (except male 107-RI mice) reported by Liao et al. (2010), we found that the genotype of a mouse had a major impact on the effect of DR on lifespan, with the effect of DR ranging from a 50% increase to a 22% decrease. No correlation was observed between the changes in either body composition or glucose tolerance induced by DR and the changes observed in lifespan of the four RI-lines of male and female mice. These four RI-lines of mice give the research community a unique resource where investigators for the first time can study the anti-aging mechanism of DR by comparing mice in which DR increases lifespan to mice where DR has either no effect or reduces lifespan.

Graphical Abstract

Brief Abstract

In this study we reevaluate the effect of the genotype and sex of the recombinant inbred strains of mice on their response to dietary restriction. Out of the eight lines studied, half of the groups showed an increase in lifespan when the diet was restricted by 40% and the other half either did not respond or showed a decrease in lifespan. The recombinant inbred lines used in this study are potentially important resource for aging research to identify pathways and understand the mechanism involved in the anti-aging action of DR.
Pan-cancer landscape of AID-related mutations, composite mutations and its potential role in the ICI response
Authors: Verdin Isaias Hernández , Akdemir Kadir C. , Ramazzotti Daniele , Caravagna Giulio , Labreche Karim , Mokhtari Karima , Hoang-Xuan Khê , Peyre Matthieu , Bielle Franck , Touat Mehdi , Idbaih Ahmed , Duval Alex , Sanson Marc , Alentorn Agustí
Published: June 2021

Activation-induced cytidine deaminase, AICDA or AID, is a driver of somatic hypermutation and class-switch recombination in immunoglobulins. In addition, this deaminase belonging to the APOBEC family, may have off-target effects genome-wide, but its effects at pan-cancer level are not well elucidated. Here, we used different pan-cancer datasets, totaling more than 50,000 samples analyzed by whole-genome, whole-exome or targeted sequencing. AID synergizes initial hotspot mutations by a second composite mutation. Analysis of 2.5 million cells, normal and oncogenic, revealed AICDA expression activation after oncogenic transformation and cell cycle regulation loss. AID mutational load was found to be independently associated with favorable outcome in immune-checkpoint inhibitors (ICI) treated patients across cancers after analyzing 2,000 samples. Finally, we found that AID related neoepitopes, resulting from mutations at more frequent hotspots if compared to other mutational signatures, enhance CXCL13/CCR5 expression, immunogenicity and T-cell exhaustion, which may increase ICI sensitivity.

In Brief

A combined bulk and single cell multi-omic analysis of over 50,000 patients and 2.5 million cells across 80 tumor types reveals oncogenic acquired AICDA expression inducing composite mutations and clonal immunogenic neoepitopes that are associated with favorable outcome in patients treated by immune-checkpoint inhibitors.

Highlights

•

Pan-cancer analysis of AID mutations using > 50,000 samples, 2,000 ICI treated cases and 2.5 million cells with genome, exome and transcriptome data

•

Oncogenic transient AICDA expression induces mutations mainly during transcription of its off-target genes in virtually all cancers

•

AID is implicated in composite mutations on weakly functional alleles and immunogenic clonal neoepitopes at hotspots with greater positive selection

•

AID mutational load predicts response and is associated with favorable outcome in ICI treated patients
Patient-derived tumor spheroid cultures as a promising tool to assist personalized therapeutic decisions in breast cancer
Authors: Hofmann Sarah , Cohen-Harazi Raichel , Maizels Yael , Koman Igor
Published: June 2021

Breast cancer is the most common cause of cancer related death in women. Treatment of breast cancer has many limitations including a lack of accurate biomarkers to predict success of chemotherapy and intrinsic resistance of a significant group of patients to the gold standard of therapy. Therefore, new tools are needed to provide doctors with guidance in choosing the most effective treatment plan for a particular patient and thus to increase the survival rate for breast cancer patients.

Here, we present a successful method to grow in vitro spheroids from primary breast cancer tissue. Samples were received in accordance with relevant ethical guidelines and regulations. After tissue dissociation, in vitro spheroids were generated in a scaffold-free 96-well plate format. Spheroid composition was investigated by immunohistochemistry (IHC) of epithelial (Pan Cytokeratin (panCK)), stromal (Vimentin) and breast cancer-specific markers (ER, PR, HER2, GATA-3). Growth and cell viability of the spheroids were assessed upon treatment with multiple anti-cancer compounds. Student’s t-test and two-way ANOVA test were used to determine statistical significance.

We were able to successfully grow spheroids from 27 out of 31 samples from surgical resections of breast cancer tissue from previously untreated patients. Recapitulation of the histopathology of the tissue of origin was confirmed. Furthermore, a drug panel of standard first- and second-line chemotherapy drugs used to treat breast cancer was applied to assess the viability of the patient-derived spheroids and revealed variation between samples in the response of the spheroids to different drug treatments.

We investigated the feasibility and the utility of an in vitro patient-derived spheroid model for breast cancer therapy, and we conclude that spheroids serve as a highly effective platform to explore cancer therapeutics and personalized treatment efficacy. These results have significant implications for the application of this model in clinical personalized medicine.
HIV-2/SIV Vpx antagonises NF-κB activation by targeting p65
Authors: Fink Douglas L. , Cai James , Whelan Matthew V. X. , Monit Christopher , de Motes Carlos Maluquer , Towers Greg J. , Sumner Rebecca P.
Published: June 2021

The NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins aimed at varied NF-κB pathway targeted to mitigate the anti-viral effects of NF-κB-dependent host immunity. In this study we have demonstrated using numerous assays, in a number of different cell types, that plasmid-encoded or virus-delivered Simian Immunodeficiency Virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65 and not NF-κB transcription factor proteins p50 or p100, preventing nuclear translocation of p65, a novel mechanism of NF-κB antagonism by lentiviruses. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity.

Importance

Broad antagonism of NF-κB activation has been described for HIV-1, but not for Vpx-encoding lentiviruses such as HIV-2. Here we extend our understanding of lentiviral antagonism by identifying an interaction between Vpx and transcription factor NF-κB p65, leading to inhibition of its nuclear translocation and broad NF-κB antagonism. This further evidences a requirement for lentiviruses to target universal regulators of immunity, including NF-κB, to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists, such as lipopolysaccharide translocation, during disruption of the gut microbiome barrier during HIV-1 infection. Further structural studies of p65 targeting by Vpx may yield translational insights in the form of novel pan-NF-κB inhibitors for pathologies characterised by excessive NF-κB activity. Our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of other pathways such as NF-κB.
Conservation of locomotion-induced oculomotor activity through evolution in higher tetrapods
Authors: França de Barros Filipa , Bacqué-Cazenave Julien , Taillebuis Coralie , Courtand Gilles , Manuel Marin , Bras Hélène , Tagliabue Michele , Combes Denis , Lambert François M , Beraneck Mathieu
Published: June 2021

Efference copies are neural replicas of motor outputs used to anticipate the sensory consequences of a self-generated motor action or to coordinate neural networks involved in distinct motor behaviors1. An established example of this motor-to-motor coupling is the efference copy of the propulsive motor command that supplements classical visuo-vestibular reflexes to ensure gaze stabilization during amphibian larval locomotion2. Such feedforward replica from spinal pattern-generating circuits produces a spino-extraocular motor coupled activity that evokes eye movements, spatio-temporally coordinated to tail undulation independently of any sensory signal3,4. Exploiting the evolutionary-development characteristic of the frog1, studies in metamorphing Xenopus demonstrated the persistence of this spino-extraocular motor command in adults, and its developmental adaptation to tetrapodal locomotion5,6. Here, we demonstrate for the first time the existence of a comparable locomotor-to-ocular motor coupling in the mouse. In neonates, ex vivo nerve recordings from brainstem-spinal cord preparation reveals a spino-extraocular motor coupled activity similar to the one described in Xenopus. In adult mice, trans-synaptic rabies injection in lateral rectus eye muscle labels cervical spinal cord neurons projecting directly to abducens motor neurons. Finally, treadmill-elicited locomotion in decerebrated preparations7 evokes rhythmic eye movements in synchrony with the limb gait pattern. Overall, our data are evidence for the conservation of locomotor-induced eye movements in higher tetrapods. Thus, in mammals as in amphibians, during locomotion CPG-efference copy feedforward signals might interact with sensory feedback to ensure efficient gaze control.

Highlights

Spino-extraocular motor coupling is evidenced from newborn mice ex vivo preparations

Adult decerebrated mice exhibit conjugated rhythmic eye movements during treadmill locomotion

Locomotor-induced oculomotor activity occurs in absence of visuo-vestibular inputs

Conserved CPG-based efference copy signal in vertebrates with common features.

eTOC blurb

We report a functional coupling between spinal locomotor and oculomotor networks in the mouse, similar to the one previously described in Amphibians. This is the first evidence for the direct contribution of locomotor networks to gaze control in mammals, suggesting a conservation of the spino-extraocular coupling in higher tetrapods during sustained locomotion.
Transcriptional activation of auxin biosynthesis drives developmental reprogramming of differentiated cells
Authors: Sakamoto Yuki , Kawamura Ayako , Suzuki Takamasa , Segami Shoji , Maeshima Masayoshi , Polyn Stefanie , De Veylder Lieven , Sugimoto Keiko
Published: June 2021

Plant cells exhibit remarkable plasticity of their differentiation states, enabling regeneration of whole plants from differentiated somatic cells. How they revert cell fate and express pluripotency, however, remains unclear. Here we show that transcriptional activation of auxin biosynthesis is crucial for reprogramming differentiated Arabidopsis leaf cells. We demonstrate that interfering with the activity of histone acetyltransferases dramatically reduces callus formation from leaf mesophyll protoplasts. Impaired histone acetylation predominantly affects transcription of auxin biosynthesis genes. Auxin biosynthesis is in turn required to accomplish initial cell division through the activation of G2/M phase genes mediated by MYB DOMAIN PROTEIN 3-RELATED (MYB3Rs). We further show that the AUXIN RESPONSE FACTOR 7 (ARF7)/ARF19 and INDOLE-3-ACETIC ACID INDUCIBLE 3 (IAA3)/IAA18-mediated auxin signaling pathway is responsible for cell cycle reactivation in protoplasts. These findings provide novel mechanistic model of how differentiated plant cells can revert their fate and reinitiate the cell cycle to become pluripotent.
Resolving the structure of phage-bacteria interactions in the context of natural diversity
Authors: Kauffman Kathryn M. , Chang William K. , Brown Julia M. , Hussain Fatima A. , Yang Joy Y. , Polz Martin F. , Kelly Libusha
Published: June 2021

Microbial communities are shaped by viral predators1. Yet, resolving which viruses (phages) and bacteria are interacting is a major challenge in the context of natural levels of microbial diversity2. Thus, fundamental features of how phage-bacteria interactions are structured and evolve in “the wild” remain poorly resolved3, 4. Here we use large-scale isolation of environmental marineVibriobacteria and their phages to obtain quantitative estimates of strain-level phage predator loads, and use all-by-all host range assays to discover how phage and host genomic diversity shape interactions. We show that killing in environmental interaction networks is sparse - with phage predator loads low for most bacterial strains and phages host-strain-specific in their killing. Paradoxically, we also find that although overlap in killing is generally rare between phages, recombination is common. Together, these results indicate that the number of hosts that phages infect is often larger than the number that they kill and suggest that recombination during cryptic co-infections is an important mode of phage evolution in microbial communities. In the development of phages for bioengineering and therapeutics it will be important to consider that nucleic acids of introduced phages may spread into local phage populations through recombination, and that the likelihood of transfer is not predictable based on killing host range.
Inhibition of cancer cells in culture. The effects of treatment with ketone bodies and/or rapamycin treatment
Authors: Miller Anna , Lin Bo , Pincus Matthew R. , Fine Eugene J. , Feinman Richard D.
Published: June 2021

Background

The potential for ketogenic diets or administration of exogenous ketone bodies to treat or prevent to cancer remains encouraging. Of particular interest is the possibility that, whatever the effect of a nutritional intervention alone, the diet might enhance the effect of existing cancer drugs, thereby requiring lower doses and a reduction in toxicity and side effects.

Methods

SW480, a human cell line derived from colon, was treated with ketone bodies (sodium 3-hydroxy butyrate (common name, □-hydroxy butyrate) or with sodium acetoacetate in the presence or absence of rapamycin. Cells were incubated for 96 hours in DMEM with 10 mM glucose medium. HSF2617, a human epithelial fibroblast line served as control and cells were subjected to similar treatment as the SW480 cells. Cell proliferation and glucose consumption were determined with standard reagents.

Results

The ketone bodies inhibited proliferation of SW480 cells in culture. Rapamycin also inhibited proliferation and its action was enhanced by the ketone bodies although there was little synergistic effect under these conditions. Human fibroblast controls were not inhibited by the ketone bodies. Both SW480 and control lines showed consumption of glucose during a 96 hour incubation period, suggesting that normal controls can switch to ketogenic metabolism while the cancer cells, which proliferate poorly, cannot. Results are consistent with recent reports of a mouse model showing the synergy of rapamycin and a ketogenic diet (Zou Y,et al. (2020)PLoS ONE15(5)) as well as earlier publications describing additive or synergistic effects of ketogenic diets with other modalities of cancer treatment.

Conclusions

The results show that the growth of a cancer cell line in culture can be inhibited by the addition of ketone bodies or rapamycin to the growth medium. The combination of treatments was found to be additive, consistent with results from a previously published mouse model. The data demonstrate the potential for a strategy whereby doses of anti-cancer agents that have detrimental or toxic side-effects can be reduced if coupled to an appropriate source of ketone bodies.
Fishing for biodiversity by balanced harvesting
Authors: Law Richard , Plank Michael J
Published: June 2021

Fisheries are damaging, and seemingly incompatible with the conservation of marine ecosystems. Yet fish are an important source of food, and support the lives of many people in coastal communities. This paper considers an idea that a moderate intensity of fishing, appropriately scaled across species, could help in maintaining biodiversity, rather than reducing it. The scaling comes from an intuition that rates of fishing mortality of species should be kept in line with production rates of the species, a notion known as balanced harvesting. This places species conservation and exploitation on an equal footing in a single equation, showing quantitatively the relative levels of fishing mortality that species of different abundance can support. Using a dynamic model of a marine ecosystem, we give numerical evidence showing for the first time that fishing, if scaled in this way, can protect rarer species, while allowing some exploitation of species with greater production. This works because fishing mortality rates, when scaled by production, are density-dependent. Such fishing, operating adaptively to follow species’ production rates over time, contains a feedback that would help to protect species from overfishing in the presence of uncertainty about how marine ecosystems work.
Population structure and reproduction of the alvinocaridid shrimp Rimicaris exoculata on the Mid-Atlantic Ridge: variations between habitats and vent fields
Authors: Hernández-Ávila Iván , Cambon-Bonavita Marie-Anne , Sarrazin Jozée , Pradillon Florence
Published: June 2021

Rimicaris exoculata is a dominant species of deep Mid-Atlantic Ridge (MAR) vent fields and inhabits areas close to vent emissions at depths below 2000 m. Its high abundance and strong genetic connectivity along the MAR point at a remarkable ability to produce dispersing larval stages. However, the reproduction of this species long remained enigmatic because brooding females were rarely observed. Here, we describe the population structure and reproduction of R. exoculata at the Snake Pit and TAG vent fields (3600m depth) for the months of January-February. We observed major differences in population structure between habitats within a single vent field: females widely dominate the large swarms near active venting while inactive peripheries are inhabited by large males. Low temperature diffusion zones are mainly colonized by small juveniles of R. chacei instead of R. exoculata. Size structure of populations from dense active areas is polymodal at both fields, suggesting discontinuous recruitment. Male and female sizes did not vary across habitats and vent fields, with sexually mature female being slightly larger than males. In contrast to previous studies, hundreds of ovigerous females were observed at both vent fields, suggesting seasonal reproduction. Proportion of ovigerous females among sexually mature females were similar between vent fields (36.7 %). However, reproductive output was lower at TAG, where ovigerous females had smaller size-specific fecundity and egg size, and more aborted broods. Broods were colonized by the dirivultid copepod Stygiopontius pectinatus at both vent fields, apparently without deleterious effect on egg development. In the light of the observed variability in R. exoculata population structure, we propose a hypothetical scenario depicting its mating system and brooding behavior, and discuss more generally intraspecific interactions during its benthic life stages.