bluuebunny/crossref_metadata_2025 huggingface dataset:
Successful Surgical Resection and Reconstruction of a Giant Facial Vascular Malformation in an Elderly Patient
Authors: Horta Ricardo , Frias Francisca , Barreiro Diogo , Jarnalo Mariana , Santos Pedro
Published: August 2022

Venous vascular malformations can be challenging, especially in an elderly patient. As these lesions can present with ulceration, deformity, pain, and swelling resulting from thrombi formed due to low flow (palpable phleboliths), removing them can be important for the well-being of the patient. A 79-year-old patient presented with a giant venous malformations occupying the left hemiface and a deprivation amblyopia in his left eye. Successful surgical resection and reconstruction was achieved and the patient was very pleased with his new appearance. Despite his age and surgical risks, we consider that never is late to improve a disfigured face.
Stop the Smudge: A Novel Solution to Loss of Vision During Laparoscopic Colorectal Surgery
Authors: Ozgur Ilker , Liska David , Valente Michael A. , Steele Scott R. , Gorgun Emre
Published: August 2022

Background:

An obscured vision of surgical field during laparoscopic surgery is inconvenient. Several temporary methods were described as solutions to loss of vision, and common practice is scope removal, cleaning, and heating. A lately developed and introduced device claims continuous clear vision during laparoscopic surgery. This study aims to present our initial experience with the device during laparoscopic colorectal surgery.

Materials and Methods:

We have included medical records of all patients scheduled for laparoscopic colorectal surgery with the device between March and August 2021 at Cleveland Clinic. Patient demographics, surgery type and time, the number of loss of vision events were recorded.

Results:

Fifteen patients underwent laparoscopic colorectal surgery during the study period. The median age was 42 (range: 25 to 86) years, and 10 (66%) were female. The median surgery time was 127 (range: 67 to 240) minutes, and the median loss of vision event number was 3 (1 to 6) per surgery. There was no need for laparoscope removal during any of the surgeries. All surgeries were completed without any intraoperative complications.

Conclusion:

The novel system, provides clear vision during laparoscopic colorectal surgery with no need of scope removal for loss of vision events. The system provides removal of particulate gathering on the tip of the scope.
Bergenin has neuroprotective effects in mice with ischemic stroke through antioxidative stress and anti-inflammation via regulating Sirt1/FOXO3a/NF-κB signaling
Authors: Zhang Xuemei , Zhang Fang , Yao Fenfen , Wang Peng , Xiong Qun , Neng Penghui
Published: September 2022

Objective

Bergenin (BGN) is a C-glycoside of 4-O-methylgallic acid with anti-inflammatory, antioxidant, and tissue-repairing abilities. Here, we probed the roles and mechanisms of BGN in ischemic stroke-mediated cerebral injury.

Methods

The middle cerebral artery occlusion (MCAO) model was established in mice, which were injected intraperitoneally with varying concentrations of BGN (10, 20, and 40 mg/kg). The modified neurological severity score (mNSS) and the water maze experiment were adopted to evaluate mice’s neural functions (movement and memory). The brain edema was assessed by the dry and wet method. TdT-mediated dUTP nick end labeling (TUNEL)-labeled apoptotic neurons and Iba1-labeled microglia in the cortex were measured by immunohistochemistry (IHC). Quantitative reverse transcription-PCR and ELISA were implemented to determine the expression of inflammatory cytokines (TNFα, IL-1β, and IL-6), neurotrophic factors (BDNF and VEGF), and oxidative stress factors (SOD and MDA) in brain tissues. The profiles of Sirt1, FOXO3a, Nrf2, NF-κB, and STAT6 in brain tissues were checked by western blot.

Results

BGN significantly improved MCAO mice’s cognitive, learning, and motor functions, reduced brain edema, hampered the production of inflammatory factors and oxidative stress mediators, and suppressed neuronal apoptosis. Additionally, BGN dampened the expression of proinflammatory cytokines and upregulated neurotrophic factors and oxidative stress factors in ischemic brain tissues of MCAO mice. Meanwhile, BGN reduced the expression of inflammatory cytokines and oxidative stressors in oxygen-glucose deprivation/reoxygenation-induced BV2 microglia. Further mechanistic studies revealed that BGN concentration dependently elevated the profiles of Sirt1, FOXO3a, STAT6, and Nrf2, and abated the NF-κB phosphorylation.

Conclusion

BGN protects against ischemic stroke in mice by boosting the Sirt1/FOXO3a pathway, suggesting its potential as a therapeutic agent for ischemic stroke.
Development and testing of a polygenic risk score for breast cancer aggressiveness
Authors: Shieh Yiwey , Roger Jacquelyn , Yau Christina , Wolf Denise M. , Hirst Gillian L. , Swigart Lamorna Brown , Huntsman Scott , Hu Donglei , Nierenberg Jovia L. , Middha Pooja , Heise Rachel S. , Shi Yushu , Kachuri Linda , Zhu Qianqian , Yao Song , Ambrosone Christine B. , Kwan Marilyn L. , Caan Bette J. , Witte John S. , Kushi Lawrence H. , van ‘T Veer Laura , Esserman Laura J. , Ziv Elad
Published: September 2022

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a novel PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2,363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2in 10-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS’s association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.05-1.21, p=0.001). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+).Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used a novel approach based on integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.
A Joint Compartmental Model for The Co-infection of SARS-CoV-2 and Influenza
Authors: Zafarnejad Reyhaneh , Griffin Paul M. , Ventresca Mario
Published: September 2022

Co-infection of COVID-19 and other respiratory pathogens, including influenza virus family, has been of importance since the beginning of the recent pandemic. As the upcoming flu season arrives in countries with ongoing COVID-19 epidemic, the need for preventive policy actions becomes more critical. We present a joint compartmental SEIRS-SIRS model for the co-circulation of SARS-CoV-2 and influenza and discuss the characteristics of the model, such as the basic reproduction number (R0) and cases of death and recovery. We implemented the model using 2020 to early 2021 data derived from global healthcare organizations and studied the impact of interventions and policy actions such as vaccination, quarantine, and public education. The VENSIM simulation of the model resulted in R0 = 7.5, which is higher than what was reported for the COVID-19 pandemic. Vaccination against COVID-19 dramatically slowed its spread and the co-infection of both diseases significantly, while other types of interventions had a limited impact on the co-dynamics of the diseases given our assumptions. These findings can help provide guidance as to which preventive policies would be most effective at the time of concurrent epidemics, and contributes to the literature as a novel model to simulate and analyze the co-circulation of respiratory pathogens in a compartmental setting that can further be used to study the co-infection of COVID-19 or similar respiratory infections with other diseases.
FairPRS: a fairness framework for Polygenic Risk Scores
Authors: Reyes Diego Machado , Bose Aritra , Karavani Ehud , Parida Laxmi
Published: September 2022

Polygenic risk scores (PRS) are increasingly used to estimate the personal risk of a trait based on genetics. However, most genomic cohorts are of European populations, with strong under-representative of multi-ethnic minority groups. Given that PRS poorly transport across racial groups, this has the potential exacerbate health disparities if used in clinical care. Hence there is a need to generate PRS that perform comparably across ethnic groups. Borrowing recent advancements in the domain adaption field of machine learning, we propose FairPRS - an Invariant Risk Minimization (IRM) approach for estimating fair PRS or debiasing pre-computed ones. We test our method on both a diverse set of synthetic data and real data form the UK Biobank. We show our method can create ancestry-invariant PRS distributions that are both racially unbiased and largely improve phenotype prediction. We hope that fair PRS will contribute to fairer characterization of patients by genetics rather than by race.
Social health and change in cognitive capability among older adults: findings from four European longitudinal studies
Authors: Maddock Jane , Gallo Federico , Wolters Frank J , Stafford Jean , Marseglia Anna , Dekhtyar Serhiy , Lenart-Bugla Marta , Verspoor Eline , Perry Marieke , Samtani Suraj , Vernooij-Dassen Myrra , Wolf-Ostermann Karin , Melis Rene , Brodaty Henry , Ikram Mohammad Arfan , Welmer Anna-Karin , Davis Daniel , Ploubidis George B , Richards Marcus , Patalay Praveetha
Published: September 2022

Introduction

In this study we examine whether social health markers measured at baseline are associated with differences in cognitive capability and in the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies.

Methods

We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline.

Results

Pooled estimates show distinct relationships between markers of social health and cognitive domains e.g., a large network size (≥6 people vs none) was associated with higher executive function (0.17 SD[95%CI:0.0, 0.34], I2=27%) but not with memory (0.08 SD[95%CI: -0.02, 0.18], I2=19%). We also observed pooled associations between being married or cohabiting, having a large network size and participating in social activities with slower decline in cognitive capability, however estimates were close to zero e.g., 0.01SD/year [95%CI: 0.01 to 0.02] I2=19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous and results for average memory were the most heterogenous.

Conclusion

Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between study differences and considering context specificity of findings in developing and deploying any interventions.
Persistence of Pulmonary Hypertension in Patients undergoing Ventricular Assist Devices and Orthotopic Heart Transplantation
Authors: Rajaratnam Arun , El-Swais Ameen , McTiernan Charles , Thoma Floyd W. , Baghal Moaaz O. , Raffensperger Kristen , Chang Chung-Chou H. , Hickey Gavin W. , Shah Faraaz A. , Ghouleh Imad Al
Published: September 2022

Background

Pulmonary hypertension (PH) is common in advanced heart failure which exhibits short-term improvement after left ventricular assist device (VAD) implantation or orthotopic heart transplantation (OHT), but long-term effects remain unknown. This study evaluated PH persistence after VAD as destination therapy (VAD-DT), bridge to transplant (VAD-BTT), or OHT-alone.

Methods

A retrospective review of patients who underwent VAD-DT (n=164), VAD-BTT (n=111), or OHT-alone (n= 138) at a single tertiary-care center. Right heart catheterization (RHC) data was collected pre-, post-intervention (VAD and/or OHT), and 1-year from final intervention (latest-RHC) to evaluate the longitudinal hemodynamic course of right ventricular (RV) function and PH. PH (Group-II and Group-I) definitions were adapted from expert guidelines.

Results

All groups showed significant improvements in mean pulmonary artery pressure (mPAP), pulmonary artery wedge pressure (PAWP), cardiac output (CO), and pulmonary vascular resistance (PVR) at each RHC with greatest improvement at post-intervention RHC (Post-VAD or Post-OHT). PH proportion reduced from 98% to 26% in VAD-BTT, 92% to 49% VAD-DT, and 76% to 28% from pre-intervention to latest-RHC. At latest-RHC mPAP remained elevated in all groups despite normalization of PAWP and PVR. VAD-supported patients exhibited suppressed pulmonary artery pulsatility index (PaPi< 3.7) with improvement only post-transplant at latest-RHC alongside improved right atrial pressures (RAP). Furthermore, post-transplant with PH at latest-RHC (n=60) exhibited lower survival (HR: 2.1 [95%CI: 1.3-3.4], p<0.001).

Conclusion

Despite an overall significant improvement in pulmonary pressures and PH proportion, a notable subset of patients exhibited residual RV derangements and PH persistence post-intervention. This post-intervention PH impacted post-transplant survival.

Condensed Abstract

This study evaluates the longitudinal hemodynamic course of right ventricular (RV) function associated with heart-failure-related Pulmonary Hypertension (PH) and the impact of advanced interventions such as ventricular assist device and/or orthotopic heart transplant on PH persistence. Patients undergoing advanced interventions exhibit differences in PH prevalence which are dependent on the intervention received. Our results highlight despite an overall improvement in pulmonary pressures and PH, a notable number of patients exhibit RV dysfunction consistent with persistent PH. Furthermore, the persistence of PH after successful cardiac transplantation in a subset of patients continues to impact mortality in the long-term.
Alcohol Intake Differentiates AD and LATE: A Telltale Lifestyle from Two Large-Scale Datasets
Authors: Wu Xinxing , Peng Chong , Nelson Peter T. , Cheng Qiang
Published: September 2022

Alzheimer’s disease (AD), as a progressive brain disease, affects cognition, memory, and behavior. Similarly, limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently defined common neurodegenerative disease that mimics the clinical symptoms of AD. At present, the risk factors implicated in LATE and those distinguishing LATE from AD are largely unknown. We leveraged an integrated feature selection-based algorithmic approach, to identify important factors differentiating subjects with LATE and/or AD from Control on significantly imbalanced data. We analyzed two datasets ROSMAP and NACC and discovered that alcohol consumption was a top lifestyle and environmental factor linked with LATE and AD and their associations were differential. In particular, we identified a specific subpopulation consisting of APOE e4 carriers. We found that, for this subpopulation, light-to-moderate alcohol intake was a protective factor against both AD and LATE, but its protective role against AD appeared stronger than LATE. The codes for our algorithms are available at https://github.com/xinxingwu-uk/PFV.
Folate receptor targeted nanoparticles containing niraparib and doxorubicin for treatment of high grade serous ovarian cancer
Authors: Wang Lucy , Evans James C. , Ahmed Lubabah , Allen Christine
Published: September 2022

Combination chemotherapy is an established approach used to manage toxicities while eliciting an enhanced therapeutic response. Delivery of combinations of drugs in specific molar ratios has been considered a means to achieve synergistic effects resulting in improvements in efficacy while minimizing dose related adverse drug reactions.

The benefits of this approach have been realized with the FDA approval of Vyxeos®, the first liposome formulation to deliver a synergistic drug combination leading to improved overall survival against standard of care. In the current study, we demonstrate the synergistic potential of the PARP inhibitor niraparib and doxorubicin for the treatment of ovarian cancer. Through in vitro screening in a panel of ovarian cancer cell lines, we find that niraparib and doxorubicin demonstrate consistent synergy/additivity at the majority of evaluated molar ratio combinations.

Further to these findings, we report formulation of a nanoparticle encapsulating our identified synergistic combination. We describe a rational design process to achieve highly stable liposomes that are targeted with folate to folate-receptor-alpha, which is known to be overexpressed on the surface of ovarian cancer cells. With this approach, we aim to achieve targeted delivery of niraparib and doxorubicin at a pre-determined synergistic molar ratio via increased receptor-mediated endocytosis.

Graphical Abstract
Digital system augmented by artificial intelligence to interpret bone marrow samples for hematological disease diagnosis
Authors: Bermejo-Peláez David , Charro Sandra Rueda , Roa María García , Trelles-Martínez Roberto , Bobes-Fernández Alejandro , Soto Marta Hidalgo , García-Vicente Roberto , Morales María Luz , Rodríguez-García Alba , Ortiz-Ruiz Alejandra , Sánchez Alberto Blanco , Urbina Adriana Mousa , Álamo Elisa , Lin Lin , Dacal Elena , Cuadrado Daniel , Postigo María , Vladimirov Alexander , Garcia-Villena Jaime , Santos Andrés , Ledesma-Carbayo Maria Jesús , Díaz Rosa Ayala , Martínez-López Joaquín , Linares María , Luengo-Oroz Miguel
Published: September 2022

Analysis of bone marrow aspirates (BMA) is an essential step in the diagnosis of hematological disorders. This analysis is usually performed based on visual examination of the samples under a conventional optical microscope, which involves a labor-intensive process, limited by clinical experience and subject to high observer variability. In this work, we present a comprehensive digital system that enables BMA analysis for cell type counting and differentiation in an efficient and objective manner. This system not only provides an accessible and simple method to digitize, store and analyze BMA samples remotely, but is also supported by an artificial intelligence (AI) pipeline that accelerates the differential cell counting (DCC) process and reduces inter-observer variability. It has been designed to integrate AI algorithms with the daily clinical routine and can be used in any regular hospital workflow.
Structural basis for antagonism of the ubiquitin ligase BIRC6 by SMAC
Authors: Dietz Larissa , Ellison Cara J. , Riechmann Carlos , Cassidy C. Keith , Felfoldi F. Daniel , Pinto-Fernández Adán , Kessler Benedikt M. , Elliott Paul R.
Published: September 2022

Apoptosis, a form of genetically programmed cell death, can be triggered by either internal or external signals ultimately activating caspases, a family of proteases1. Certain members of the inhibitors of apoptosis (IAP) family are sentinel proteins preventing untimely cell death by inhibiting caspases. IAPs are in turn regulated by antagonists including second mitochondria-derived activator of caspase (SMAC). Baculoviral IAP repeat-containing protein 6 (BIRC6), a giant IAP, possesses dual E2/E3 ubiquitin ligase activity and is implicated in apoptosis via caspase inhibition2–7. How this is achieved remains unknown. Here we show BIRC6 directly restricts activated caspase-3, and ubiquitinates activated caspases-3, −7 and −9 working exclusively with the non-canonical E1, UBA6. Importantly, we show SMAC supresses both mechanisms. Cryo-electron microscopy (cryo-EM) structures of BIRC6 alone and in complex with SMAC reveal BIRC6 exists as an anti-parallel dimer with a substrate-binding module juxtaposed to the catalytic domain at each end, and we identify multiple highly conserved unannotated domains important for architecture and function. Through our structural, biochemical and biophysical findings, we discover SMAC engages BIRC6 at multiple sites resulting in a sub-nanomolar affinity enabling SMAC to competitively displace caspases, thus antagonising BIRC6-mediated caspase inhibition.
Asymmetric horseshoe-like assembly of peroxisomal Yeast Oxalyl-CoA synthetase
Authors: Bürgi Jérôme , Lill Pascal , Giannopoulou Evdokia-Anastasia , Jeffries Cy M. , Chojnowski Grzegorz , Raunser Stefan , Gatsogiannis Christos , Wilmanns Matthias
Published: September 2022

Oxalyl-CoA synthetase from Saccharomyces cerevisiae is one of the most abundant peroxisomal protein in yeast and hence has become a model to study peroxisomal translocation. It contains a C-terminal Peroxisome Targeting Signal 1, which however is partly dispensable, suggesting additional receptor bindings sites. To unravel any additional features that may contribute to its capacity to be recognized as peroxisomal target, we determined its assembly and overall architecture by an integrated structural biology approach, including X-ray crystallography, single particle cryo-electron microscopy and small angle X-ray scattering. Surprisingly, it assembles into mixture of concentration-dependent dimers, tetramers and hexamers by dimer self-association. Hexameric particles form an unprecedented asymmetric horseshoe-like arrangement, which considerably differs from symmetric hexameric assembly found in many other protein structures. A single mutation within the self-association interface is sufficient to abolish any higher-level oligomerization, resulting in homogenous dimeric assembly. The small C-terminal domain of yeast Oxalyl-CoA synthetase is connected by a partly flexible hinge with the large N-terminal domain, which provides the sole basis for oligomeric assembly. Our data provide a basis to mechanistically study peroxisomal translocation of this target.
A Bayesian approach to estimate the probability of resistance to bedaquiline in the presence of a genomic variant
Authors: Anlay Degefaye Zelalem , Rivière Emmanuel , Trang Tu Pham Hien , Abrams Steven , Van Rie Annelies
Published: August 2022

Background

Bedaquiline is a core drug for treatment of rifampicin-resistant tuberculosis. Few genomic variants have been statistically associated with bedaquiline resistance. Alternative approaches for determining the genotypic-phenotypic association are needed to guide clinical care.

Methods

Using published phenotype data for variants inRv0678, atpE, pepQandRv1979cgenes in 756Mycobacterium tuberculosisisolates and survey data of the opinion of 33 experts, we applied Bayesian methods to estimate the posterior probability of bedaquiline resistance and corresponding 95% credible intervals.

Results

Experts agreed on the role ofRv0678, andatpE, were uncertain about the role ofpepQandRv1979cvariants and overestimated the probability of bedaquiline resistance for most variant types, resulting in lower posterior probabilities compared to prior estimates. The posterior median probability of bedaquiline resistance was low for synonymous mutations inatpE(0.1%) andRv0678(3.3%), high for missense mutations inatpE(60.8%) and nonsense mutations inRv0678(55.1%), relatively low for missense (31.5%) mutations and frameshift (30.0%) inRv0678and low for missense mutations inpepQ(2.6%) andRv1979c(2.9%), but 95% credible intervals were wide.

Conclusions

Bayesian probability estimates of bedaquiline resistance given the presence of a specific mutation could be useful for clinical decision-making as it presents interpretable probabilities compared to standard odds ratios. For a newly emerging variant, the probability of resistance for the variant type and gene can still be used to guide clinical decision-making. Future studies should investigate the feasibility of using Bayesian probabilities for bedaquiline resistance in clinical practice.
NF-κB Decoy ODN-Loaded Poly lactic-co-glycolic Acid Nanospheres Inhibit Alveolar Ridge Resorption
Authors: Huang Albert Chun Shuo , Ishida Yuji , Li Kai , Rintanalert Duantawan , Hatano-sato Kasumi , Oishi Shuji , Hosomichi Jun , Usumi-Fujita Risa , Yamaguchi Hiroyuki , Tsujimoto Hiroyuki , Sasai Aiko , Ochi Ayaka , Watanabe Hajime , Ono Takashi
Published: September 2022

Residual ridge resorption combined with dimensional loss resulting from tooth extraction has a prolonged correlation with early excessive inflammation. Nuclear factor-kappa B (NF-κB) decoy oligodeoxynucleotide (ODN) is a member of a group of double-stranded DNA capable of downregulating the expression of downstream genes of the NF-κB pathway. The healing action of its embellished effect combined with poly(lactic-co-glycolic acid) (PLGA) nanospheres on tooth extraction socket still remains unknown. Hence, the aim of this study was to investigate the therapeutic effect of NF-κB decoy ODN-loaded PLGA nanospheres (PLGA-NfD) transfected into extraction sockets in Wistar/ST rats. Micro-computed tomography and trabecular bone analysis following treatment with PLGA-NfD demonstrated inhibition of vertical alveolar bone loss with increased bone volume, smoother trabecular bone surface, thicker trabecular bone, larger trabecular number and separation, and fewer bone porosities. Histomorphometric and reverse transcription-quantitative polymerase chain reaction analysis revealed reduced tartrate-resistant acid phosphatase-expressing osteoclasts, interleukin-1β, tumor necrosis factor-α, receptor activator of NF-κB ligand, turnover rate and increased transforming growth factor-β1 immunopositive reactions and relative gene expressions. These data demonstrate that local delivery of PLGA-NfD could be used as a substantial suppressor of inflammation during the healing process in a tooth extraction socket, with the potential of accelerated new bone formation.
Honeybees vary communication and collective decision making across landscapes
Authors: Palmer Joseph , Samuelson Ash E. , Gill Richard J. , Leadbeater Ellouise , Jansen Vincent A.A.
Published: September 2022

Honeybee (Apis mellifera) colony foraging decisions arise from the waggle dances of individual foragers, processed and filtered through a series of feedback loops that produce emergent collective behaviour. This process is an example of animal communication at the height of eusociality, yet a growing body of evidence suggests that its value for colony foraging success is heavily dependent on local ecology. Although colonies are thought to vary their use of the waggle dance in response to local ecological conditions, this is yet to be empirically established. Here, we quantify waggle dance use based on colony level dance-decoding and show that the impact of dance use on collective foraging is clear in some colonies but nearly negligible in others. We outline how these estimates of dance use can be combined with land-use data to explore the landscape characteristics that drive collective foraging. Our methodology provides a means to quantify the real-world importance of a celebrated example of animal communication and opens the door to the exploration of the selection pressures that may have driven the evolution of this remarkable collective behaviour.
Kmer-Node2Vec: a Fast and Efficient Method for Kmer Embedding from the Kmer Co-occurrence Graph, with Applications to DNA Sequences
Authors: Yu Zhaochong , Yang Zihang , Lan Qingyang , Wang Yuchuan , Huang Feijuan , Cai Yuanzhe
Published: September 2022

Learning low-dimensional continuous vector representation for short k-mers divided from long DNA sequences is key to DNA sequence modeling that can be utilized in many bioinformatics investigations, such as DNA sequence classification and retrieval. DNA2Vec is the most widely used method for DNA sequence embedding. However, it poorly scales to large data sets due to its extremely long training time in kmer embedding. In this paper, we propose a novel efficient graph-based kmer embedding method, named Kmer-Node2Vec, to tackle this concern. Our method converts the large DNA corpus into one kmer co-occurrence graph and extracts kmer relation on the graph by random walks to learn fast and high-quality kmer embedding. Extensive experiments show that our method is faster than DNA2Vec by 29 times for training on a 4GB data set, and on par with DNA2Vec in terms of task-specific accuracy of sequence retrieval and classification.
HADEG: A Curated Hydrocarbon Aerobic Degradation Enzymes and Genes Database
Authors: Rojas-Vargas Jorge , Castelán-Sánchez Hugo G. , Pardo-López Liliana
Published: September 2022

Databases of genes and enzymes involved in hydrocarbon degradation have been previously reported. However, these databases specialize on only a specific group of hydrocarbons and/or are constructed partly based on enzyme sequences with putative functions indicated byin silicoresearch, with no experimental evidence. Here, we present a curated database of Hydrocarbon Aerobic Degradation Enzymes and Genes (HADEG) containing proteins and genes involved in alkane, alkene, aromatic, and plastic aerobic degradation and biosurfactant production based solely on experimental evidence, which are present in bacteria, and fungi. HADEG includes 259 proteins for petroleum hydrocarbon degradation, 160 for plastic degradation, and 32 for biosurfactant production. This database will help identify and predict hydrocarbon degradation genes/pathways and biosurfactant production in genomes.

Graphical abstract

Data summary

The HADEG database repository ishttps://github.com/jarojasva/HADEG. All Supplementary Material file is available on:https://figshare.com/articles/dataset/Supplementary_Material_HADEG/20752642.
The cancer-associated RBM39 bridges the pre-mRNA, U1 and U2 snRNPs to regulate alternative splicing
Authors: Campagne Sébastien , Jutzi Daniel , Malard Florian , Matoga Maja , Romane Ksenija , Feldmuller Miki , Colombo Martino , Ruepp Marc-David , Allain Frédéric H-T.
Published: August 2022

Pharmacologic depletion of RNA-binding motif 39 (RBM39) using aryl sulfonamides represents a promising anti-cancer therapy. However, its efficiency correlates with the expression level of DCAF15 which acts at the interface between RBM39, the drug and the E3-ubiquitin ligase. Consequently, the identification of alternative approaches to deplete RBM39 independently of DCAF15 is required. Here, we combined transcriptomic analysis, functional assays, and structural biology to elucidate the molecular mechanisms governing RBM39 homeostasis. Our data revealed that RBM39 autoregulates the splicing of its own pre-mRNA by triggering the inclusion of a poison exon. During this process, RBM39 selects the 3’-splice site of the toxic exon, helps the recruitment of U1 snRNP on its weak 5’-splice site and bridges the 3’-splice site recognition machinery. The elucidation of the molecular mechanisms controlling RBM39 homeostasis provides unprecedented insights into alternative 3’-splice site selection and a solid frame to design alternative anti-cancer therapies.
Chitosan diet alters the microbiome of adult house flies
Authors: Schaal Hila , Choudoir Mallory J. , Diwanji Vedang , Stoffolano John , DeAngelis Kristen M.
Published: September 2022

House flies are disease vectors, carrying human pathogens which include Escherichia coli and Vibrio cholera. To explore the use of chitosan as a bioinsecticide, we evaluated the effects of a chitosan-amended diet on Musca domestica (house fly). We first conducted longevity experiments to understand the impact of chitosan on house fly longevity. We confirmed that chitosan diet amendment is associated with reduced longevity and that this is not due to starvation. We then extracted fly microbiome DNA and used 16S ribosomal RNA gene amplicon sequencing and quantitative PCR to assess the composition and load of the microbiome for flies fed chitosan-amended diets compared to controls. Diversity of the chitosan-fed fly microbiomes was lower than the control, with significant dissimilarities in community composition. Chitosan-fed flies showed lower Ralstonia relative abundance but increased relative abundance of Serratia. Both control and chitosan-fed flies had highly uneven communities, but the control flies were dominated by genera Ralstonia and Providencia, while the chitosan-fed flies were dominated by genera Serratia, Kosakonia, and Providencia. Contrary to our expected results, chitosan-fed flies also contained 56% more bacteria compared to controls. Gut microbiome changes appear to result from chitinolytic bacteria becoming more relatively abundant, and our results suggest that chitosan-amended diet alters the house fly microbiome resulting in higher fly mortality.
Plasmodium falciparum CRK4 links early mitotic events to the onset of S-phase during schizogony
Authors: Machado Marta , Klaus Severina , Klaschka Darius , Guizetti Julien , Ganter Markus
Published: September 2022

Plasmodium falciparum proliferates through schizogony in the clinically relevant blood stage of infection. During schizogony, consecutive rounds of DNA replication and nuclear division give rise to multinucleated stages before cellularization occurs. Although these nuclei reside in a shared cytoplasm, DNA replication and nuclear division occur asynchronously. Here, by mapping the proteomic context of the S-phase-promoting kinase PfCRK4, we show that it has a dual role for nuclear-cycle progression: PfCRK4 orchestrates not only DNA replication, but also the rearrangement of intranuclear microtubules. Live-cell imaging of a reporter parasite showed that these microtubule rearrangements coincide with the onset of DNA replication. Together, our data render PfCRK4 the key factor for nuclear-cycle progression, linking entry into S-phase with the initiation of mitotic events. In part, such links may compensate for the absence of canonical cell cycle checkpoints in P. falciparum.
BNIP3L-mediated mitophagy triggered by Brucella in host cells is required for bacterial egress
Authors: Verbeke Jérémy , Fayt Youri , Martin Lisa , Yilmaz Oya , Sedzicki Jaroslaw , Reboul Angeline , Jadot Michel , Renard Patricia , Dehio Christoph , Renard Henri-François , Letesson Jean-Jacques , De Bolle Xavier , Arnould Thierry
Published: September 2022

The facultative intracellular pathogen Brucella abortus interacts with several organelles of the host cell to reach its replicative niche inside the endoplasmic reticulum. However, little is known about the interplay between the bacteria and the host cell mitochondria. Here, we showed that B. abortus triggers a strong mitochondrial network fragmentation accompanied by mitophagy and the formation of mitochondrial Brucella-containing vacuoles in the late steps of cellular infection. The expression of the mitophagy receptor BNIP3L induced by B. abortus is essential for these events and relies on the iron-dependent stabilization of the hypoxia-inducible factor 1 alpha. Functionally, BNIP3L-mediated mitophagy appears to be advantageous for bacterial exit of the host cell as BNIP3L depletion drastically reduced the number of reinfection events. Altogether, these findings highlight the intricate link between Brucella trafficking and the mitochondria during host cell infection.
Mapping mitonuclear epistasis using a novel recombinant yeast population
Authors: Nguyen Tuc H.M. , Tinz-Burdick Austen , Lenhardt Meghan , Geertz Margaret , Ramirez Franchesca , Schwartz Mark , Toledano Michael , Bonney Brooke , Gaebler Benjamin , Liu Weiwei , Wolters John F. , Chiu Ken , Fiumera Anthony C. , Fiumera Heather L.
Published: September 2022

Natural genetic variation in mitochondrial and nuclear genomes can influence phenotypes by perturbing coadapted mitonuclear interactions. Mitonuclear epistasis, i.e. non-additive phenotype effects of interacting mitochondrial and nuclear alleles, is emerging as a general feature in eukaryotes, yet very few mitonuclear loci have been identified. Here, we present a novel advanced intercrossed population of S. cerevisiae yeasts, called the Mitonuclear Recombinant Collection (MNRC), designed explicitly for detecting mitonuclear loci contributing to complex traits, and use this population to map the genetic basis to mtDNA loss. In yeast, spontaneous deletions within mtDNAs lead to the petite phenotype that heralded mitochondrial research. We show that in natural populations, rates of petite formation are variable and influenced by genetic variation in nuclear, mtDNAs and mitonuclear interactions. We then mapped nuclear and mitonuclear alleles contributing mtDNA stability using the MNRC by integrating mitonuclear epistasis into a genome-wide association model. We found that associated mitonuclear loci play roles in mitotic growth most likely responding to retrograde signals from mitochondria, while associated nuclear loci with main effects are involved in genome replication. We observed a positive correlation between growth rates and petite frequencies, suggesting a fitness tradeoff between mitotic growth and mtDNA stability. We also found that mtDNA stability was influenced by a mobile mitochondrial GC-cluster that is expanding in certain populations of yeast and that selection for nuclear alleles that stabilize mtDNA may be rapidly occurring. The MNRC provides a powerful tool for identifying mitonuclear interacting loci that will help us to better understand genotype-phenotype relationships and coevolutionary trajectories.

Author Summary

Genetic variation in mitochondrial and nuclear genomes can perturb mitonuclear interactions and lead to phenotypic differences between individuals and populations. Despite their importance to most complex traits, it has been difficult to identify the interacting loci. Here, we created a novel population of yeast designed explicitly for mapping mitonuclear loci contributing to complex traits and used this population to map genes influencing the stability of mitochondrial DNA (mtDNA). We found that mitonuclear interacting loci were involved in mitotic growth while non-interacting loci were involved in genome replication. We also found evidence that selection for mitonuclear loci that stabilize mtDNAs occurs rapidly. This work provides insight into mechanisms underlying maintenance of mtDNAs. The mapping population presented here is an important new resource that will help to understand genotype/phenotype relationships and coevolutionary trajectories.
Transcriptional response of circadian clock genes to an ‘artificial light at night’ pulse in the cricketGryllus bimaculatus
Authors: Levy Keren , Fishman Bettina , Barnea Anat , Ayali Amir , Tauber Eran
Published: September 2022

Light is the major signal entraining the circadian clock that regulates physiological and behavioral rhythms in most organisms, including insects. Artificial Light at Night (ALAN) disrupts the natural light-dark cycle and negatively impacts animals at various levels. We simulated ALAN using dim light stimuli and tested their impact on gene expression in the cricketGryllus bimaculatus, a model of insect physiology and chronobiology. At night, adult LD crickets were exposed for 30 minutes to a light pulse of 2-40 lx. The relative expression of five circadian clock associated genes was compared using qPCR. A dim ALAN pulse elicited tissue-dependent differential expression in some of these genes. The strongest effect was observed in the brain and in the optic lobe, the cricket’s circadian pacemaker. Expression ofopsin-Long Wave(opLW)was upregulated, as well ascryptochrome1-2 (cry), andperiod(per). Our findings demonstrate that even a dim ALAN exposure may affect insects at the molecular level, underscoring the detrimental impact of ALAN on the circadian clock system.
Genetic control of RNA editing in Neurodegenerative disease
Authors: Wu Sijia , Xue Qiuping , Yang Mengyuan , Wang Yanfei , Kim Pora , Zhou Xiaobo , Huang Liyu
Published: September 2022

A-to-I RNA editing diversifies human transcriptome to confer its functional effects on the downstream genes or regulations, potentially involving in neurodegenerative pathogenesis. Its variabilities are attributed to multiple regulators, including the key factor of genetic variant. To comprehensively investigate the potentials of neurodegenerative disease-susceptibility variants from the view of A-to-I RNA editing, we analyzed matched genetic and transcriptomic data of 1,596 samples across nine brain tissues and whole blood from two large consortiums, Accelerating Medicines Partnership - Alzheimer’s Disease (AMP-AD) and Parkinson’s Progression Markers Initiative (PPMI). The large-scale and genome-wide identification of 95,637 RNA editing quantitative trait loci revealed the preferred genetic effects on adjacent editing events. Furthermore, to explore the underlying mechanisms of the genetic controls of A-to-I RNA editing, several top RNA binding proteins were pointed out, such as EIF4A3, U2AF2, NOP58, FBL, NOP56, and DHX9, since their regulations on multiple RNA editing events probably interfered by these genetic variants. Moreover, these variants may also contribute to the variability of other molecular phenotypes associated with RNA editing, including the functions of four proteins, expressions of 148 genes, and splicing of 417 events. All the analyses results shown in NeuroEdQTL (https://relab.xidian.edu.cn/NeuroEdQTL/) constituted a unique resource for the understanding of neurodegenerative pathogenesis from genotypes to phenotypes related to A-to-I RNA editing.
Physical association of low density lipoprotein particles and extracellular vesicles unveiled by single particle analysis
Authors: Lozano-Andrés Estefanía , Enciso-Martinez Agustin , Gijsbers Abril , Libregts Sten F.W.M. , Pinheiro Cláudio , Van Niel Guillaume , Hendrix An , Peters Peter J. , Otto Cees , Arkesteijn Ger J.A. , Wauben Marca H.M.
Published: September 2022

Extracellular vesicles (EVs) in blood plasma are recognized as potential biomarkers for disease. Although blood plasma is easily obtainable, analysis of EVs at the single particle level is still challenging due to the biological complexity of this body fluid. Besides EVs, plasma contains different types of lipoproteins particles (LPPs), that outnumber EVs by orders of magnitude and which partially overlap in biophysical properties such as size, density and molecular makeup. Consequently, during EV isolation LPPs are often co-isolated. Furthermore, physical EV-LPP complexes have been observed in purified EV preparations. Since co-isolation or association of LPPs can impact single EV-based analysis and biomarker profiling, we investigated whether under physiological conditions LPPs and EVs can associate by using cryo-electron tomography, label-free synchronous Rayleigh and Raman scattering analysis of optically trapped particles and fluorescence-based high resolution single particle flow cytometric analysis. Furthermore, we evaluated the impact on flow cytometric analysis in the absence or presence of different types of LPPs usingin vitrospike-in experiments of purified tumor cell line-derived EVs in different classes of purified human LPPs. Based on orthogonal single-particle analysis techniques we demonstrated that EV-LPP complexes can form under physiological conditions. Furthermore, we show that in fluorescence-based flow cytometric EV analysis staining of LPPs, as well as EV-LPP associations can influence EV analysis in a quantitative and qualitative manner. Our findings demonstrate that the biological colloidal matrix of the biofluid in which EVs reside impacts their buoyant density, size and/or refractive index (RI), which may have consequences for down-stream EV analysis.
NRF2 activation induces NADH-reductive stress providing a metabolic vulnerability in lung cancer
Authors: Weiss-Sadan Tommy , Ge Maolin , de Groot Addriaan , Carlin Alexander , Gohar Magdy , Fischer Hannah , Shi Lei , Wei Ting-Yu , Adelmann Charles H. , Vornbäumen Tristan , Dürr Benedkit R. , Takahashi Mariko , Richter Marianne , Zhang Junbing , Yang Tzu-Yi , Vijay Vindhya , Hayashi Makiko , Fischer David E. , Hata Aaron N. , Papaginanakopoulos Thales , Mostoslavsky Raul , Bardeesy Nabeel , Bar-Peled Liron
Published: September 2022

Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers, however the role of this pathway in cancers with wildtype KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines—an effect that was completely rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.