bluuebunny/crossref_metadata_2025 huggingface dataset:
Incidental Diagnosis of Right Renal Subcapsular Urinoma on an 18F-FDG PET/CT Scan Performed for Staging of Cervical Cancer
Authors: Liu Weiting , Yao Xilan , Ou Xiaohong
Published: April 2022

A 53-year-old woman with cervical cancer underwent FDG PET/CT staging, which demonstrated an avid cervical mass with right parametrial involvement and presence of bilateral lymph node metastases. The right ureter was encased, resulting in obstruction and renal pelvic dilatation. Avid right renal subcapsular lesions were also noted, which were hyperintense on T2-weighted imaging compatible to encapsulated fluid collections. These lesions were diagnosed as subcapsular urinoma due to transmitted back pressure caused by obstruction of the right ureter.
Is Glucagon Administration Compatible With FDG PET/MRI?
Authors: Maucherat Bruno , Movassaghi Roshanack , Fleury Vincent , Le Thiec Maelle , Geffroy Delphine , Labbe-Devilliers Catherine , Rousseau Caroline
Published: April 2022

Digestive peristalsis generates many artifacts that limit the abdominal and pelvic MRI interpretation. Apart from the hypoglycemia treatment in patients with diabetes, glucagon analog is also indicated for the digestive peristalsis reduction to reduce MRI artifacts. However, its use in PET/MRI is not described, given the risk of interaction with the metabolism of FDG. To assess the importance of this interaction on the FDG PET images, we report FDG PET/MRI images obtained with and without glucagon analog injection.
Neuro-Ophthalmological Complications of the COVID-19 Vaccines: A Systematic Review
Authors: Lotan Itay , Lydston Melissa , Levy Michael
Published: April 2022

Background:

A worldwide mass vaccination campaign against the coronavirus disease 2019 (COVID-19) pandemic is currently underway. Although the safety data of the clinical trials did not report specific concerns regarding neuro-ophthalmological adverse events, they involved a limited number of individuals and were conducted over a relatively short time. The aim of the current review is to summarize the available postmarketing data regarding the occurrence of neuro-ophthalmological and other ocular complications of the COVID-19 vaccines.

Evidence Acquisition:

Electronic searches for published literature were conducted using Ovid MEDLINE, Embase, Web of Science, Google Scholar, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov. The search strategy incorporated controlled vocabulary and free-text synonyms for the concepts of COVID, vaccines, and visual and neuro-ophthalmologic diseases and symptoms.

Results:

A total of 14 case reports and 2 case series have been selected for inclusion in the final report, reporting 76 cases of post-COVID-vaccination adverse events. The most common adverse event was optic neuritis (n = 61), followed by uveitis (n = 3), herpes zoster ophthalmicus (n = 2), acute macular neuroretinopathy (n = 2), optic disc edema as an atypical presentation of Guillain–Barré syndrome (n = 1), (arteritic anterior ischemic optic neuropathy; n = 1), abducens nerve palsy (n = 1), oculomotor nerve palsy (n = 1), Tolosa–Hunt syndrome (n = 1), central serous retinopathy (n = 1), acute zonal occult outer retinopathy (n = 1), and bilateral choroiditis (n = 1). Most cases were treated with high-dose steroids and had a favorable clinical outcome.

Conclusion:

Since the implementation of the COVID-19 vaccination campaign in the past year, several post-COVID-vaccination neuro-ophthalmological complications have been described. However, considering the number of individuals that have been exposed to the vaccines, the risk seems very low, and the clinical outcome in most cases is favorable. Therefore, on a population level, the benefits of the vaccines far outweigh the risk of neuro-ophthalmological complications.
Ganglion Cell Layer Thickness Variance Using SPECTRALIS Optical Coherence Tomography
Authors: Mallory Paul , Wagley Sushant , Chen John , McClelland Collin M. , Downie Peter A. , Lindgren Bruce , Lee Michael S.
Published: April 2022

Background:

To determine the normal variance of the mean macular ganglion cell layer (GCL) volume among subjects without significant ocular pathology using SPECTRALIS optical coherence tomography (OCT).

Methods:

Fifty subjects underwent a baseline scan using SPECTRALIS OCT followed by 2 more studies with (reg-ON) and without (reg-OFF) eye registration all taken at the same session. The mean GCL volume was measured using built-in SPECTRALIS software. Eyes with macular pathology were excluded. The reproducibility of the measurements of the GCL volume was evaluated with Bland–Altman plots and limits of agreement, intraclass correlation coefficient (ICC), and the coefficient of repeatability (CR).

Results:

A total of 98 eyes met criteria for the analysis. The mean GCL volume difference was 0.0002 ± 0.029 and −0.0005 ± 0.035 mm3 for scans 1 versus 2 (baseline vs reg-ON) and 3 (baseline vs reg-OFF), respectively. The ICCs were 0.985 and 0.977 for the baseline vs reg-ON and reg-OFF groups. The CR for baseline vs reg-ON was 0.056 while CR for baseline vs reg-OFF was 0.069. Ninety percent of eyes fell within 0.04 mm3 of test–retest reliability.

Conclusions:

Our model found a predictable threshold of 0.07 mm3 or less for SPECTRALIS OCT mean GCL volume variance, which did not significantly change with eye registration in eyes without macular pathology. Clinicians may also consider a threshold of 0.04 mm3 when determining stable vs progressive changes in mean GCL volume using this device.
Does Angiosarcoma of the Breast Need Nodal Staging?
Authors: Herb Joshua , Maduekwe Ugwuji N , Goel Neha , Rosenberger Laura H , Spanheimer Philip M
Published: April 2022

BACKGROUND:

Breast angiosarcoma is a rare malignancy classically associated with hematogenous metastases. We sought to determine the prevalence of pathologic nodal involvement in patients with nonmetastatic, resected breast angiosarcoma and its association with overall survival.

STUDY DESIGN:

The National Cancer Database was used to identify patients with nonmetastatic angiosarcoma of the breast who underwent surgical resection from 2004 to 2017. The prevalence of regional lymph node operation and nodal positivity was calculated. The Kaplan–Meier method was used to evaluate overall survival among node-positive and node-negative patients. Cox proportional hazard modeling was used to evaluate the adjusted association of nodal positivity with overall survival.

RESULTS:

We included 991 patients with angiosarcoma. The median age was 69 years (interquartile range 57 to 78), and the cohort was 99% female. A total of 298 patients (30%) had pathologic regional nodal evaluation. Of those, 15 (5.0%) had positive regional lymph nodes. Node-positive patients had significantly worse survival than patients with negative regional lymph nodes. After adjusting for patient, tumor, and treatment factors, a positive regional lymph node was associated with worse overall survival compared with patients with no nodal evaluation (hazard ratio 3.20; 95% CI 1.75 to 5.86; p < 0.001).

CONCLUSIONS:

Patients with nonmetastatic angiosarcoma of the breast have a 5% regional lymph node positivity rate, which is at a common threshold to consider evaluation, and identifies patients with poor survival. A prospective study to determine performance characteristics of sentinel lymph node biopsy is warranted.
Validated Risk-Score Model Predicting Lymph Node Metastases in Patients with Non-Functional Gastroenteropancreatic Neuroendocrine Tumors
Authors: Shannon Adrienne B , Straker Richard J , Fraker Douglas L , Miura John T , Karakousis Giorgos C
Published: April 2022

BACKGROUND:

The incidence of, and factors associated with, lymph node metastasis (LN+) in non-functional gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are not well characterized.

METHODS:

Patients were identified from the 2010–2015 National Cancer Database who underwent surgical resection with lymphadenectomy for clinical stage I–III non-functional GEP NETs. Among a randomly selected training subset of 75% of the study population, variables associated with LN+ were identified using multivariable logistic regression analysis, and these variables were used to create a risk-score model for LN+, which was internally validated among the remaining 25% of the cohort.

RESULTS:

Of 12,228 patients evaluated, 6,902 (56.4%) had LN+. Among the training set, variables associated with LN+ included age (70 years of age or older: odds ratio [OR] 1.12, 95% CI 1.00–1.24; ref: less than 70 years), tumor location (stomach: OR 3.72, 95% CI 2.94–4.71; small intestine: OR 19.60, 95% CI 17.31–22.19; ref: pancreas), tumor grade (moderately differentiated: OR 1.47, 95% CI 1.30–1.67; poorly differentiated/anaplastic: OR 1.53, 95% CI 1.21–1.95; ref: well-differentiated), tumor size (2–4 cm: OR 2.40, 95% CI 2.13–2.70; >4 cm: OR 5.25, 95% CI 4.47–6.17; ref: <2 cm), and lymphovascular invasion (OR 5.62, 95% CI 5.08–6.21; ref: no lymphovascular invasion). After internal validation, a risk-score model for LN+ using these variables was developed composed of low- (N = 2,779), intermediate- (N = 2,598), high- (N = 3,433), and very-high-risk (N = 3,418) groups; within each group the rate of LN+ was 8.7%, 48.6%, 64.9%, and 92.8%, respectively.

CONCLUSIONS:

This developed risk-score model, including both patient and tumor variables, can be used to calculate the risk for LN metastases in patients with GEP NETs.
Concurrent Validity Evidence for Entrustable Professional Activities in General Surgery Residents
Authors: Brazelle Morgan , Zmijewski Polina , McLeod Chandler , Corey Britney , Porterfield John R , Lindeman Brenessa
Published: April 2022

BACKGROUND:

A subset of Entrustable Professional Activities (EPAs) has been developed for general surgery. We aim to contribute validity evidence for EPAs as an assessment framework for general surgery residents, including concurrent validity compared to ACGME milestones, the current gold standard for evaluating competency.

STUDY DESIGN:

This is a cross-sectional study in a general surgery training program within a tertiary academic medical center. EPA assessments were submitted using a mobile app and scored on a numerical scale, mirroring milestones. EPA score distribution was analyzed with respect to post-graduate year (PGY) level and phase of care. Proportional odds logistic regression identified significant predictors. Spearman rank and Wilcoxon rank tests were used for comparisons with milestone ratings.

RESULTS:

From August 2018 to December 2019, 320 assessments were collected. EPA scores increased by PGY level. Operative phase EPA scores were significantly lower than nonoperative phase scores. PGY level, operative phase, and case difficulty significantly influenced entrustment scoring. EPA scores demonstrated strong correlation with nonoperative milestones patient care-1, medical knowledge-1, interpersonal and communication skills-2, interpersonal and communication skills-3, professionalism-1, professionalism-3, and practice-based learning and improvement-2 (ρ > 0.5, p < 0.05) and a weaker correlation with operative milestones patient care-3 and medical knowledge-2 (ρ < 0.5, p < 0.05).

CONCLUSIONS:

The influence of PGY level and operative phase on entrustment scoring supports the validity of EPAs as a formative evaluation framework for general surgery resident performance. In addition, evident correlations between EPA scores and respective milestone ratings provide concurrent validity evidence.
Unique Metabolic Profiles Associate with Gestational Diabetes and Ethnicity in Low and High-Risk Women Living in the UK
Authors: Fuller Harriett , Iles Mark , Moore J. Bernadette , Zulyniak Michael A.
Published: April 2022

Background

Gestational Diabetes Mellitus (GDM) is the most common global pregnancy complication; however, prevalence varies substantially between ethnicities with South Asians (SA) experiencing up to 3-times the risk of the disease compared to white Europeans (WEs). Factors driving this discrepancy are unclear, although the metabolome is of great interest as GDM is known to be characterised by metabolic dysregulation.

Objective

This primary aim was to characterise and compare the metabolic profiles of GDM in SA and WE women (at < 28 weeks’ gestation) from the Born in Bradford (BIB) prospective birth cohort in the UK.

Methods

146 fasting serum metabolites, from 2668 pregnant WE and 2671 pregnant South Asian (SA) women (average BMI 26.2 kg/m2, average age 27.3 years) were analysed using partial least squares discriminatory analyses to characterise GDM status. Linear associations between metabolite values and post-oral glucose tolerance test measures of dysglycemia (fasting glucose and 2-hour post glucose) were also examined.

Results

Seven metabolites associated with GDM status in both ethnicities (variable importance in projection (VIP) ≥1), while 6 additional metabolites associated with GDM only in WE women. Unique metabolic profiles were observed in healthy weight women who later developed GDM, with distinct metabolite patterns identified by ethnicity and BMI status. Of the metabolite values analysed in relation to dysglycemia, lactate, histidine, apolipoprotein A1, HDL cholesterol, HDL2 cholesterol associated with decreased glucose concentration, while DHA and the diameter of very low-density lipoprotein particles (nm) associated with increased glucose concertation in WE women; while in SAs albumin alone associated with decreased glucose concentration.

Conclusions

This study shows that the metabolic risk profile for GDM differs between WE and SA women enrolled in BiB the UK. This suggests that aetiology of the disease differs between ethnic groups and that ethnic-appropriate prevention strategies may be beneficial.
Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition
Authors: Breeur Marie , Ferrari Pietro , Dossus Laure , Jenab Mazda , Johansson Mattias , Rinaldi Sabina , Travis Ruth C. , His Mathilde , Key Tim J. , Schmidt Julie A. , Overvad Kim , Tjønneland Anne , Kyrø Cecilie , Rothwell Joseph A. , Laouali Nasser , Severi Gianluca , Kaaks Rudolf , Katzke Verena , Schulze Matthias B. , Eichelmann Fabian , Palli Domenico , Grioni Sara , Panico Salvatore , Tumino Rosario , Sacerdote Carlotta , Bueno-de-Mesquita Bas , Olsen Karina Standahl , Sandanger Torkjel Manning , Nøst Therese Haugdahl , Quirós J. Ramón , Bonet Catalina , Barranco Miguel Rodríguez , Chirlaque María-Dolores , Ardanaz Eva , Sandsveden Malte , Manjer Jonas , Vidman Linda , Rentoft Matilda , Muller David , Tsilidis Kostas , Heath Alicia K. , Keun Hector , Adamski Jerzy , Keski-Rahkonen Pekka , Scalbert Augustin , Gunter Marc J. , Viallon Vivian
Published: April 2022

Background

Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.

Methods

We analyzed targeted metabolomics data available for 5,828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites, and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data shared lasso penalty.

Results

Out of the 50 studied metabolites, (i) six were inversely associated with risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2 and three clusters of phosphatidylcholines (PCs); (ii) three were positively associated with most cancer types: proline, decanoylcarnitine and one cluster of PCs; and (iii) 10 were specifically associated with particular cancer types, including histidine that was inversely associated with colorectal cancer risk, and one cluster of sphingomyelins that was inversely associated with risk of hepatocellular carcinoma and positively with endometrial cancer risk.

Conclusions

These results could provide novel insights for the identification of pathways for cancer development, in particular those shared across different cancer types.
Nowcasting and Forecasting COVID-19 Waves: The Recursive and Stochastic Nature of Transmission
Authors: Albani Vinicius V.L. , Albani Roseane , Massad Eduardo , Zubelli Jorge P.
Published: April 2022

We propose a parsimonious, yet effective, susceptible-exposed-infected-removed-type model that incorporates the time change in the transmission and death rates. The model is calibrated by Tikhonov-type regularization from official reports from New York City (NYC), Chicago, the State of São Paulo, in Brazil, and British Columbia, in Canada. To forecast, we propose different ways to extend the transmission parameter, considering its estimated values. The forecast accuracy is then evaluated using real data from the above referred places. All the techniques accurately provided forecast scenarios for periods 15 days long. One of the models effectively predicted the magnitude of the four waves of infections in NYC, including the one caused by the Omicron variant for periods of 45 days long using out-of-sample data.
Carbohydrates complement high protein diets to maximize the growth of an actively hunting predator
Authors: Wiggins Will D. , Wilder Shawn M.
Published: April 2022

In nature, food is often variable in composition and availability. As a consequence, predators may need to seek non-prey food sources. Some predators are known to feed on nectar when food is limited. Nectar and other carbohydrate resources could also be beneficial when prey are more abundant if it helps predators balance protein-biased diets. We tested if an actively hunting predator, the jumping spider, Phidippus audax, benefited from liquid carbohydrates when prey were not limited. We also tested if the benefit of carbohydrates varied with the nutrient content of prey (i.e., from protein to lipid-biased). Spiders were reared on one of six live prey, Drosophila melanogaster, treatments that ranged from high protein to high lipid. Half of the spiders were given access to a 20% sucrose solution. After two months, we measured spider mass, cephalothorax width, instar duration, percent body fat, survival, and estimated number of prey eaten. Spiders reared on high protein diets with carbohydrates were larger and heavier than spiders on other treatments. Access to carbohydrates also increased percent body fat and survival across prey treatments. Our results suggest that carbohydrates may be a valuable component of spider diets, especially when prey have high protein and low lipid content as is commonly observed in prey in the field. Our results highlight the importance of diet balancing for predators, and that liquid carbohydrates can be an important nutrient to supplement a diet of prey rather than just being an energy supplement during periods of starvation.

Significance statement

Protein and lipid are thought to be the primary nutrients used by predators, including spiders. Yet, some spiders have been observed feeding on carbohydrate-rich nectar from flowers. We tested if the addition of carbohydrates to a high protein or high lipid diet affected the growth of the North American jumping spider, Phidippus audax. Spiders grew largest on high protein diets with carbohydrates, demonstrating that plant-based foods rich in carbohydrates can be important for some predators.
Spatial reasoning via recurrent neural dynamics in mouse retrosplenial cortex
Authors: Voigts Jakob , Kanitscheider Ingmar , Miller Nicholas J. , Toloza Enrique H.S. , Newman Jonathan P. , Fiete Ila R. , Harnett Mark T.
Published: April 2022

From visual perception to language, sensory stimuli change their meaning depending on prior experience. Recurrent neural dynamics can interpret stimuli based on externally cued context, but it is unknown whether similar dynamics can compute and employ internal hypotheses to resolve ambiguities. Here, we show that mouse retrosplenial cortex (RSC) can form hypotheses over time and perform spatial reasoning through recurrent dynamics. In our task, mice navigated using ambiguous landmarks that are identified through their mutual spatial relationship, requiring sequential refinement of hypotheses. Neurons in RSC and in artificial neural networks encoded mixtures of hypotheses, location, and sensory information, and were constrained by robust low dimensional dynamics. RSC encoded hypotheses as locations in activity space with divergent trajectories for identical sensory inputs, enabling their correct interpretation. Our results indicate that interactions between internal hypotheses and external sensory data in recurrent circuits can provide a substrate for complex sequential cognitive reasoning.
Adding gene transcripts into genomic prediction improves accuracy and reveals sampling time dependence
Authors: Perez B.C. , Bink M.C.A.M. , Svenson K.L. , Churchill G.A. , Calus M.P.L.
Published: April 2022

Recent developments allowed generating multiple high quality ‘omics’ data that could increase predictive performance of genomic prediction for phenotypes and genetic merit in animals and plants. Here we have assessed the performance of parametric and non-parametric models that leverage transcriptomics in genomic prediction for 13 complex traits recorded in 478 animals from an outbred mouse population. Parametric models were implemented using best linear unbiased prediction (BLUP), while non-parametric models were implemented using the gradient boosting machine algorithm (GBM). We also propose a new model named GTCBLUP that aims to remove between-omics-layer covariance from predictors, whereas its counterpart GTBLUP does not do that. While GBM models captured more phenotypic variation, their predictive performance did not exceed the BLUP models for most traits. Models leveraging gene transcripts captured higher proportions of the phenotypic variance for almost all traits when these were measured closer to the moment of measuring gene transcripts in the liver. In most cases, the combination of layers was not able to outperform the best single-omics models to predict phenotypes. Using only gene transcripts, the GBM model was able to outperform BLUP for most traits except body weight, but the same pattern was not observed when using both SNP genotypes and gene transcripts. Although the GTCBLUP model was not able to produce the most accurate phenotypic predictions, it showed highest accuracies for breeding values for 9 out of 13 traits. We recommend using the GTBLUP model for prediction of phenotypes and using the GTCBLUP for prediction of breeding values.
The use of alternative spawning habitats by the American horseshoe crab,Limulus polyphemus
Authors: Sasson Daniel A. , Chabot Christopher C. , Mattei Jennifer H. , Kendrick Michael R. , Brunson Jeffrey F. , Huber Jeanette H. , Kasinak Jo-Marie E. , Puckette Paul T. , Sundin Gary , Kingsley-Smith Peter R.
Published: April 2022

For animals that develop externally, habitats where environmental conditions are optimal for embryonic development are sometimes assumed to represent the highest recruitment potential and thus support the majority of reproductive output for a species. However, organisms may spawn in areas considered sub-optimal for embryonic development. Thus, understanding spawning habitat selection decisions and their potential impacts on recruitment and ecological interactions is necessary for predicting population status and identifying critical habitats to inform sustainable conservation decisions and effective management approaches. The American horseshoe crab,Limulus polyphemus, is ecologically, economically, and biomedically important. Females come ashore to spawn in the sediment where eggs develop for 2 – 4 weeks. Horseshoe crabs have been thought to primarily use sandy beach habitat for spawning in part because this habitat has been shown to be optimal for embryonic development. Horseshoe crab eggs on sandy beaches are an essential part of the diet of many organisms, including shorebirds such as therufared knot which requires the eggs to fuel their migration to arctic spawning grounds. While horseshoe crabs have been observed spawning in alternative habitats such as salt marshes and peat beds, this behavior has been assumed to be rare and non-adaptive. In this study, we compare the use of beach and alternative habitats by horseshoe crabs for spawning. To do so, we conducted adult horseshoe crab spawning surveys and horseshoe crab egg surveys in beach andSpartina-dominated salt marsh alternative habitats in South Carolina, Connecticut, and New Hampshire, U.S.A. While spawning horseshoe crabs were more likely to be observed on beach habitats than in alternative habitats, potentially due to logistical constraints surveying alternative habitats, we found similar densities of spawning horseshoe crabs in both habitat types. We also tended to find more eggs in alternative habitats than on beaches. Taken together, these results suggest that alternative habitats likely represent a significant source of horseshoe crab spawning activity and recruitment that had not previously been quantified. We recommend this information be incorporated into horseshoe crab population assessments, habitat protections, and more directed research at understanding variability in habitat-specific horseshoe crab spawning and its relationship to migratory shorebirds.
Microvesicle-Mediated Tissue Regeneration Mitigates the Effects of Cellular Ageing
Authors: Panagiotou Nikolaos , McGuiness Dagmara , Jaminon Armand M.G. , Mees Barend , Selman Colin , Schurgers Leon , Shiels Paul G.
Published: April 2022

An ageing global population brings with it a significant burden of age-related morbidities. Recently, a novel intervention strategy to mitigate this burden has emerged, involving the use of Extracellular Vesicles (EV), comprising use of Microvesicles (MV) and Exosomes (Exo). These membranous vesicles are secreted by cells and mediate repair of cellular and tissue damage via paracrine mechanisms, involving interaction of their bioactive cargoes with stem cells. The actions of EV under normative and morbid conditions in the context of ageing remains largely unexplored. We now show that MV, but not Exo, from Pathfinder cells (PC), a putative stem cell regulatory cell type, enhance the repair of Human Dermal Fibroblast (HDF) and Mesenchymal Stem Cell (MSC) co-cultures following both mechanical and genotoxic stress. Critically, this effect was found to be both cellular age and stress-specific. Notably, MV treatment was unable to repair mechanical injury in older co-cultures, but still remained therapeutic following genotoxic stress. These observations were further confirmed in HDF and Vascular Smooth Muscle Cell (VSMC) co-cultures of increasing cellular age. In a model of comorbidity, comprising co-cultures of HDF and highly senescent Abdominal Aortic Aneurysm (AAA) VSMC, MV administration appeared to be senolytic following both mechanical and genotoxic stress, prior to enabling regeneration. To our knowledge, this is the first description of EV-based senolysis. It provides novel insight into understanding the biology of EV and the specific roles they play during tissue repair and ageing. These data will potentiate development of novel cell-free therapeutic interventions capable of attenuating age-associated morbidities and avoiding undesired effects. Ultimately, this might act as a possible intervention strategy to extend human healthspan.
ATF6 Activation Reduces Amyloidogenic Transthyretin Secretion Through Increased Interactions with Endoplasmic Reticulum Proteostasis Factors
Authors: Mesgarzadeh Jaleh S. , Romine Isabelle C. , Smith-Cohen Ethan M. , Grandjean Julia M.D. , Kelly Jeffery W. , Genereux Joseph C. , Wiseman R. Luke
Published: April 2022

The extracellular aggregation of destabilized transthyretin (TTR) variants is implicated in the onset and pathogenesis of familial TTR-related amyloid diseases. One strategy to reduce toxic, extracellular aggregation of TTR is to decrease the population of aggregation-prone protein secreted from mammalian cells. Stress-independent activation of the unfolded protein response (UPR)-associated transcription factor ATF6 preferentially decreases secretion and subsequent aggregation of destabilized, aggregation-prone TTR variants. However, the mechanism of this reduced secretion was previously undefined. Here, we implement a mass spectrometry-based interactomics approach to identify endoplasmic reticulum (ER) proteostasis factors involved in ATF6-dependent reductions of destabilized TTR secretion. We show that ATF6 activation reduces amyloidogenic TTR secretion and subsequent aggregation through a mechanism involving ER retention that is mediated by increased interactions with ATF6-regulated ER proteostasis factors including BiP and PDIA4. Intriguingly, the PDIA4-dependent retention of TTR is independent of both the single TTR cysteine residue and the redox activity of PDIA4, indicating that PDIA4 retains destabilized TTR in the ER through a redox-independent chaperoning activity. Our results define a mechanistic basis to explain the ATF6 activation-dependent reduction of destabilized, amyloidogenic TTR secretion that could be therapeutically accessed to improve treatments of TTR-related amyloid diseases.
Comparative genomics of orobanchaceous species with different parasitic lifestyles reveals the origin and stepwise evolution of plant parasitism
Authors: Xu Yuxing , Zhang Jingxiong , Ma Canrong , Lei Yunting , Shen Guojing , Jin Jianjun , Eaton Deren A. R. , Wu Jianqiang
Published: April 2022

Orobanchaceae is the largest family of parasitic plants, containing autotrophic and parasitic plants with all degrees of parasitism. This makes it by far the best family for studying the origin and evolution of plant parasitism. Here we provide three high-quality genomes of orobanchaceous plants, the autotrophic Lindenbergia luchunensis and the holoparasitic plants Phelipanche aegyptiaca and Orobanche cumana. Phylogenomic analysis of these three genomes together with those previously published and the transcriptomes of other orobanchaceous species, created a robust phylogenetic framework for Orobanchaceae. We found that an ancient whole-genome duplication (WGD; about 73.48 Mya), which occurred earlier than the origin of Orobanchaceae, might have contributed to the emergence of parasitism. However, no WGD events occurred in any lineage of orobanchaceous parasites except for Striga after divergence from their autotrophic common ancestor, suggesting that, in contrast to previous speculations, WGD is not associated with the emergence of holoparasitism. We detected evident convergent gene loss in all parasites within Orobanchaceae and between Orobanchaceae and dodder Cuscuta australis. The gene families in the orobanchaceous parasites showed a clear pattern of recent gains and expansions. The expanded gene families are enriched in functions related to the development of the haustorium, suggesting that recent gene family expansions may have facilitated the adaptation of orobanchaceous parasites to different hosts. This study illustrates a stepwise pattern in the evolution of parasitism in the orobanchaceous parasites, and will facilitate future studies on parasitism and the control of parasitic plants in agriculture.
Glossiness perception and its pupillary response
Authors: Tamura Hideki , Nakauchi Shigeki , Minami Tetsuto
Published: April 2022

Recent studies have discovered that pupillary response changes depend on cognitive factors, such as subjective brightness caused by optical illusions and luminance. However, it remains unclear how the cognitive factor derived from the glossiness perception of object surfaces affects pupillary response. We investigated the relationship between glossiness perception and pupillary response through a gloss rating experiment that includes recording pupil diameter. For the stimuli, we prepared general object images (original) and randomized images (shuffled) that comprised of the same images with randomized small square regions. The image features were then controlled by matching the luminance histogram. The observers were asked to rate the perceived glossiness of the stimuli presented for 3,000 ms and changes in their pupil diameter were recorded. Consequently, if glossiness of the original images were rated as high, those of the shuffled were rated as low, and vice versa. High-gloss images constricted the pupil size more than the low-gloss ones near the pupillary light reflex. By contrast, the shuffled images dilated the pupil size more than the original image at a relatively later stage. These results suggest that local features comprising specular highlights involve the cognitive factor for pupil constriction, and this process is faster than pupil dilation derived from the inhibition of object recognition.
Tauroursodeoxycholic acid inhibits Clostridioides difficile toxin induced apoptosis
Authors: Pike Colleen M. , Tam John , Melnyk Roman A. , Theriot Casey M.
Published: April 2022

C. difficile infection (CDI) is a highly inflammatory disease mediated by the production of two large toxins that weaken the intestinal epithelium and cause extensive colonic tissue damage. Antibiotic alternative therapies for CDI are urgently needed as current antibiotic regimens prolong the perturbation of the microbiota and lead to high disease recurrence rates. Inflammation is more closely correlated with CDI severity than bacterial burden, thus therapies that target the host response represent a promising yet unexplored strategy for treating CDI. Intestinal bile acids are key regulators of gut physiology that exert cytoprotective roles in cellular stress, inflammation and barrier integrity, yet the dynamics between bile acids and host cellular processes during CDI have not been investigated. Here we show that several bile acids are protective against apoptosis caused by C. difficile toxins in Caco-2 cells and that protection is dependent on conjugation. Out of 20 tested bile acids, taurine conjugated ursodeoxycholic acid (TUDCA) was the most potent inhibitor yet unconjugated UDCA did not alter toxin-induced apoptosis. TUDCA treatment decreased expression of genes in lysosome associated and cytokine signaling pathways. TUDCA did not affect C. difficile growth or toxin activity in vitro whereas UDCA significantly reduced toxin activity in a Vero cell assay and decreased tcdA gene expression. These results demonstrate that bile acid conjugation can have profound effects on C. difficile as well as the host and that conjugated and unconjugated bile acids may exert different therapeutic mechanisms against CDI.
Acute appendicitis manifests as two microbiome state types with oral pathogens influencing severity
Authors: Blohs Marcus , Mahnert Alexander , Brunnader Kevin , Flucher Christina , Castellani Christoph , Till Holger , Singer Georg , Moissl-Eichinger Christine
Published: April 2022

Mounting evidence suggests that acute appendicitis (AA) is not one but two diseases: complicated appendicitis, which is associated with necrosis leading to perforation or periappendicular abscess, and uncomplicated appendicitis, which does not necessarily result in perforation. Even though AA is the most frequent cause of surgery from abdominal pain, little is known about the origins and etiopathogenesis of this disease, much less regarding the different disease types.

In this study, we investigated the microbiome of samples from the appendix, rectum and peritoneum of 60 children and adolescents with AA to assess the composition and potential function of bacteria, archaea and fungi. The analysis of the appendix microbial community revealed a shift depending on the severity of the AA. This shift was reflected by two major community state types that represented the complicated and uncomplicated cases. We could demonstrate that complicated, but not uncomplicated, appendicitis is associated with a significant local expansion of oral, bacterial pathogens in the appendix, most strongly influenced by necrotizing Fusobacterium spp., Porphyromonas and Parvimonas. Uncomplicated appendicitis, however, was characterised by gut-associated microbiomes. Our findings support the hypothesis that two disease types exist in AA, which cannot be distinguished beyond doubt using standard clinical characterization methods or by analysis of the patient’s rectal microbiome. An advanced microbiome diagnosis, however, could improve non-surgical treatment of uncomplicated AA.

Importance

With a lifetime risk of up to 17%, acute appendicitis is one of the most frequent causes of emergency abdominal surgery in westernized countries. Latest literature reports suggests that appendicitis manifests in two disease types: complicated and uncomplicated appendicitis with different, yet unknown, etiopathogenesis.

In this study, we investigated the microbial composition (bacteria, archaea and fungi) from 60 children and adolescents that were diagnosed with acute appendicitis. Appendix, rectal and peritoneal samples were analysed using amplicon and metagenomic sequencing. Our results suggest that acute appendicitis manifests in three microbial state types that reflect complicated and uncomplicated appendicitis as well as special cases that are caused by bacterial overgrowth. Strikingly, uncomplicated appendicitis appears to be caused by gut-associated pathogens while complicated appendicitis is driven by oral-associated microbes such as Fusobacterium sp. or Porphyromonas sp. The findings provided in our study are of special interest to understand the etiopathogenesis of both complicated and uncomplicated appendicitis.
Hormones do not make the mole-rat: no steroid hormone signatures of subordinate behavioral phenotypes
Authors: Toor Ilapreet , Faykoo-Martinez Mariela , Edwards Phoebe D. , Boonstra Rudy , Holmes Melissa M.
Published: April 2022

In some cooperatively breeding groups, individuals have distinct behavioral characteristics that are often stable and predictable across time. However, in others, like the eusocial naked mole-rat, evidence for behavioral phenotypes is ambiguous. Here, we study whether the naked mole-rat can be divided into discrete phenotypes and if circulating hormone levels underpin these differences. Naked mole-rat colonies consist of a single breeding female and dozens to hundreds of non-reproductive subordinates. The subordinates can potentially be divided into soldiers, who defend the colony; workers, who maintain it; and dispersers, who want to leave it. We established six colonies de novo, tracked them over three years, and assessed the behavior and hormone levels of the subordinates. We found that soldiers tended to be from earlier litters and were higher ranked compared to workers, whereas dispersers were distributed throughout litters and rankings. There was no difference in estradiol, testosterone, or dehydroepiandrosterone (DHEA) levels amongst phenotypes. Progesterone levels were higher in soldiers but this difference appeared to be driven by a few individuals. Principal component analysis demonstrated that soldiers separated into a discrete category relative to workers/dispersers, with the highest ranked loadings being age, weight, and testosterone levels. However, the higher testosterone in soldiers was correlated with large body size instead of strictly behavioral phenotype. Workers and dispersers have more overlap with each other and no hormonal differences. Thus the behavioral variation in subordinate naked mole-rats is likely not driven by circulating steroid hormone levels but rather stems from alternative neural and/or neuroendocrine mechanisms.
Metabolic compatibility and the rarity of prokaryote endosymbioses
Authors: Libby Eric , Kempes Christopher , Okie Jordan
Published: April 2022

The evolution of the mitochondria was a significant event that gave rise to the eukaryotic lineage and most large complex life. Central to the origins of the mitochondria was an endosymbiosis between prokaryotes. Yet, despite the potential benefits that can stem from a prokaryotic endosymbiosis, their modern occurrence is exceptionally rare. While many factors may contribute to their rarity, we lack methods for estimating the extent to which they constrain the appearance of a prokaryotic endosymbiosis. Here, we address this knowledge gap by examining the role of metabolic compatibility between a prokaryotic host and endosymbiont. We use genome-scale metabolic models from three different databases (AGORA, KBase, and CarveMe) to assess the viability, fitness, and adaptability of potential prokaryotic endosymbioses. We find that while more than half of host-endosymbiont pairings are metabolically viable, the resulting endosymbioses have reduced growth rates compared to their ancestral metabolisms and are unlikely to gain mutations to overcome these fitness differences. In spite of these challenges, we do find that they may be more robust in the face of environmental perturbations at least in comparison with the ancestral host metabolism lineages. Our results provide a critical set of null models and expectations for understanding the forces that shape the structure of prokaryotic life.
Redox-controlled structural reorganization and flavin strain within the ribonucleotide reductase R2b-NrdI complex monitored by serial femtosecond crystallography
Authors: John Juliane , Aurelius Oskar , Srinivas Vivek , Kim In-Sik , Bhowmick Asmit , Simon Philipp S. , Dasgupta Medhanjali , Pham Cindy , Gul Sheraz , Sutherlin Kyle D. , Aller Pierre , Butryn Agata , Orville Allen M. , Cheah Mun Hon , Owada Shigeki , Tono Kensuke , Fuller Franklin D. , Batyuk Alexander , Brewster Aaron S. , Sauter Nicholas K. , Yachandra Vittal K. , Yano Junko , Kern Jan , Lebrette Hugo , Högbom Martin
Published: April 2022

Redox reactions are central to biochemistry and are both controlled by and induce protein structural changes. Here we describe structural rearrangements and crosstalk within the Bacillus cereus ribonucleotide reductase R2b-NrdI complex, a di-metal carboxylate- flavoprotein system, as part of the mechanism generating the essential catalytic free radical of the enzyme. Femtosecond crystallography at an X-ray free-electron laser was utilized to obtain structures at room temperature in defined redox states without suffering photoreduction. We show that the flavin in the hydroquinone state is under steric strain in the R2b-NrdI protein complex, presumably tuning its redox potential to promote superoxide generation. Moreover, a binding site in close vicinity to the expected flavin O2-interacton site is observed to be controlled by the redox state of the flavin and linked to the channel proposed to funnel the produced superoxide species from NrdI to the di-manganese site in protein R2b. These specific features are coupled to further structural changes around the R2b- NrdI interaction surface. The mechanistic implications for the control of reactive oxygen species and radical generation in protein R2b are discussed.
A congenital hydrocephalus causing mutation in Trim71 results in stem cell differentiation defects through inhibitingLsd1mRNA translation
Authors: Liu Qiuying , Novak Mariah K. , Pepin Rachel M. , Maschhoff Katharine R. , Chen Xiaoli , Zhang Shaojie , Hu Wenqian
Published: April 2022

Congenital hydrocephalus (CH) is a major cause of childhood morbidity. Mono-allelic mutations in Trim71, a conserved stem-cell-specific RNA-binding protein, cause CH, however, molecular basis for pathogenesis mediated by these mutations remains unknown. Here, using mouse embryonic stem cells as a model, we reveal that the mouse R783H mutation (R796H in human) significantly alters Trim71’s mRNA substrate specificity and leads to accelerated stem-cell differentiation and neural lineage commitment. The mutant Trim71, but not the wild-type Trim71, bindsLsd1 (Kdm1a)mRNA and represses its translation. Specific inhibition of this repression or a slight increase of Lsd1 in the mutant cells alleviates the defects in stem cell differentiation and neural lineage commitment. These results determine a functionally relevant target of the CH-causing Trim71 mutant that can potentially be a therapeutic target and provide molecular mechanistic insights into the pathogenesis of this disease.
ProFeatMap: a customizable tool for 2D feature representation of protein sets
Authors: Bich G. , Monsellier E. , Travé G. , Nominé Y.
Published: April 2022

Here, we present ProFeatMap, an intuitive Python-based website allowing to quickly display protein features such as domains, repeats, post-translational modifications location and so forth, into a highly customizable graphical 2D map. Starting from a user-defined protein list, ProFeatMap automatically extracts the main protein features from the Uniprot database. The resulting high-quality maps can help to gain insights, e.g. feature redundancy, that were previously overlooked but which may be useful for the research project. ProFeatMap is freely accessible on the web at: https://profeatmap.pythonanywhere.com/

Availability

Source code is freely accessible at https://github.com/profeatmap/ProFeatMap under the GPL license.

Contact

bichg@igbmc.fr, yves.nomine@igbmc.fr

Supplementary information

detailed user guide of ProFeatMap
A mitochondrial iron-sensing pathway regulated by DELE1
Authors: Sekine Yusuke , Houston Ryan , Fessler Evelyn , Jae Lucas T , Narendra Derek P , Sekine Shiori
Published: April 2022

The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism is incompletely understood. Here, we show that iron deficiency-induced HRI activation involves a heme-independent mechanism that requires the mitochondrial protein DELE1. Notably, mitochondrial import of DELE1 and its subsequent protein stability are regulated by iron availability. Under steady state conditions, DELE1 is degraded by the mitochondrial matrix-resident protease LONP1 soon after mitochondrial import. Upon iron chelation, DELE1 import is arrested, thereby stabilizing DELE1 on the mitochondrial surface to activate the HRI-mediated integrated stress response (ISR). Moreover, depletion of the mitochondrial ABC transporter ABCB7 that is involved in iron-sulfur cluster (ISC) metabolism markedly abrogates iron deficiency-induced ISR activation, suggesting the possible involvement of ISC-related molecules in this activation. Our findings highlight mitochondrial import regulation of DELE1 as the core component of a previously unrecognized iron monitoring system that connects the mitochondria to the cytosol.