bluuebunny/crossref_metadata_2025 huggingface dataset:
A Spatial Attention Guided Deep Learning System for Prediction of Pathological Complete Response Using Breast Cancer Histopathology Images
Authors: Duanmu Hongyi , Bhattarai Shristi , Li Hongxiao , Zhan Shi , Wang Fusheng , Teodoro George , Gogineni Keerthi , Subhedar Preeti , Kiraz Umay , Janssen Emiel A.M. , Aneja Ritu , Kong Jun
Published: May 2022

Predicting pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients accurately is direly needed for clinical decision making. pCR is also regarded as a strong predictor of overall survival. In this work, we propose a deep learning system to predict pCR to NAC based on serial pathology images stained with hematoxylin and eosin (H&E) and two immunohistochemical biomarkers (Ki67 and PHH3). To support human prior domain knowledge based guidance and enhance interpretability of the deep learning system, we introduce a human knowledge derived spatial attention mechanism to inform deep learning models of informative tissue areas of interest. For each patient, three serial breast tumor tissue sections from biopsy blocks were sectioned, stained in three different stains, and integrated. The resulting comprehensive attention information from the image triplets is used to guide our prediction system for prognostic tissue regions. The experimental dataset consists of 26,419 pathology image patches of 1,000 × 1,000 pixels from 73 TNBC patients treated with NAC. Image patches from randomly selected 43 patients are used as a training dataset and images patches from the rest 30 are used as a testing dataset. By the maximum voting from patch-level results, our proposed model achieves a 93% patient-level accuracy, outperforming baselines and other state-of-the-art systems, suggesting its high potential for clinical decision making. The codes, the documentation, and example data are available on an open source at: https://github.com/jkonglab/PCR_Prediction_Serial_WSIs_biomarkers
Genomic signatures associated with transitions to viviparity in Cyprinodontiformes
Authors: Yusuf Leeban H. , Lemus Yolitzi Saldívar , Thorpe Peter , Garcia Constantino Macías , Ritchie Michael G.
Published: May 2022

The transition from oviparity to viviparity has occurred independently over a hundred times across vertebrates, presenting a compelling case of phenotypic convergence. However, whether repeated, independent evolution of viviparity is driven by redeployment of similar genetic mechanisms and whether these leave a common genetic signature in genomic divergence remains unknown. Whilst investigations into the evolution of viviparity have demonstrated striking similarity among the genes and pathways involved across vertebrate groups, quantitative tests for genome-wide convergence provide ambivalent answers. Here, we investigate molecular convergence during independent transitions to viviparity across an order of ray-finned freshwater fish (Cyprinodontiformes). We assembledde novoand publicly-available genomes of viviparous and oviparous species to quantify molecular convergence across coding and non-coding regions. We found no evidence for an excess of molecular convergence in amino acid substitutions and rates of sequence divergence, implying independent genetic changes are associated with these transitions. However, statistical power and biological confounds (hemiplasy and introgression) could constrain our ability to detect correlated evolution. We therefore also identified candidate genes with potential signatures of molecular convergence in viviparousCyprinodontiformeslineages. While we detected no evidence of positive or relaxed selection for these genes in branches associated with the evolution of viviparity inCyprinodontiformes, motif-enrichment and gene ontology analyses suggest transcriptional changes associated with early morphogenesis, brain development and immunity occurred alongside the evolution of viviparity. Overall, our findings indicate that an excess of molecular convergence, at any level, is not strongly associated with independent transitions to viviparity in these fish.
Basal Ganglia Neurons in Healthy and Parkinsonian Primates Generate Recurring Sequences of Spikes
Authors: Galvan Adriana , Wichmann Thomas
Published: May 2022

The spiking activity of basal ganglia neurons can be characterized by summary statistics such as the average firing rate, or by measures of firing patterns, such as burst discharges, or oscillatory fluctuations of firing rates. Many of these features are altered by the presence of parkinsonism. This study examined another distinct attribute of firing activity, i.e., the occurrence of repeating sequences of inter-spike intervals. We studied this feature in extracellular electrophysiologic recordings that were made in the basal ganglia of Rhesus monkeys, before and after they had been rendered parkinsonian by treatment with the neurotoxin 1-methyl-4-phyl-1,2,3,6-tetrahydropyridine (MPTP). Neurons in both pallidal segments and in the subthalamic nucleus tended to fire in repeating sequences, typically 2 ISIs long (i.e., involving three spikes). In recordings that were 5000 inter-spike intervals long, 20-40% of spikes participated in one of many sequences with each ISI replicating the sequence pattern with a timing error of ≤1%. Compared to similar analyses in shuffled representations of the same data, sequences were more common in the original representation of ISIs in the subthalamic nucleus and the external pallidal segment. Induction of parkinsonism reduced the proportion of sequence spikes in the external pallidum but increased it in the subthalamic nucleus. We found no relation between the sequence generation and the firing rate of neurons, and, at most, a weak correlation between sequence generation and the incidence of bursts. We conclude that basal ganglia neurons fire in recognizable sequences of ISIs, whose incidence is influenced by the induction of parkinsonism.
Molecular Investigations of Selected Spike Protein Mutations in SARS-CoV-2: Delta and Omicron Variants and Omicron Subvariants
Authors: Roy Urmi
Published: May 2022

Among the multiple SARS-CoV-2 variants recently reported, the Delta variant has generated most perilous and widespread effects. Another variant, Omicron, has been identified specifically for its high transmissibility. Omicron contains numerous spike (S) protein mutations and in numbers much larger than those of its predecessor variants. In this report we discuss some essential structural aspects and time-based structure changes of a selected set of spike protein mutations within the Delta and Omicron variants. The expected impact of multiple-point mutations within the spike protein’s receptor-binding domain (RBD) and S1 of these variants are examined. Additionally, RBD of the more recently emerged subvariants BA.4, BA.5 and BA.2.12.1 are discussed. Within the latter group, BA.5 represents globally, the most prevalent form of SARS-CoV-2 at the present time. Temporal mutation profile for the subvariant BF.7 and currently circulating variants of interest (VOI) and variants under monitoring (VUMs) including XBB.1.5, BQ.1, BA.2.75, CH.1.1, XBB and XBF are computationally explored here briefly with the expectation that these structural data will be helpful to identify drug targets and to neutralize antibodies for the evolving variants/subvariants of SARS-CoV-2.
A Van Gogh/Vangl tyrosine phosphorylation switch regulates its interaction with core Planar Cell Polarity factors Prickle and Dishevelled
Authors: Humphries Ashley C. , Hazelett C. Clayton , Molina-Pelayo Claudia , Devenport Danelle , Mlodzik Marek
Published: May 2022

Epithelial tissues can be polarized along two axes, in addition to apical-basal polarity they are often also polarized within the plane of the epithelium, known as planar cell polarity (PCP). PCP depends upon the conserved Wnt/Frizzled (Fz) signaling factors, including Fz itself and Van Gogh (Vang/Vangl). Here, taking advantage of the complementary features of Drosophila wing and mouse skin PCP establishment, we dissect how Vang phosphorylation on a specific conserved tyrosine residue affects its interaction with two cytoplasmic core PCP factors, Dsh/Dvl and Pk. We demonstrate that Pk and Dsh/Dvl bind to Vang/Vangl in an overlapping region centered around this tyrosine. Strikingly, Vang/Vangl2 phosphorylation promotes its binding to Pk, a key effector of the Vang/Vangl complex, and inhibits its interaction with Dsh/Dvl, and thus phosphorylation of this tyrosine appears to promote the formation of the mature and stable Vang/Vangl-Pk complex during PCP establishment. Interestingly, as our single point mutations allow selective binding inhibition of either Dsh or Pk, we can demonstrate for the first time that Dsh interaction with Vang is physiologically important, as all single point mutations fail to rescue the Vang null mutant wing phenotype.
Space-Time Mapping Identifies Concerted Multicellular Patterns and Gene Programs in Healing Wounds and their Conservation in Cancers
Authors: Hu Kenneth H. , Kuhn Nicholas F. , Courau Tristan , Krummel Matthew F.
Published: May 2022

Tissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell based characterization covering this coordination is lacking. Here, we captured transcriptional states of single cells over space and time during skin wound closure, revealing choreographed gene expression profiles. We identified shared and prominent space-time patterns of cellular and gene expression enrichment: which we call multicellular ‘movements’ and which spanned multiple cell types. We validated some of the discovered space-time movements using large volume imaging of cleared wounds and demonstrated the value of this analysis to predict gene products made by macrophages or fibroblasts, which activated gene programs in the opposite cell type. Finally, using two different tumor models, we tested the hypothesis that tumors are like ‘wounds that never heal’ finding conserved wound healing movements in the tumor space, wherein some movements were preferentially used in one tumor versus another.

Graphical Abstract
The ELT-3 GATA Factor Specifies Endoderm inCaenorhabditis angariain an ancestral gene network
Authors: Broitman-Maduro Gina , Maduro Morris F.
Published: May 2022

Endoderm specification in the nematode,C. elegans, occurs through a well-characterized pathway that is initiated by maternally provided SKN-1/Nrf, and with additional input from POP-1/TCF, which activates the GATA factor cascade MED-1,2 → END-1,3 → ELT-2,7. Orthologues of the MED and END factors, and ELT-7, are found only among nematodes of the Elegans Supergroup consisting of species closely related toC. elegans, which raises the question of how gut is specified in their absence. In this work, we investigate gut specification outside the Elegans Supergroup. We find that theC. angariaandC. portoensisorthologues of theelt-3GATA factor gene are expressed in the early E lineage, just before theirelt-2orthologues. InC. angaria, bothCan-pop-1(RNAi)andCan-elt-3(RNAi)result in a penetrant ‘gutless’ phenotype.Can-pop-1is necessary forCan-elt-3activation, showing that it acts upstream. When introduced intoC. elegansas transgenes, overexpressedCan-elt-3is sufficient to specify gut, whileCan-elt-2can rescue gut differentiation under the control of its own promoter. Our results demonstrate an ancestral mechanism for gut specification and differentiation inCaenorhabditisinvolving a simplified gene network consisting of POP-1 → ELT-3 → ELT-2.

Summary statement

Specification of the gut progenitor E in a distant relative ofC. elegansuses a different GATA factor, ELT-3, suggesting that the ancestral network was simpler.
Pseudotemporal whole blood transcriptional profiling of COVID-19 patients stratified by clinical severity reveals differences in immune responses and possible role of monoamine oxidase B
Authors: Broderick Claire , Calle Irene Rivero , Gómez Carballa Alberto , Gómez-Rial Jose , Li Ho Kwong , Mehta Ravi , Jackson Heather , Salas Antonio , Martinón-Torres Federico , Sriskandan Shiranee , Levin Michael , Kaforou Myrsini ,   the BioAID Consortium and GEN-COVID Study Group
Published: May 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with highly variable clinical outcomes. Studying the temporal dynamics of host whole blood gene expression during SARS-CoV-2 infection can elucidate the biological processes that underlie these diverse clinical phenotypes. We employed a novel pseudotemporal approach using MaSigPro to model and compare the trajectories of whole blood transcriptomic responses in patients with mild, moderate and severe COVID-19 disease. We identified 5,267 genes significantly differentially expressed (SDE) over pseudotime and between severity groups and clustered these genes together based on pseudotemporal trends. Pathway analysis of these gene clusters revealed upregulation of multiple immune, coagulation, platelet and senescence pathways with increasing disease severity and downregulation of T cell, transcriptional and cellular metabolic pathways. The gene clusters exhibited differing pseudotemporal trends. Monoamine oxidase B was the top SDE gene, upregulated in severe>moderate>mild COVID-19 disease. This work provides new insights into the diversity of the host response to SARS-CoV-2 and disease severity and highlights the utility of pseudotemporal approaches in studying evolving immune responses to infectious diseases.
The Cultural Evolution of Vaccine Hesitancy: Modeling the Interaction between Beliefs and Behaviors
Authors: Anderson Kerri-Ann , Creanza Nicole
Published: May 2022

Health perceptions and health-related behaviors can change at the population level as cultures evolve. In the last decade, despite the proven efficacy of vaccines, the developed world has seen a resurgence of vaccine-preventable diseases (VPDs) such as measles, pertussis, and polio. Vaccine hesitancy, an individual attitude influenced by historical, political, and socio-cultural forces, is believed to be a primary factor responsible for decreasing vaccine coverage, thereby increasing the risk and occurrence of VPD outbreaks. In recent years, mathematical models of disease dynamics have begun to incorporate aspects of human behavior, however they do not address how beliefs and motivations influence these health behaviors. Here, using a mathematical modeling framework, we explore the effects of cultural evolution on vaccine hesitancy and vaccination behavior. With this model, we shed light on facets of cultural evolution (vertical and oblique transmission, homophily, etc.) that promote the spread of vaccine hesitancy, ultimately affecting levels of vaccination coverage and VPD outbreak risk in a population. In addition, we present our model as a generalizable framework for exploring cultural evolution when humans’ beliefs influence, but do not strictly dictate, their behaviors. This model offers a means of exploring how parents’ potentially conflicting beliefs and cultural traits could affect their children’s health and fitness. We show that vaccine confidence and vaccine-conferred benefits can both be driving forces of vaccine coverage. We also demonstrate that an assortative preference among vaccine-hesitant individuals can lead to increased vaccine hesitancy and lower vaccine coverage.
SHIVIR - An Agent-Based Model to assess the transmission of COVID-19 in India
Authors: Narassima M.S. , John Denny , Anbuudayasankar S.P. , Jammy Guru Rajesh , Pant Rashmi , Choudhury Lincoln
Published: May 2022

Background

COVID-19 has tormented the global health and economy like no other event in the recent past. Researchers and policymakers have been working strenuously to end the pandemic completely.

Methodology/Principal Findings

Infectious disease dynamics could be well-explained at an individual level with established contact networks and disease models that represent the behaviour of the infection. Hence, an Agent-Based Model, SHIVIR (Susceptible, Infected, Admitted, ICU, Ventilator, Recovered, Immune) that can assess the transmission dynamics of COVID-19 and the effects of Non-Pharmaceutical Interventions (NPI) was developed. Two models were developed using to test the synthetic populations of Rangareddy, a district in Telangana state, and the state itself respectively. NPI such as lockdowns, masks, and social distancing along with the effect of post-recovery immunity were tested across scenarios.

The actual and forecast curves were plotted till the unlock phase began in India. The Mean Absolute Percentage Error of scenario MD100I180 was 6.41 percent while those of 3 other scenarios were around 10 percent each. Since the model anticipated lifting of lockdowns that would increase the contact rate proportionately, the forecasts exceeded the actual estimates. Some possible reasons for the difference are discussed.

Conclusions

Models like SHIVIR that employ a bottom-up Agent-Based Modelling are more suitable to investigate various aspects of infectious diseases owing to their ability to hold details of each individual in the population. Also, the scalability and reproducibility of the model allow modifications to variables, disease model, agent attributes, etc. to provide localized estimates across different places.

Author Summary

The world has witnessed several infectious disease outbreaks from time to time. COVID-19 is one such event that tormented the life of mankind. Healthcare practitioners, policymakers, and governments struggled enormously to handle the influx of infections and devise suitable interventions. Agent-Based Models that use the population data could cater to these requirements better. Hence, we developed a disease model that represents various states acquired by COVID-19 infected individuals. The contact network among the individuals in the population was defined based on which the simulation progresses. The effect of various Non-Pharmaceutical Interventions such as lockdowns, the use of masks and social distancing along with post-recovery immunity were enacted considering two case studies viz. population of Rangareddy district and Telangana state. The capability of these models to adapt to different input data fields and types make them handy to be tailored based on available inputs and desired outputs. Simulating them using local population data would fetch useful estimates for policymakers.
Association of LGBTQ+ Affirming Care With Chronic Disease and Preventive Care Outcomes
Authors: McKay Tara , Tran Nathaniel M. , Barbee Harry , Min Judy K.
Published: May 2022

Introduction

Experiences of discrimination and bias in health care contribute to health disparities for LGBTQ+ and other minority populations. To avoid discrimination, many LGBTQ+ people go to great lengths to find healthcare providers who they trust and are knowledgeable about their health needs. This study examines whether access to an LGBTQ+ affirming provider may improve health outcomes for LGBTQ+ populations across a range of preventive health and chronic disease management outcomes.

Methods

This cross-sectional study uses Poisson regression models to examine original survey data (n=1,120) from Wave 1 of the Vanderbilt University Social Networks, Aging, and Policy Study (VUSNAPS), a panel study examining older (50□76 years) LGBTQ+ adults’ health and aging, collected between April 2020 and September 2021.

Results

Overall, access to an LGBTQ+ affirming provider is associated with greater uptake of preventive health screenings and improved management of mental health conditions among older LGBTQ+ adults. Compared to participants reporting a usual source of care that is not affirming, participants with an LGBTQ+ affirming provider are more likely to have ever and recently received several types of preventive care, including past year provider visit, flu shot, colorectal cancer screening, and HIV test. Access to an LGBTQ+ affirming provider is also associated with better management of mental health conditions.

Conclusions

Inclusive care is essential for reducing health disparities among LGBTQ+ populations. Health systems can reduce disparities by expanding education opportunities for providers regarding LGBTQ+ medicine, adopting nondiscrimination policies for LGBTQ+ patients and employees, and ensuring LGBTQ+ care is included in health insurance coverage.
Radiographically Successful Periacetabular Osteotomy Does Not Achieve Optimal Contact Mechanics in Dysplastic Hips
Authors: Aitken Holly D. , Miller Aspen , Rivas Dominic J.L. , Tatum Marcus , Westermann Robert W. , Willey Michael C. , Goetz Jessica E.
Published: May 2022

Introduction

Optimal correction of hip dysplasia deformity with periacetabular osteotomy (PAO) that minimizes elevated contact stresses may reduce osteoarthritis (OA) development.

Questions/Purposes

We used a computational approach based on discrete element analysis (DEA) to determine (1) if computational optimization can identify patient-specific acetabular corrections that optimize joint contact mechanics, (2) whether a strictly mechanically optimal correction is clinically feasible, and (3) whether the contact mechanics of optimal corrections differ from those of surgically achieved corrections.

Methods

Preoperative and postoperative hip models were created from CT scans of a retrospective cohort (n=20) who underwent PAO to treat hip dysplasia. A digitally extracted acetabular fragment was computationally rotated in two-degree increments of lateral and anterior coverage to simulate candidate PAO reorientations. DEA-computed contact stress for each candidate reorientation model was used to select a purely mechanically optimal reorientation that minimized chronic contact stress exposures above damaging thresholds and a clinically optimal reorientation that balanced reducing chronic exposures with achieving clinically realistic acetabular orientations. Radiographic coverage, contact area, peak/mean contact stress, and peak/mean cumulative exposure were compared between preoperative, mechanically optimal, clinically optimal, and surgically achieved acetabular orientations.

Results

Computationally optimal reorientations had significantly (p<0.001) more lateral and anterior coverage than surgically achieved PAO corrections. The mechanically/clinically optimal reorientations also had significantly more contact area (p<0.001/p=0.001) and significantly lower peak contact stress (p<0.001/p<0.001), mean contact stress (p<0.001/p=0.001), peak chronic exposure (p=0.001/p=0.003), and mean chronic exposure (p<0.001/p=0.001) than the surgically achieved corrections.

Conclusions

This computational approach identified patient-specific mechanically optimal and clinically optimal acetabular reorientations. Surgically achieved reorientations did not reduce contact stress exposure to the extent achieved with computed optimal reorientations. However, optimal orientations identified for many patients risk secondary femoroacetabular impingement. Identifying patient-specific corrections that balance optimizing mechanics with clinical reality is necessary to reduce the risk of OA progression after PAO.
Real world external validation of metabolic gestational age assessment in Kenya
Authors: Hawken Steven , Ward Victoria , Bota A. Brianne , Lamoureux Monica , Ducharme Robin , Wilson Lindsay A. , Otieno Nancy , Munga Stephen , Nyawanda Bryan O. , Atito Raphael , Chakraborty Pranesh , Darmstadt Gary L. , Wilson Kumanan
Published: May 2022

Using data from Ontario Canada, we previously developed machine learning-based algorithms incorporating newborn screening metabolites to estimate gestational age (GA). The objective of this study was to evaluate the use of these algorithms in a population of infants born in Siaya county, Kenya.

Cord and heel prick samples were collected from newborns in Kenya and metabolic analysis was carried out by Newborn Screening Ontario in Ottawa, Canada. Postnatal GA estimation models were developed with data from Ontario with multivariable linear regression using ELASTIC NET regularization. Model performance was evaluated by applying the models to the data collected from Kenya and comparing model-derived estimates of GA to reference estimates from early pregnancy ultrasound.

Heel prick samples were collected from 1,039 newborns from Kenya. Of these, 8.9% were born preterm and 8.5% were small for GA. Cord blood samples were also collected from 1,012 newborns. In data from heel prick samples, our best-performing model estimated GA within 9.5 days overall of reference GA [mean absolute error (MAE) 1.35 (95% CI 1.27, 1.43)]. In preterm infants and those small for GA, MAE was 2.62 (2.28, 2.99) and 1.81 (1.57, 2.07) weeks, respectively. In data from cord blood, model accuracy slightly decreased overall (MAE 1.44 (95% CI 1.36, 1.53)). Accuracy was not impacted by maternal HIV status and improved when the dating ultrasound occurred between 9 and 13 weeks of gestation, in both heel prick and cord blood data (overall MAE 1.04 (95% CI 0.87, 1.22) and 1.08 (95% CI 0.90, 1.27), respectively).

Compared to internal validation performance using Ontario data and to our previously published external validations, model performance was diminished in the Kenya cohort, suggesting that reference ultrasound timing is an important factor in model performance. Our study highlights the challenges in reliably estimating GA in low resource settings, even those with access to dating ultrasound, given that the timing of dating ultrasound is critical to develop algorithms for accurate estimation of GA based on metabolic analysis of blood obtained at birth.
Protection against Omicron conferred by mRNA primary vaccine series, boosters, and prior infection
Authors: Chin Elizabeth T. , Leidner David , Lamson Lauren , Lucas Kimberley , Studdert David M. , Goldhaber-Fiebert Jeremy D. , Andrews Jason R. , Salomon Joshua A.
Published: May 2022

Background

Prisons and jails are high-risk settings for Covid-19 transmission, morbidity, and mortality. We evaluate protection conferred by prior infection and vaccination against the SARS-CoV-2 Omicron variant within the California state prison system.

Methods

We employed a test-negative design to match resident and staff cases during the Omicron wave (December 24, 2021—April 14, 2022) to controls according to a case’s test-week as well as demographic, clinical, and carceral characteristics. We estimated protection against infection using conditional logistic regression, with exposure status defined by vaccination, stratified by number of mRNA doses received, and prior infection, stratified by periods before or during Delta variant predominance.

Results

We matched 15,783 resident and 8,539 staff cases to 180,169 resident and 90,409 staff controls. Among cases, 29.7% and 2.2% were infected before or during the emergence of the Delta variant, respectively; 30.6% and 36.3% were vaccinated with two or three doses, respectively. Estimated protection from Omicron infection for two and three doses were 14.9% (95% Confidence Interval [CI], 12.3—19.7%) and 43.2% (42.2—47.4%) for those without known prior infections, 47.8% (95% CI, 46.6—52.8%) and 61.3% (95% CI, 60.7—64.8%) for those infected before the emergence of Delta, and 73.1% (95% CI, 69.8—80.1%) and 86.8% (95% CI, 82.1—92.7) for those infected during the period of Delta predominance.

Conclusion

A third mRNA dose provided significant, additional protection over two doses, including among individuals with prior infection. Our findings suggest that vaccination should remain a priority—even in settings with high levels of transmission and prior infection.
Epidemiology of adverse events attributed to airway management in pediatric anesthesia: A protocol for a Japan Pediatric Difficult Airway in Anesthesia study (J-PEDIA)
Authors: Kojima Taiki , Yamauchi Yusuke , Watanabe Fumio , Ichiyanagi Shogo , Kobayashi Yasuma , Kaiho Yu , Kasuya Shugo , Urayama Kevin Y. , Kuratani Norifumi , Suzuki Yasuyuki
Published: May 2022

Introduction

Failure to secure an airway during general anesthesia is a major cause of adverse events (AEs) in children. The safety of peddiatric anesthesia may be improved by identifying the incidence of AEs and their attributed risk factors. However, previous large cohort studies have not been appropriately designed to explore such aspects. Thus, this study aims to deternine the incidence of AEs and the risk factors attributed to airway management under general anesthesia in children.

Methods and design

This prospective, multi-center, registry-based, observational study will be conducted in four tertiary care hospitals in Japan from June 2022 to May 2025. Children younger than 18 years of age undergoing surgical and/or diagnostic test procedures under general anesthesia or sedation by anesthesiologists will be enrolled in this study. Data on patient characteristics, discipline of anesthesia providers, and methodology of airway management will be collected through a standardized verification system under monitoring by institutional research leaders among the recruited institutions to minimize the loss of collected data. The primary outcome and exposure are AEs and presence of difficult airway features with potential confounders, which are related to the failure to secure the airway, and the variability in the anesthesia providers’ levels, adjusted using hierarchical multivariable regression models with mixed effects.

Discussion

This study will determine the incidence of AEs and the risk factors related to airway management under general anesthesia in children.

Trial registration

This study is registered as a prospective observational study in the University hospital Medical Information Network (UMIN) (registration number UMIN000047351, April 1, 2022).
Is family social exclusion associated with child psychomotor and social development delay in southeastern Brazil?
Authors: de Oliveira Clariana Vitória Ramos , Nery Teixeira Palombo Cláudia , Jeong Joshua , Solís Cordero Katherine Maria , Fujimori Elizabeth
Published: May 2022

The early years of life are a crucial period for shaping child development. Children from socially excluded families may have less opportunity to attain their full development. The objective was to identify if family social exclusion is associated with child psychomotor and social development delay in Southeastern Brazil. A cross-sectional study was conducted using data from a sample of 348 children under three years. We measured psychomotor and social development delays. An index was used to evaluate social exclusion. The prevalence of child psychomotor and social developmental delay was 27.6% and 17.2%, respectively. Children in the most social excluded group were more likely to have delayed psychomotor development (OR = 3.4; 95% CI = 1.14; 10.55) and social developmental delay (OR = 3.9; 95% CI = 1.05; 9.02) than children in the least social excluded group. The results confirm the association between family social exclusion and child development delay.
Enhanced Direct Joint Attenuation and Scatter Correction of Whole-Body PET Images via Context-Aware Deep Networks
Authors: Izadi Saeed , Shiri Isaac , Uribe Carlos F. , Geramifar Parham , Zaidi Habib , Rahmim Arman , Hamarneh Ghassan
Published: May 2022

In positron emission tomography (PET), attenuation and scatter corrections is necessary steps towards accurate quantitative reconstruction of the radiopharmaceutical distribution. Inspired by recent advances in deep learning, many algorithms based on convolutional neural networks have been proposed for automatic attenuation and scatter correction, enabling applications to CT-less or MR-less PET scanners to improve performance in the presence of CT-related artifacts. A known characteristic of PET imaging is to have varying tracer uptakes for various patients and/or anatomical regions. However, existing deep learning-based algorithms utilize a fixed model across different subjects and/or anatomical regions during inference, which could result in spurious outputs. In this work, we present a novel deep learning-based framework for direct reconstruction of attenuation and scatter corrected PET from non-attenuation-corrected images in absence of structural information. To deal with inter-subject and intra-subject uptake variations in PET imaging, we propose a novel model to perform subject- and region-specific filtering through modulating the convolution kernels in accordance to the contextual coherency within the neighboring slices. This way, the context-aware convolution can guide the composition of intermediate features in favor of regressing input-conditioned and/or region-specific tracer uptakes. We also utilize a large cohort of 910 whole-body studies for training and evaluation purposes, which is more than one order of magnitude larger than previous works. In our experimental studies, qualitative assessments showed that our proposed CT-free method is capable of producing corrected PET images that accurately resemble ground truth images corrected with the aid of CT scans. For quantitative assessments, we evaluated our proposed method over 112 held-out subjects and achieved absolute relative error of 14.30 ± 3.88% and relative error of − 2.11% ± 2.73% in whole-body.
CSR-1 RNA interference pathway restricts holocentromere protein CENP-A/HCP-3 localization in Caenorhabditis elegans
Authors: Yu Wong Charmaine Yan , Yee Yuen Karen Wing
Published: May 2022

CSR-1 is an argonaute of a RNA interference pathway that is important for chromosome segregation in C. elegans. Live-cell imaging revealed that CSR-1 depletion slows down spindle pole separation in a kinetochore-dependent manner. In csr-1(RNAi) embryos, the kinetochores may be misattached to the microtubules and chromosome segregation is disrupted. On the holocentromeres, there are increased levels of some kinetochore proteins, including the centromeric epigenetic mark, CENP-A or HCP-3. Without affecting HCP-3 expression level, HCP-3 density is higher on stretched chromatin fibers in CSR-1-depleted embryos. The increased HCP-3 deposition on chromatin after CSR-1 depletion is at least partially independent of HCP-3 loading factors, KNL-2 and LIN-53, suggesting a non-classical, improper HCP-3 loading pathway. Negative regulation of HCP-3 holocentromere loading by CSR-1 required its slicer activity and the b isoform. CSR-1 acts as a HCP-3 repressor for its chromosomal occupancy, shedding light on the role of RNAi pathways in specifying the localization of centromere proteins.
Bridging between mouse and human enhancer-promoter long-range interactions in neural stem cells, to understand enhancer function in neurodevelopmental disease
Authors: D’Aurizio Romina , Catona Orazio , Pitasi Mattia , Li Yang Eric , Ren Bing , Nicolis Silvia K.
Published: May 2022

Non-coding variation in complex human disease has been well established by genome-wide association studies, and it is thought to involve regulatory elements, such as enhancers, whose variation affects the expression of the gene responsible for the disease. The regulatory elements often lie far from the gene they regulate, or within introns of genes differing from the regulated gene, making it difficult to identify the gene whose function is affected by a given enhancer variation.

Enhancers are connected to their target gene promoters via long-range physical interactions (loops). In our study, we re-mapped, onto the human genome, more than 10,000 enhancers connected to promoters via long-range interactions, that we had previously identified in mouse brain-derived neural stem cells by RNApolII-ChIA-PET analysis, coupled to ChIP-seq mapping of DNA/chromatin regions carrying epigenetic enhancer marks. These interactions are thought to be functionally relevant. We discovered, in the human genome, thousands of DNA regions syntenic with the interacting mouse DNA regions (enhancers+connected promoters). We further annotated these human regions regarding their overlap with sequence variants (single nucleotide polymorphisms, SNPs; copy number variants, CNVs), that were previously associated with neurodevelopmental disease in human. We document various cases in which the genetic variant, associated in human to neurodevelopmental disease, affects an enhancer involved in long-range interactions: SNPs, previously identified by genome-wide association studies to be associated with schizophrenia, bipolar disorder, and intelligence, are located within our human syntenic enhancers, and alter transcription factors recognition sites. Similarly, CNVs associated to autism spectrum disease and other neurodevelopmental disorders overlap with our human syntenic enhancers. Some of these enhancers are connected (in mouse) to homologs of genes already associated to the human disease, strengthening the hypothesis that the gene is indeed involved in the disease. Other enhancers are connected to genes not previously associated with the disease, pointing to their possible pathogenetic involvement.

Our observations provide a resource for further exploration of neural disease, in parallel with the now widespread genome-wide identification of DNA variants in patients with neural disease.
Prediction of Resistant Mutations against Upcoming ALK-TKIs, Repotrectinib (TPX-0005) and Ensartinib (X-396)
Authors: Doi Yuta , Tagaya Hiroaki , Noge Ayaka , Semba Kentaro
Published: May 2022

ALK gene rearrangement is observed in approximately 4% of patients with non-small cell lung cancer. These individuals benefit clinically from a range of approved ALK-TKIs; however, using many ALK-TKIs in a row will always result in resistant compound mutations in the kinase domain. Therefore, next-generation ALK-TKIs which are potent to these resistant mutations are still under development. In this context, preclinical prediction of resistant mutations generated by developing ALK-TKIs will provide useful information about the effective sequential treatment of ALK-TKIs. In this study, we developed a simple error-prone PCR-based mutation prediction system, and as a model study, we predicted resistant mutations against upcoming ALK-TKI, repotrectinib, and ensartinib. According to the predictive mutation patterns, repotrectinib and ensartinib may be used as second-line therapeutic options following the first-line alectinib treatment.
Perfect adaptation achieved by transport limitations governs the inorganic phosphate response in S. cerevisiae
Authors: Yip Hon Ming , Cheng Shiyu , Olson Evan J. , Crone Michael , Maerkl Sebastian J.
Published: May 2022

Cells cope with and adapt to ever-changing environmental conditions. Sophisticated regulatory networks allow cells to adjust to these fluctuating environments. One such archetypal system is theS. cerevisiaePho regulon. When external inorganic phosphate (Pi) concentration is low, the Pho regulon activates, expressing genes that scavenge external and internalPi. However, the precise mechanism controlling this regulon remains elusive. We conducted a systems analysis of the Pho regulon on the single cell level under well-controlled environmental conditions. This analysis identified a robust, perfectly adapted Pho regulon state in intermediatePiconditions, and we discovered a hitherto unknown intermediate nuclear localization state of the transcriptional master regulator Pho4p. The existence of an intermediate nuclear Pho4p state unifies and resolves outstanding incongruities associated with the Pho regulon, explains the observed programmatic states of the Pho regulon, and improves our general understanding of how nature evolves and controls sophisticated gene regulatory networks. We further propose that robustness and perfect adaptation are not achieved through complex network-centric control, but by simple transport biophysics. The ubiquity of multi-transporter systems suggests that similar mechanisms could govern the function of other regulatory networks as well.
Specific Pupylation as IDEntity Reporter (SPIDER) for the identification of Protein-Biomolecule interactions
Authors: Jiang He-Wei , Chen Hong , Zheng Yun-Xiao , Wang Xue-Ning , Meng Qingfeng , Xie Jin , Zhang Jiong , Zhang ChangSheng , Xu Zhao-Wei , Chen ZiQing , Wang Lei , Kong Wei-Sha , Zhou Kuan , Ma Ming-Liang , Zhang Hai-Nan , Guo Shu-Juan , Xue Jun-Biao , Hou Jing-Li , Liu Zhe-Yi , Niu Wen-Xue , Wang Fang-Jun , Wang Tao , Li Wei , Wang Rui-Na , Dang Yong-Jun , Czajkowsky Daniel M. , Qiao Yu , Dong Jia-Jia , Pei JianFeng , Tao Sheng-Ce
Published: May 2022

Protein-biomolecule interactions play pivotal roles in almost all biological processes, the identification of the interacting protein is essential. By combining a substrate-based proximity labelling activity from the pupylation pathway of Mycobacterium tuberculosis, and the streptavidin (SA)-biotin system, we developed Specific Pupylation as IDEntity Reporter (SPIDER) for identifying protein-biomolecular interactions. As a proof of principle, SPIDER was successfully applied for global identification of interacting proteins, including substrates for enzyme (CobB), the readers of m6A, the protein interactome of mRNA, and the target proteins of drug (lenalidomide). In addition, by SPIDER, we identified SARS-CoV-2 Omicron variant specific receptors on cell membrane and performed in-depth analysis for one candidate, Protein-g. These potential receptors could explain the differences between the Omicron variant and the Prototype strain, and further serve as target for combating the Omicron variant. Overall, we provide a robust technology which is applicable for a wide-range of protein-biomolecular interaction studies.
Baculovirusbv/odv-e26is required for host behavioral manipulation by optimizing viral virulence to lepidopteran hosts
Authors: Hikida Hiroyuki , Katsuma Susumu
Published: May 2022

Host behavioral manipulation is a widely used strategy for parasites to enhance their transmission. Lepidopteran nucleopolyhedroviruses (NPVs) induce hyperactivity and alteration of behavioral patterns in host insect larvae. Previous studies revealed thatBombyx mori nucleopolyhedrovirus(BmNPV) does not induce hyperactivity in larvalBombyx mori, whenBm8, a homologue of the baculovirusbv/odv-e26gene, is knocked out.Bm8knockout also enhances pathogenicity, but the relationship betweenBm8functions and host behavioral manipulation is still unknown. This study revealed thatBm8is dispensable for altering behavioral patterns but crucial for inducing hyperactivity.Bm8overexpression decreased pathogenicity inB. morilarvae and delayed viral infection in cultured cells. These results suggest thatBm8maintains larval locomotory activity and synchronizes hyperactivity induction with behavioral pattern alteration by suppressing viral virulence. Conserved amino acid residues were also identified in the coiled-coil domain of the Bm8 protein, which is required for suppressing viral virulence in cultured cells and larval hosts. Althoughbv/odv-e26is previously thought to be conserved in a limited group of lepidopteran NPVs, our synteny-based bioinformatics approach discovered putative homologues in the genomes of most lepidopteran NPVs. Functional analyses revealed that phylogenetically close and distantbv/odv-e26homologues possess suppressive activity with functionally essential common residues in their coiled-coil domains. Collectively, these findings indicate that baculovirusbv/odv-e26is a conserved gene optimizing viral virulence for establishing behavioral manipulation in NPV-infected larval hosts.

Author Summary

Baculovirus-induced host abnormal behavior has been described in various lepidopteran insects for a long time, although it is still largely unknown how the virus establishes this complex trait. We showed that baculovirusbv/odv-e26is a factor that suppresses viral virulence and synchronizes hyperactivity and behavioral pattern alteration. We also revealed that putativebv/odv-e26homologues are encoded by a wider range of baculoviruses than previously thought, with functionally conserved residues. We confirmed the suppressive function in both phylogenetically close and distantbv/odv-e26homologues. These results indicate that acquiring a suppressive factor for viral virulence is a crucial event for the evolution of a host manipulation strategy by baculoviruses.
Landscape scale ecology of Tetracladium spp. fungal root endophytes
Authors: Lazar Anna , Mushinski Ryan M. , Bending Gary D.
Published: May 2022

Background

The genus Tetracladium has been traditionally regarded as an Ingoldian fungus or aquatic hyphomycete – a group of phylogenetically diverse, polyphyletic fungi which grow on decaying leaves and plant litter in streams. Recent sequencing evidence has shown that Tetracladium spp. may also exist as root endophytes in terrestrial environments, and furthermore may have beneficial effects on the health and growth of their host. However, the diversity of Tetracladium spp. communities in terrestrial systems and the factors which shape their distribution are largely unknown.

Results

Using a fungal community internal transcribed spacer amplicon dataset from 37 UK Brassica napus fields we found that soils contained diverse Tetracladium spp., most of which represent previously uncharacterised clades. The two most abundant OTUs, related to previously described aquatic T. furcatum and T. maxilliforme, were enriched in roots relative to bulk and rhizosphere soil. For both taxa, relative abundance in roots, but not rhizosphere or bulk soil was correlated with B. napus yield. The relative abundance of T. furcatum and T. maxilliforme OTUs across compartments showed very similar responses with respect to agricultural management practices and soil characteristics. The factors shaping the relative abundance of T. furcatum and T. maxilliforme OTUs in roots was assessed using linear regression and structural equation modelling. Relative abundance of Tetracladium maxilliforme and Tetracladium furcatum in roots increased with pH, concentrations of phosphorus, and increased rotation frequency of OSR. While it decreased with increased soil water content, concentrations of extractable phosphorus, chromium, and iron.

Conclusions

The genus Tetracladium as a root colonising endophyte is a diverse and wildly distributed part of the oilseed rape microbiome that positively correlates to crop yield. The main drivers of its community composition are crop management practices and soil nutrients.
Pleiotropic fitness effects of the lncRNA Uhg4 in Drosophila melanogaster
Authors: MacPherson Rebecca A. , Shankar Vijay , Sunkara Lakshmi T. , Hannah Rachel C. , Campbell Marion R. , Anholt Robert R. H. , Mackay Trudy F. C.
Published: May 2022

Long noncoding RNAs (lncRNAs) are a diverse class of RNAs that are critical for gene regulation, DNA repair, and splicing, and have been implicated in development, stress response, and cancer. However, the functions of many lncRNAs remain unknown. In Drosophila melanogaster, U snoRNA host gene 4 (Uhg4) encodes an antisense long noncoding RNA that is host to seven small nucleolar RNAs (snoRNAs). Uhg4 is expressed ubiquitously during development and in all adult tissues, with maximal expression in ovaries; however, it has no annotated function(s). Here, we used CRISPR-Cas9 germline gene editing to generate multiple deletions spanning the promoter region and first exon of Uhg4. Females showed arrested egg development and both males and females were sterile. In addition, Uhg4 deletion mutants showed delayed development and decreased viability, and changes in sleep and responses to stress. Whole-genome RNA sequencing of Uhg4 deletion flies and their controls identified co-regulated genes and genetic interaction networks associated with Uhg4. Gene ontology analyses highlighted a broad spectrum of biological processes, including regulation of transcription and translation, morphogenesis, and stress response. Thus, Uhg4 is a lncRNA essential for reproduction with pleiotropic effects on multiple fitness traits.