bluuebunny/crossref_metadata_2025 huggingface dataset:
Near-infrared II hyperspectral imaging improves the accuracy of pathological sampling of multiple cancer specimens
Authors: Zhang Lingling , Liao Jun , Wang Han , Zhang Meng , Han Dandan , Jiang Chen , Jia Zhanli , Liu Yao , Qin Chenchen , Niu ShuYao , Bu Hong , Yao Jianhua , Liu Yueping
Published: November 2022

Pathological histology is the clinical gold standard for cancer diagnosis. Incomplete or excessive sampling of the formalin-fixed excised cancer specimen will result in inaccurate histology assessment or excessive workload. Conventionally, pathologists perform specimen sampling relying on naked-eye observation which is subjective and limited by human perception. Precise identification of tumor beds, size, and margin is challenging, especially for lesions with inconspicuous tumor beds. To break the limits of human eye perception (visible: 400-700 nm) and improve the sampling efficiency, in this study, we propose using a second near-infrared window (NIR-II: 900-1700 nm) hyperspectral imaging (HSI) system to assist specimen sampling on the strength of the verified deep anatomical penetration and low scattering characteristics of the NIR-II optical window. We use selected NIR-II HSI narrow bands to synthesize color images for human eye observation and also apply artificial intelligence (AI)-based algorithm on the complete NIR-II HSI data for automatic tissue classification to assist doctors in specimen sampling. Our study employing 5 pathologists, 92 samples and 7 cancer types shows that NIR-II HSI-assisted methods have significant improvements in determining tumor beds compared with conventional methods (Conventional color image with or without X-ray). The proposed system can be easily integrated into the current workflow, and has high imaging efficiency and no ionizing radiation. It may also find applications in intraoperative detection of residual lesions and identification of different tissues.
Improved prediction of blood biomarkers using deep learning
Authors: Sigurdsson Arnór I. , Ravn Kirstine , Winther Ole , Lund Ole , Brunak Søren , Vilhjálmsson Bjarni J. , Rasmussen Simon
Published: November 2022

Blood and urine biomarkers are an essential part of modern medicine, not only for diagnosis, but also for their direct influence on disease. Many biomarkers have a genetic component, and they have been studied extensively with genome-wide association studies (GWAS) and methods that compute polygenic scores (PGSs). However, these methods generally assume both an additive allelic model and an additive genetic architecture for the target outcome, and thereby risk not capturing non-linear allelic effects nor epistatic interactions. Here, we trained and evaluated deep-learning (DL) models for PGS prediction of 34 blood and urine biomarkers in the UK Biobank cohort, and compared them to linear methods. For lipid traits, the DL models greatly outperformed the linear methods, which we found to be consistent across diverse populations. Furthermore, the DL models captured non-linear effects in covariates, non-additive genotype (allelic) effects, and epistatic interactions between SNPs. Finally, when using only genome-wide significant SNPs from GWAS, the DL models performed equally well or better for all 34 traits tested. Our findings suggest that DL can serve as a valuable addition to existing methods for genotype-phenotype modelling in the era of increasing data availability.
Association of genetic variation at the GJA5/ACP6 locus with motor progression in Parkinson’s
Authors: Martinez-Carrasco Alejandro , Real Raquel , Lawton Michael , Reynolds Regina H , Tan Manuela M. X. , Wu Lesley , Williams Nigel M. , Carroll Camille , Corvol Jean-Christophe , Hu Michele T.M. , Grosset Donald G. , Hardy John , Ryten Mina , Ben-Shlomo Yoav , Shoai Maryam , Morris Huw R.
Published: November 2022

Importance

There is a pressing need to understand the biology of Parkinson’s disease (PD) progression and to identify biological pathways as possible therapeutic targets.

Objective

To identify genomic variation associated with PD motor presentation and early stage progression.

Design

GWAS meta-analysis of early PD motor progression, from multiple longitudinal cohorts, using MDS-UPDRS III clinical assessments.

Setting

Multicentre

Participants

3572 unrelated European ancestry individuals diagnosed with PD from 6 studies.

Main Outcomes and Measures

Linear mixed effect models under an additive model corrected for age at diagnosis, gender, and the first 5 genetic principal components (PCs), with axial, limb, and total MDS-UPDRS III as outcomes of the model.

Results

We identified an association between the PD axial rate of progression and variation at theGJA5locus at 1q12 (Beta = -0.25, SE = 0.04,P= 3.4e-10). Exploration of the regulation of gene expression in the region (cis-eQTL analysis) showed that the lead variant was associated with expression ofACP6, a lysophosphatidic acid phosphatase that regulates mitochondrial lipid biosynthesis (cis-eQTLs p-values in blood and brain RNA expression datasets: < 10−8in eQTLGen and 10−7in PsychEncode). In addition, we found a nominal association between axial motor presentation and theMAD1L1gene at 7q21.11 (Beta = 0.54, SE = 0.11,P= 1.6e-7), a gene previously associated with neuropsychiatric disease, and in the long non-coding RNALINC00511at 17q21.31 (Beta = -0.62, SE = 0.11,P= 6.3e-8). Further functional annotation allowed us to nominate the likely causal variants and determine that variants at 7q21.11 may be related to dysregulation ofMAD1L1expression. Variants atLINC00511may cause a disruption of a distal epigenetic regulation ofSOX9through an anchored chromatin loop.

Conclusions and Relevance

Our large multicentre study sheds new light on the genetic architecture of PD progression, which is distinct from PD susceptibility. Our study highlights the potential role of mitochondrial lipid homeostasis in the progression of PD, which may be important in establishing new drug targets to tackle disease progression.
An implementation framework to improve the transparency and reproducibility of computational models of infectious diseases
Authors: Pokutnaya Darya , Childers Bruce , Arcury-Quandt Alice , Hochheiser Harry , Van Panhuis Willem G
Published: November 2022

Computational models of infectious diseases have become valuable tools for research and the public health response against epidemic threats. The reproducibility of computational models has been limited, undermining the scientific process and possibly trust in modeling results and related response strategies, such as vaccination. We translated published reproducibility guidelines from a wide range of scientific disciplines into an implementation framework for improving reproducibility of infectious disease computational models. The framework comprises twenty-two elements that should be described, grouped into six categories: computational environment, analytical software, model description, model implementation, data, and experimental protocol. The framework can be used by scientific communities to develop actionable tools for sharing computational models in a reproducible way.
Factors Associated with the Outcomes of ST-Elevation Myocardial Infarction Patients in the ED
Authors: Hum Bill , Shibly Yusef , Taneja Kamil , Patel Karan , Diaz Michael J. , Baccouche Basil M. , Taneja Tanisha , Batchu Sai , Mohamed Aleem , Zhang Alex , Hsiung Hailey , Patel Urvish
Published: November 2022

Background

ST-elevation myocardial infarction (STEMI) places a significant burden on the US healthcare system. However, there are gaps in our understanding of how patient demographics influence a STEMI’s risk to be admitted and the length of stay (LOS).

Methods

We conducted a retrospective analysis of the 2019 Nationwide Emergency Department Sample of patients with a primary diagnosis of STEMI. Multivariate regressions were used to determine factors associated with being admitted and longer length of stay (LOS).

Results

In 2019, 175,689 STEMI patients presented to the ED and 136,738 (77.8%) patients were admitted. Factors associated with higher risk of being admitted were coronary artery disease (OR:14.34, 95% confidence interval (CI): 12.43-16.54, p<0.001), modified Charlson Comorbidity Index (mCCI) of at least 3 (OR: 9.45, 95% CI: 7.33-12.17, p<0.001), and hyperlipidemia (OR:4.65, 95% CI:4.01-5.39, p<0.001). Black STEMI patients were less likely to be admitted than White STEMI patients (OR: 0.57, 95%CI: 0.43-0.75, p<0.001). Factors associated with a longer LOS include a mCCI of at least 3 (p<0.001), heart failure (p<0.001), and being an elderly patient (p<0.001). Black patients had a longer LOS than White patients (p<0.001). Medicaid beneficiaries were associated with a longer LOS than non-Medicaid beneficiaries (p<0.001).

Conclusion

Race and insurance status substantially affect a STEMI patient’s outcome in the ED.
Emphysema Quantification and Severity Classification with 3-Dimensional Averaging Kernel and Airways Removal
Authors: Zhang Jianxiang , Chaudhari Gunvant R. , Bonderenko Masha , Sohn Jae Ho
Published: November 2022

Background

Emphysema is a common pulmonary pathology known to be associated with increased risk of lung cancer and lung biopsy complications. Prevailing quantitation method of calculating voxel-wise percentage of low attenuation area (LAA) of lung tissue from CT scans is prone to noise and error due overcounting of single voxel LAA and incomplete segmentation of airways.

Purpose

We aim to develop an accurate algorithm to quantitatively measure emphysema and classify its severity..

Methods and Materials

Two chest CT datasets were obtained from two tertiary hospitals as training and external validation datasets. Exclusion criteria included any patients whose emphysema extent was not specified by the accompanying report. The training dataset included 722 patients, and the validation dataset included 1006 patients. Following lung segmentation and airways removal, we applied convolution of the segmented lung with averaging kernels of different sizes in 2D and 3D. Cutoffs between “none,” “mild to moderate,” and “severe” emphysema were determined via weighted logistic regression on the training dataset, and the categorical emphysema extent was obtained for each patient. The main measure for evaluating model performance was area under the curve (AUC) of the receiver operating characteristic (ROC) on the training dataset and accuracy of classification on both the training and the validation dataset. The 1×1×1 kernel, which is equivalent to the traditional LAA score, was used for comparison to other kernels for performance evaluation.

Results

The best model used a 3D 3×3×3 kernel for average filtering with airways post processing and achieved a mean AUC of 0.782 and 0.985 for “none”-versus-rest and “severe”-versus-rest classifications respectively. It achieved a 0.676 and 0.757 multiclass classification accuracy on the training and validation dataset respectively.

Conclusions and Relevance

We present an automated pipeline that can achieve accurate emphysema quantification and severity classification. We showed that convolving the segmented lung with a 3D 3×3×3 kernel and post-processing to remove airways can reliably quantify emphysema.
Meta-analysis of gestational duration and spontaneous preterm birth identifies new maternal risk loci
Authors: Pasanen A. , Karjalainen M. K. , FinnGen  , Zhang G. , Tiensuu H. , Haapalainen A. M. , Ojaniemi M. , Feenstra B. , Jacobsson B. , Palotie A. , Laivuori H. , Muglia L. J. , Rämet M. , Hallman M.
Published: November 2022

Background

Preterm birth (<37 weeks of gestation) is a major cause of neonatal death and morbidity. Up to 40% of the variation in timing of birth results from genetic factors, mostly due to the maternal genome.

Methods

We conducted a genome-wide meta-analysis of gestational duration and spontaneous preterm birth in 68,732 and 98,371 European mothers, respectively.

Results

We detected 19 associated loci of which seven were novel. The loci mapped to several biologically plausible genes, includingHAND2whose expression was previously shown to decrease during gestation, associated with gestational duration, andGCencoding Vitamin D-binding protein, associated with preterm birth. Downstreamin silico-analysis suggested regulatory roles as underlying mechanisms for the associated loci. LD score regression found birth weight measures as the most strongly correlated traits, highlighting the unique nature of spontaneous preterm birth phenotype. Tissue expression and colocalization analysis revealed reproductive tissues and immune cell types as the most relevant sites of action.

Conclusion

We report novel genetic risk loci that associate with preterm birth or gestational duration, and reproduce findings from previous genome-wide association studies. Altogether, our findings provide new insight into the genetic background of preterm birth. Better characterization of the causal genetic mechanisms will be important to public health as it could suggest new strategies to treat and prevent preterm birth.
Informed consent and trial prioritization for human subject research during the COVID-19 pandemic. Stakeholder experiences and viewpoints
Authors: Weigold Stefanie , Schorr Susanne Gabriele , Faust Alice , Woydack Lena , Strech Daniel
Published: November 2022

Background

Very little is known about the practice-oriented challenges and mitigation strategies for effective and efficient translation of informed consent and study prioritization in times of a pandemic. This stakeholder interview study aimed to identify the full spectrum of challenges and mitigation strategies for informed consent and study prioritization in a pandemic setting.

Methods

We performed semi-structured interviews with German stakeholders involved in human subject research during the COVID-19 pandemic. We continued sampling and thematic text analysis of interview transcripts until thematic saturation of challenges and mitigation strategies was reached.

Results

We conducted 21 interviews with investigators, oversight bodies, funders and research support units. For the first topic informed consent we identified three main categories: consent challenges, impact of consent challenges on clinical research, and potential response strategies for consent challenges. For the second topic prioritization of trials, we identified two main categories: need for prioritization of clinical studies and potential response strategies for prioritization of clinical studies. All main categories are further specified with subcategories. A supplementary table provides original quotes from the interviews for all subcategories.

Discussion

Mitigation strategies for challenges with informed consent and study prioritization partly share common ground. High quality procedures for study prioritization, for example, seem to be a core mitigation strategy in dealing with informed consent challenges. Especially in a research environment with particularly high uncertainty regarding potential treatment effects and further limitations for valid informed consent should the selection of clinical trials be very well justified from a scientific, medical, and ethics viewpoint.
Digital tools to improve parenting behavior in low-income settings: A mixed-methods feasibility study
Authors: Jäggi Lena , Melgar Leonel Aguilar , Llatance Milagros Alvarado , Castellanos Andreana , Fink Günther , Hinckley Kristen , Bustamante Maria-Luisa Huaylinos , McCoy Dana C. , Verastegui Hector , Mäusezahl Daniel , Pena Stella M. Hartinger
Published: November 2022

Introduction

Digital parenting interventions could be potentially cost-effective means for providing early child development services in low-income settings. This 5-month mixed-methods pilot study evaluated the feasibility of usingAfinidata, a comprehensiveFBMessenger-based digital parenting intervention in a remote rural setting in Latin America and explored necessary adaptations to local context.

Methods

The study was conducted in three provinces in the Cajamarca region, Peru, from February to July 2021. 180 mothers with children aged between 2-24 months and regular access to a smartphone were enrolled. Mothers were interviewed three times in-person. Selected mothers also participated in focus groups or in-depth qualitative interviews.

Results

Despite the rural and remote study site, 88% of local families with children between 0-24 months had access to internet and smartphones. Two months after baseline, 84% of mothers reported using the platform at least once, and of those, 87% rated it as useful to very useful. After 5 months, 42% of mothers were still active on the platform, with little variation between urban and rural settings. Modifications to the intervention focused on assisting mothers in navigating the platform independently and included adding a laminated booklet with general information on child development, sample activities and detailed instructions on how to self-enroll in case of lost phones.

Conclusions

We found high access to smartphones and the intervention was well received and used in very remote areas of Peru, suggesting that digital parenting interventions could be a promising path forward for supporting low-income families in remote parts of Latin America.

What is already known on this topic–Digital parenting interventions are potentially cost-effective means for providing early child development services in low-income settings but have not been well-studied to date.

What this study adds–This mixed-methods pilot study in a very remote setting in Latin America showed that 88% of local families with children between 0-24 months had access to smartphones with internet and 42% were still engaging with a digital parenting intervention after 5 months.

How this study might affect research, practice or policy–High access to smartphones suggest that digital parenting interventions could be a promising path forward for supporting low-income families in remote parts of Latin America, but mothers might benefit from additional instructions to navigate all features of digital interventions on their own.
A bistable autoregulatory module in the developing embryo commits cells to binary fates
Authors: Zhao Jiaxi , Perkins Mindy Liu , Norstad Matthew , Garcia Hernan G.
Published: November 2022

Positive autoregulation has been repeatedly proposed as a mechanism for cells to adopt binary fates during embryonic development through bistability. However, without quantitatively determining their parameters, it is unclear whether the plethora of positive autoregulatory modules found within developmental gene regulatory networks are actually bistable. Here, we combinein vivolive imaging with mathematical modeling to dissect the binary cell fate dynamics of the fruit fly pair-rule genefushi tarazu(ftz), which is regulated by two known enhancers: the early (non-autoregulating) element and the autoregulatory element. Live imaging of transcription and protein concentration in the blastoderm revealed that binary Ftz cell states are achieved asftzexpression rapidly transitions from being dictated by the early element to the autoregulatory element. Moreover, we discovered that Ftz concentration alone is insufficient to activate the autoregulatory element, and that this element only becomes responsive to Ftz at a prescribed developmental time. Based on these observations, we developed a dynamical systems model, and quantitated its kinetic parameters directly from experimental measurements. Our model demonstrated that theftzautoregulatory module is indeed bistable and that the early element transiently establishes the content of the binary cell fate decision to which the autoregulatory module then commits. Further analysisin silicorevealed that the autoregulatory element locks the Ftz expression fate quickly, within 35 min of exposure to the transient signal of the early element. Overall, our work confirms the widely held hypothesis that autoregulation can establish developmental fates through bistability and, most importantly, provides a framework for the quantitative dissection of cellular decision-making based on systems dynamics models and real-time measurements of transcriptional and protein dynamics.
Reconstructing Computational Dynamics from Neural Measurements with Recurrent Neural Networks
Authors: Durstewitz Daniel , Koppe Georgia , Thurm Max Ingo
Published: November 2022

Mechanistic and computational models in neuroscience usually take the form of systems of differential or time-recursive equations. The spatio-temporal behavior of such systems is the subject of dynamical systems theory (DST). DST provides a powerful mathematical toolbox for describing and analyzing neurobiological processes at any level, from molecules to behavior, and has been a mainstay of computational neuroscience for decades. Recently, recurrent neural networks (RNNs) became a popular machine learning tool for studying the nonlinear dynamics underlying neural or behavioral observations. By training RNNs on the same behavioral tasks as employed for animal subjects and dissecting their inner workings, insights and hypotheses about the neuro-computational underpinnings of behavior could be generated. Alternatively, RNNs may be traineddirectlyon the physiological and behavioral time series at hand. Ideally, the once trained RNN would then be able to generate data with thesame temporal and geometrical propertiesas those observed. This is calleddynamical systems reconstruction, a burgeoning field in machine learning and nonlinear dynamics. Through this more powerful approach the trained RNN becomes asurrogatefor the experimentally probed system, as far as its dynamical and computational properties are concerned. The trained system can then be systematically analyzed, probed and simulated. Here we will review this highly exciting and rapidly expanding field, including recent trends in machine learning that may as yet be less well known in neuroscience. We will also discuss important validation tests, caveats, and requirements of RNN-based dynamical systems reconstruction. Concepts and applications will be illustrated with various examples from neuroscience.
Cooltools: enabling high-resolution Hi-C analysis in Python
Authors:   Open2C, Abdennur Nezar , Abraham Sameer , Fudenberg Geoffrey , Flyamer Ilya M. , Galitsyna Aleksandra A. , Goloborodko Anton , Imakaev Maxim , Oksuz Betul A. , Venev Sergey V.
Published: November 2022

Chromosome conformation capture (3C) technologies reveal the incredible complexity of genome organization. Maps of increasing size, depth, and resolution are now used to probe genome architecture across cell states, types, and organisms. Larger datasets add challenges at each step of computational analysis, from storage and memory constraints to researchers’ time; however, analysis tools that meet these increased resource demands have not kept pace. Furthermore, existing tools offer limited support for customizing analysis for specific use cases or new biology. Here we introducecooltools(https://github.com/open2c/cooltools), a suite of computational tools that enables flexible, scalable, and reproducible analysis of high-resolution contact frequency data.Cooltoolsleverages the widely-adopted cooler format which handles storage and access for high-resolution datasets.Cooltoolsprovides a paired command line interface (CLI) and Python application programming interface (API), which respectively facilitate workflows on high-performance computing clusters and in interactive analysis environments. In short,cooltoolsenables the effective use of the latest and largest genome folding datasets.
Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1, and XBB.1 by 4 doses of parental mRNA vaccine or a BA.5-bivalent booster
Authors: Kurhade Chaitanya , Zou Jing , Xia Hongjie , Liu Mingru , Chang Hope C. , Ren Ping , Xie Xuping , Shi Pei-Yong
Published: November 2022

The newly emerged SARS-CoV-2 Omicron BQ.1.1, XBB.1, and other sublineages have accumulated additional spike mutations that may affect vaccine effectiveness. Here we report neutralizing activities of three human serum panels collected from individuals 1-3 months after dose 4 of parental mRNA vaccine (post-dose-4), 1 month after a BA.5-bivalent-booster (BA.5-bivalent-booster), or 1 month after a BA.5-bivalent-booster with previous SARS-CoV-2 infection (BA.5-bivalent-booster-infection). Post-dose-4 sera neutralized USA-WA1/2020, BA.5, BF.7, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 SARS-CoV-2 with geometric mean titers (GMTs) of 1533, 95, 69, 62, 26, 22, and 15, respectively; BA.5-bivalent-booster sera improved the GMTs to 3620, 298, 305, 183, 98, 73, and 35; BA.5-bivalent-booster-infection sera further increased the GMTs to 5776, 1558,1223, 744, 367, 267, and 103. Thus, although BA.5-bivalent-booster elicits better neutralization than parental vaccine, it does not produce robust neutralization against the newly emerged Omicron BA.2.75.2, BQ.1.1, and XBB.1. Previous infection enhances the magnitude and breadth of BA.5-bivalent-booster-elicited neutralization.
Structure of the human UBR5 E3 ubiquitin ligase
Authors: Wang Feng , He Qing , Zhan Wenhu , Yu Ziqi , Finkin-Groner Efrat , Ma Xiaojing , Lin Gang , Li Huilin
Published: November 2022

The human UBR5 (also known as EDD) is a single polypeptide chain HECT-type E3 ubiquitin ligase essential for embryonic development in mammals. Although widely expressed,UBR5is markedly amplified and overexpressed in breast, ovarian, prostate, gastric and pancreatic cancers. Dysregulated UBR5 functions like an oncoprotein to promote cancer growth and metastasis, making UBR5 a potential target for therapeutics. Unexpectedly, we found that human UBR5 assembles a dimer and a tetramer in solution. We determined the dimer structure at 2.8 Å and the tetramer structure at 3.5 Å average resolution. UBR5 is a crescent shaped molecule with a seven-bladed β-propeller and two small β-barrel domains (SBB1/2) at the N-terminal region, a catalytic HECT domain at the C-terminus, and an extended helical scaffold and an N-degron-recognizing UBR box in the middle. The dimer is assembled as a stable head-to-tail dimer via extensive interactions in the middle helical scaffold region. The tetramer is assembled via SBB2-SBB2 interaction from two face-to-face dimers, forming a large cage with all four catalytic HECT domains facing the central cavity. Importantly, the N-terminal region of one subunit and the HECT of the other form an “intermolecular jaw” in the dimer. Using enzymatic and cellular assays, we showed that the jaw-lining residues are important for function, suggesting that the intermolar jaw functions to recruit ubiquitin loaded E2 to UBR5 for the transthiolation reaction. Further work is needed to understand how oligomerization regulates the UBR5 ligase activity. This work provides a framework for structure-based anticancer drug development against the distinctive HECT E3 ligase and contributes to a growing appreciation of E3 ligase diversity.
Protein design using structure-based residue preferences
Authors: Ding David , Shaw Ada , Sinai Sam , Rollins Nathan , Prywes Noam , Savage David F. , Laub Michael T. , Marks Debora S.
Published: November 2022

Recent developments in protein design have adapted large neural networks with up to 100s of millions of parameters to learn complex sequence-function mappings. However, it is unclear which dependencies between residues are critical for determining protein function, and a better empirical understanding could enable high quality models that are also more data- and resource-efficient. Here, we observe that the per residue amino acid preferences - without considering interactions between mutations are sufficient to explain much, and sometimes virtually all of the combinatorial mutation effects across 7 datasets (R2∼ 78-98%), including one generated here. These preference parameters (20*N, where N is the number of mutated residues) can be learned from as few as ∼5*20*N observations to predict a much larger number (potentially up to 20N) of combinatorial variant effects with high accuracy (Pearson r > 0.8). We hypothesized that the local structural dependencies surrounding a residue could be sufficient to learn these required mutation preferences, and developed an unsupervised design approach, which we term CoVES for ‘CombinatorialVariantEffects fromStructure’. We show that CoVES outperforms not just model free sampling approaches but also complicated, high-capacity autoregressive neural networks in generating functional and diverse sequence variants for two example proteins. This simple, biologically-rooted model can be an effective alternative to high-capacity, out of domain models for the design of functional proteins.
Yeast population dynamics in Brazilian bioethanol production
Authors: Rego-Costa Artur , Huang I-Ting , Desai Michael M. , Gombert Andreas K.
Published: November 2022

The large scale and non-aseptic fermentation of sugarcane feedstocks into fuel ethanol in biorefineries represents a unique ecological niche, in which the yeastSaccharomyces cerevisiaeis the predominant organism. Several factors, such as sugarcane variety, process design, and operating and weather conditions, make each of the ∼400 industrial units currently operating in Brazil a unique ecosystem. Here, we track yeast population dynamics in two different biorefineries through two production seasons (April to November of 2018 and 2019), using a novel statistical framework on a combination of metagenomic and clonal sequencing data. We find that variation from season to season in one biorefinery is small compared to the differences between the two units. In one biorefinery, all lineages present during the entire production period derive from one of the starter strains, while in the other, invading lineages took over the population and displaced the starter strain. However, despite the presence of invading lineages and the non-aseptic nature of the process, all yeast clones we isolated are phylogenetically related to other previously sequenced bioethanol yeast strains, indicating a common origin from this industrial niche. Despite the substantial changes observed in yeast populations through time in each biorefinery, key process indicators remained quite stable through both production seasons, suggesting that the process is robust to the details of these population dynamics.
Prevalence and Factors Associated With Delay in Presentation of Breast Cancer Patients in Ethiopia: A Cross-Sectional Institution-Based Study
Authors: Muhammed Jabir Abdella , Kroeber Eric Sven , Deribe Bedilu , Unverzagt Susanne , Taylor Lesley , Aynalem Amdehiwot , fetene Deriba
Published: November 2022

Background

In developing countries, the high mortality of breast cancer (BC) patients is strongly related to delayed presentation and subsequent advanced stage diagnosis, pointing to the need for improved detection programs. This study aims to assess the prevalence and factors associated with delayed presentation of BC patients at Hawassa University Oncology Center (HUOC), Hawassa, Ethiopia.

Methods

A cross-sectional institution-based survey was conducted among BC patients between May 1stand August 30th, 2021. BC patients attending HUOC were included by consecutive sampling. Data was collected using an interviewer-administered questionnaire and medical record data extraction. A multivariable binary logistic regression model was carried out to identify associations between delayed presentation and potential risk factors.

Results

A total of 150 BC patients participated in the study giving a response rate of 100%. Of these, 86 (57.3%) women presented with a long delay of ≥ 3 months. The median time to visit a health care provider after recognition of the first symptoms was 5.5 months. Urban residence (adjusted odds ratio (AOR) = 0.42; 95 %-CI=0.18-0.97) and not visiting of traditional healer (AOR=0.15, 95 %-CI=0.07-0.34) was associated with shorter delay time. No breast pain symptoms (AOR=8.57; 95 %-CI=3.47-21.15), no family history of BC (AOR=5.12; 95 %-CI=1.36-19.33), and travel distance ≥ 5 km (AOR=3.00, 95 %-CI=1.25-7.21) were associated with longer delay in presentation.

Conclusion

A substantial proportion of patients with BC in southern Ethiopia have delays in seeking medical care. Interventional programs like public BC awareness campaigns are strongly needed to reduce delayed presentation and to increase early detection of cancer cases.
High performance, large-scale multi-compartment Hodgkin-Huxley simulation of Drosophila’s whole-brain neural circuit model
Authors: Higuchi Kaoruko , Kazawa Tomoki , Sakai Buntaro , Namiki Shigehiro , Haupt Stephan Shuichi , Kanzaki Ryohei
Published: November 2022

A major challenge in neurosciences is the elucidation of neural mechanisms in brains that are crucial for the processing of sensory information and the generation of adaptive behavior. In conjunction with the ever-growing body of experimental data, computational simulations have become crucial in integrating information and testing hypotheses, requiring fast large-scale simulators. We constructed a whole-brain neural circuit model of the fly Drosophila with biophysically detailed multi-compartment Hodgkin-Huxley models based on the morphologies of individual neurons published in open databases. Performance tuning of the simulator enabled near real-time simulation of the resting state of the Drosophila whole-brain model in the large-scale computational environment of the supercomputer Fugaku, for which we achieved in excess of 630 TFLOPS using 480k cores. In our whole-brain model, neural circuit dynamics related to a standard insect learning paradigm, the association of taste rewards with odors could be simulated.
Biochemical characterization and NMR study of a PET-hydrolyzing cutinase fromFusarium solani pisi
Authors: Hellesnes Kristina Naasen , Vijayaraj Shunmathi , Fojan Peter , Petersen Evamaria , Courtade Gaston
Published: November 2022

In recent years, the drawbacks of plastics have become evident, with plastic pollution becoming a major environmental issue. There is an urgent need to find solutions to efficiently manage plastic waste by using novel recycling methods. Biocatalytic recycling of plastics by using enzyme-catalyzed hydrolysis is one such solution that has gained interest, in particular for recycling polyethylene terephthalate (PET). To provide insights into PET hydrolysis by cutinases, we have here characterized the kinetics of a PET-hydrolyzing cutinase fromFusarium solani pisi(FsC) at different pH values, mapped the interaction between FsC and the PET analog BHET by using NMR spectroscopy, and monitored product release directly and in real time by using time-resolved NMR experiments. We found that primarily aliphatic side chains around the active site participate in the interaction with BHET, and that pH conditions and mutation around the active site (L182A) can be used to tune the relative amounts of degradation products. Moreover, we propose that the low catalytic performance of FsC on PET is caused by poor substrate binding combined with slow MHET hydrolysis. Overall, our results provide insights into obstacles that preclude efficient PET hydrolysis by FsC and suggest future approaches for overcoming these obstacles and generating efficient PET-hydrolyzing enzymes.

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Capsular polysaccharide inhibits vaccine-induced O-antigen antibody binding and function across both classical and hypervirulent K2:O1 strains ofKlebsiella pneumoniae
Authors: Wantuch Paeton L. , Knoot Cory J. , Robinson Lloyd S. , Vinogradov Evgeny , Scott Nichollas E. , Harding Christian M. , Rosen David A.
Published: November 2022

Klebsiella pneumoniaepresents as two circulating pathotypes: classicalK. pneumoniae(cKp) and hypervirulentK. pneumoniae(hvKp). Classical isolates are considered urgent threats due to their antibiotic resistance profiles, while hvKpisolates have historically been antibiotic susceptible. Recently, however, increased rates of antibiotic resistance have been observed in both hvKpand cKp, further underscoring the need for preventive and effective immunotherapies. Two distinct surface polysaccharides have gained traction as vaccine candidates againstK. pneumoniae: capsular polysaccharide and the O-antigen of lipopolysaccharide. While both targets have practical advantages and disadvantages, it remains unclear which of these antigens included in a vaccine would provide superior protection against matchedK. pneumoniaestrains. Here, we report the production of two bioconjugate vaccines, one targeting the K2 capsular serotype and the other targeting the O1 O-antigen. Using murine models, we investigated whether these vaccines induced specific antibody responses that recognize K2:O1K. pneumoniaestrains. While each vaccine was immunogenic in mice, both cKpand hvKpstrains exhibited decreased O-antibody binding in the presence of capsule. Further, O1 antibodies demonstrated decreased killing in serum bactericidal assays with encapsulated strains, suggesting that the presence ofK. pneumoniaecapsule blocks O1-antibody binding and function. Finally, the K2 vaccine outperformed the O1 vaccine against both cKpand hvKpin two different murine infection models. These data suggest that capsule-based vaccines may be superior to O-antigen vaccines for targeting hvKpand some cKpstrains, due to capsule blocking the O-antigen.

Significance Statement

Currently there are no licensed vaccines targetingK. pneumoniae, but several are in development. Two prominentK. pneumoniaesurface polysaccharides (capsule and O-antigen) represent attractive vaccine targets; however, the relative efficacy of these potential vaccines againstK. pneumoniaestrains has not been directly compared. To inform future vaccine development, we evaluate two bioconjugate vaccines (targeting either capsule or O-antigen) demonstrating that each are immunogenic in murine models. However, we find thatK. pneumoniaecapsule largely inhibits recognition by antibodies raised against O-antigen. Further, we demonstrate that a capsule-based vaccine outperforms an O-antigen vaccine against both cKpand hvKpin murine models of pneumonia and bacteremia, suggesting that capsule-based vaccines offer superior protection from someK. pneumoniaeinfections.
P bodies coat germ granules to promote transgenerational gene silencing inC. elegans
Authors: Du Zhenzhen , Shi Kun , Brown Jordan S. , He Tao , Wu Wei-Sheng , Zhang Ying , Lee Heng-Chi , Zhang Donglei
Published: November 2022

The formation of biomolecular condensates has emerged as a critical mechanism for compartmentation in living cells. Despite interactions between distinct condensates having been reported, the biological relevance of these interactions remains elusive. In germ cells, small RNA silencing factors are enriched in germ granule condensates, where distinct factors are organized into sub-compartments with specific functions linked to genome surveillance or transgenerational gene silencing. Here we showed that perinuclear germ granules are coated by P body condensates, which are known for housing translationally-inactive mRNAs and mRNA degradation factors. Disruption of P body factors, including CGH-1/DDX6 and CAR-1/LSM14, lead to dispersal of small RNA factors from perinuclear germ granules and disorganization of sub-compartments within germ granules. We further found that CAR-1 promotes the interaction between CGH-1 and germ granule factors, and these interactions are critical for the ability of CGH-1 to promote piRNA-mediated gene silencing. Importantly, we observed thatcgh-1mutants are competent in triggering gene silencing but exhibit defects in maintaining gene silencing in subsequent generations. Small RNA sequencing further showed thatcgh-1mutants exhibit defects in amplifying secondary small RNAs, known carriers of gene silencing memories. Together, our results uncover the function of P body factors in small RNA-mediated transgenerational gene silencing and highlight how the formation and function of one condensate can be regulated by an adjacent, interacting condensate in cells.
Prefrontal stimulation disrupts motor memory consolidation at the micro timescale
Authors: Gann Mareike A. , Dolfen Nina , King Bradley R. , Robertson Edwin M. , Albouy Geneviève
Published: November 2022

Functional brain responses in hippocampo- and striato-cortical networks during initial motor sequence learning (MSL) are critical for memory consolidation. We have recently shown that prefrontal stimulation applied prior to initial MSL can alter these learning-related responses. In the present study, we investigated whether such stimulation-induced modulations of brain responses can influence motor memory consolidation at different timescales. Specifically, we examined the effect of prefrontal stimulation on the behavioral and neural responses associated to (i) fast consolidation processes occurring during short rest episodes interspersed with practice during initial learning (i.e., micro timescale) and (ii) slow consolidation process taking place across practice sessions separated by 24h (i.e., macro timescale). To do so, we applied active (inhibitory or facilitatory) or control theta-burst stimulation to the prefrontal cortex of young healthy participants before they were trained on an MSL task while their brain activity was recorded using functional magnetic resonance imaging (fMRI). Motor performance was retested, in the MRI scanner, after a night of sleep. Both our behavioral and brain imaging results indicate that while stimulation did not modulate consolidation at the macro timescale, it disrupted the micro-offline consolidation process. Specifically, our behavioral data indicate that active - as compared to control - stimulation resulted in a decrease in micro-offline gains in performance over the short rest intervals. At the brain level, stimulation disrupted activity in the caudate nucleus and the hippocampus during the micro-offline intervals. Additionally, multivariate pattern persistence from task into inter-practice rest episodes - which is thought to reflect the reactivation of learning-related patterns - was hindered by active prefrontal stimulation in the hippocampus and caudate nucleus. Importantly, stimulation also altered the link between the brain and the behavioral markers of the micro-offline consolidation process. These results collectively suggest that active prefrontal stimulation prior to MSL disrupted both the behavioral and neural correlates of motor memory consolidation at the micro timescale.
Bax Forms a Membrane Surface Protein-Lipid Complex as it Initiates Apoptosis
Authors: Clifton Luke A. , Wacklin-Knecht Hanna P. , Ådén Jörgen , Mushtaq Ameeq Ul , Sparrman Tobias , Gröbner Gerhard
Published: November 2022

Cellular clearance by apoptosis is essential in life. In its intrinsic (mitochondrial) pathway apoptotic members of the Bcl-2 (B cell CLL/lymphoma-2) protein family, such as Bax (Bcl-2-associated X) protein, perforate the mitochondrial outer membrane (MOM), which causes release of apoptotic factors and final cell death. How those apoptotic proteins mechanistically exert their action at the membrane level still however remains elusive. Upon internal stress signals Bax is massively recruited to the MOM, where it oligomerizes and partially penetrates into the membrane. Using neutron reflectometry (NR) and attenuated total reflection Fourier-Transform infrared spectroscopy (ATR-FTIR) spectroscopy we unraveled key molecular steps of this membrane-affiliation process of Bax on a spatial and temporal scale. By titrating intact human Bax to MOM-like bilayers containing cardiolipin, essential for protein recruitment, we could identify different functional phases. Initially, there is a fast adsorption event to the membrane surface with high affinity. Thereafter, a kinetically slower (minutes to hours) event occurs with Bax penetration, thereby triggering a major reorganizing of the mitochondrial bilayer. Finally, a membrane-Bax complex is generated, with a minor Bax population remaining membrane-inserted, while the main population is relocated to the membrane surface upon lipid redistribution into a complex with Bax; a process enabling membrane perforation. We propose a comprehensive molecular model of mitochondrial membrane penetration by formation of complex Bax/lipid clusters; a concept which provides a new foundation to understand the cell-killing activity of Bax and its apoptotic relatives in human cells.

Significance Statement

The apoptotic Bax protein is a key player in the mitochondrial apoptotic pathway. Here, neutron reflectometry (NR) unravels the mechanism by which Bax is targeting and perforating mitochondria to release apoptotic factors for final cell death. We found that this cardiolipin driven process of the outer mitochondrial membrane system has two main phases. Upon a fast (10-20 min) phase of membrane association Bax initiates the formation of pores by removing lipids and depositing them as Bax/lipid complexes on top of the bilayer on a time scale of several hours similar toin vivoapoptotic cell death. Our results provide a mechanistic rationale for cell-killing processes driven by apoptotic Bcl-2 proteins; and their molecular inhibition in many cancers.
HAND1 knockdown disrupts trophoblast global gene expression
Authors: Fresch Robert , Courtney Jennifer , Brockway Heather , Wilson Rebecca L. , Jones Helen
Published: November 2022

Congenital heart disease (CHD) affects nearly 1% of births annually, and CHD pregnancies carry increased risk of developing pathologies of abnormal placentation. We previously reported significant developmental impacts of disruptingHand1, a gene associated with CHD, expression in placenta trophoblast and endothelial cells in multiple mouse models. In this study, we aimed to build upon this knowledge and characterize the mechanistic impacts of disruptingHAND1on human placenta trophoblast and vascular endothelial cell gene expression.HAND1gene expression was silenced in BeWo cells, a choriocarcinoma model of human cytotrophoblasts, (n=3-9 passages) and isolated human placental microvascular endothelial cells (HPMVEC; n=3 passages), withHAND1siRNA for 96 h. Cells were harvested, mRNA isolated and RNA sequencing performed using the Illumina NextSeq 550 platform. Normalization and differential gene expression analyses were conducted using general linear modeling in edgeR packages. Statistical significance was determined using a log2 fold change of >1.0 or <−1.0 and unadjusted p-value ≤0.05. Panther DB was used for overrepresentation analysis, and String DB for protein association network analysis. There was downregulation of 664 genes, and upregulation of 59 genes in BeWo cells with directHAND1knockdown. Overrepresentation analysis identified disruption to pathways including cell differentiation, localization, and cell projection organization. In contrast, only 7 genes were changed with directHAND1knockdown in HPMVECs. Disruption toHAND1expression significantly alters gene expression profile in trophoblast but not endothelial cells. This data provides further evidence that future studies on genetic perturbations in CHDs should consider the extra-embryonic tissue in addition to the fetal heart.