bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal CNN Models Allow for the Accurate Classification and Grading of Preoperative Meningioma Tumors
Authors: Rane Mihir
Published: March 2023

Magnetic resonance imaging (MRI) and computed tomography (CT) scans are vital for diagnosing brain tumors, but human error, image subtleties, cyst growth, and nuances in World Health Organization (WHO) grading can impede accuracy. Invasive biopsies remain the only definitive method for meningioma diagnosis. Convolutional Neural Networks (CNNs), machine learning models used in image classification, offer a promising solution. By fine-tuning the pre-trained CNN EfficientNetB0 on various preoperative brain tumors and meningioma subtypes, image-based diagnosis can become more robust and accurate. In this study, two CNN models either classified or graded multimodal CT and MRI images. One dataset included tumor types (meningioma, glioma, pituitary, cysts, or none), while the other had images WHO graded one to three. The data, from accurately annotated and diverse open-source databases, was normalized, augmented, and stripped of excess information. Additionally, class-average and Focal Tversky Loss were included to assess and reduce incorrect outputs. Results were analyzed using accuracy, f1, recall, precision, loss, confusion matrices, Receiver Operating Characteristic (ROC) analysis, and attention studies. Both CNNs achieved over 98% accuracy with high recall and precision scores. ROC area under the curve (AUC) scores above 0.978 indicated strong class discrimination. The attention study indicated focus on tumor mass instead of extraneous variables. Multimodal CNNs, particularly the EfficientNetB0 model, are potential alternatives to invasive biopsies and human evaluation. Their capability to handle complex meningioma cases suggests promising avenues for other tumor types or diagnostic modalities at a cheap cost.
ADCC-activating antibodies correlate with protection against congenital human cytomegalovirus infection
Authors: Semmes Eleanor C. , Miller Itzayana G. , Rodgers Nicole , Phan Caroline T. , Hurst Jillian H. , Walsh Kyle M. , Stanton Richard J. , Pollara Justin , Permar Sallie R.
Published: March 2023

Human cytomegalovirus (HCMV) is the most common vertically transmitted infection worldwide, yet there are no licensed vaccines or therapeutics to prevent congenital HCMV (cCMV) infection. Emerging evidence from studies of natural infection and HCMV vaccine trials indicates that antibody Fc effector functions may defend against HCMV infection. We previously reported that antibody-dependent cellular phagocytosis (ADCP) and IgG activation of FcγRI/FcγRII were associated with reduced risk of cCMV transmission, leading us to hypothesize that other Fc-mediated antibody functions may also contribute to protection. In this same cohort of HCMV transmitting (n = 41) and non-transmitting (n = 40) mother-infant dyads, we found that higher maternal sera antibody-dependent cellular cytotoxicity (ADCC) activation was also associated with decreased risk of cCMV infection. We determined that NK cell-mediated ADCC responses correlated strongly with anti-HCMV IgG FcγRIII/CD16 activation and IgG binding to the HCMV immunoevasin protein UL16. Notably, anti-UL16 IgG binding and engagement of FcγRIII/CD16 were higher in non-transmitting versus transmitting dyads and interacted significantly with ADCC responses. These findings indicate that ADCC-activating antibodies against novel targets such as UL16 may represent an important protective maternal immune response against cCMV infection, which can guide future HCMV correlates studies and vaccine development.
Effect of behavioural activation for individuals with post-stroke depression: A systematic review and meta-analysis
Authors: Walsh Sandra , Yisma Engida , Hillier Susan , Gillam Marianne , Gray Richard , Jones Martin
Published: March 2023

Objectives

Post-stroke depression (PSD) affects one third of stroke survivors and substantially impacts recovery, so it is important to identify effective treatments for PSD. Behavioural activation (BA), a relatively simple intervention, has demonstrated efficacy in the treatment of adults with unipolar depression. However, its use and efficacy in the treatment of PSD has not been documented in a systematic review. This systematic review and meta-analysis considers: What effect does BA have on reducing depression symptoms in individuals diagnosed with PSD?

Method

MEDLINE, Embase, Emcare, Cochrane Library, and PsycINFO, were searched for randomised controlled trials (RCTs) published in English, on 13 July 2021. To chart the data, we employed a customized extraction sheet. The Cochrane Collaboration risk-of-bias 2 tool was used to determine study quality.

Results

Two papers, written by the same lead authors, met the inclusion criteria. The Communication and Low Mood trial and the Behavioural Activation Therapy for Post-Stroke Depression trial were conducted in the United Kingdom and published in 2012 and 2019, respectively. Meta-analysis showed BA was associated with a decrease in depression symptoms in patients with PSD relative to treatment as usual (standard mean difference (SMD) -0.54; 95% confidence interval (CI) -0.90 to -0.18).

Conclusion

BA may be more effective when compared to treatment as usual in reducing depression symptoms in individuals with PSD. Although our meta-analysis found positive effects of BA, the evidence is inconclusive due to the small number of studies. High-quality RCTs are needed to confirm the benefits of BA in PSD.

Strengths and limitations of this study

This review followed PRISMA guidelines with a protocol published in advance of the review being conducted.

This is the first review to consider whether BA is effective in reducing PSD.

We focused on depression as a single primary outcome; other outcome measures, such as quality of life, could have been considered.

Based on the review questions inclusion was limited to experimental designs. Other designs provide additional insights into the application of BA to PSD that is beyond the scope of this study.

Our review was restricted to studies published in English and did not examine grey literature; therefore, some studies may not have been included.
Association of Time Course of Thrombectomy and Outcomes for Large Acute Ischemic Region: RESCUE-Japan LIMIT Sub-Analysis
Authors: Ishihara Hideyuki , Nishimoto Takuma , Shimokawa Mototsugu , Oka Fumiaki , Sakai Nobuyuki , Yamagami Hiroshi , Toyoda Kazunori , Matsumaru Yuji , Matsumoto Yasushi , Kimura Kazumi , Ishikura Reiichi , Inoue Manabu , Uchida Kazutaka , Sakakibara Fumihiro , Morimoto Takeshi , Yoshimura Shinichi ,   the RESCUE Japan LIMIT Investigators
Published: March 2023

Background

The effectiveness of endovascular thrombectomy (EVT) has been proven even in patients with large cerebral infarction in early time window. However, the association of the time course with the treatment effect is unknown. The aim of this analysis was to evaluate the influence of the time course from stroke onset to reperfusion on the therapeutic effect of EVT.

Methods

The subjects were patients with occlusion of large vessels and sizable strokes on imaging (ASPECTS 3 to 5) in RESCUE-Japan LIMIT (a multicenter, randomized clinical open-label trial of EVT vs. medical care alone). In the current analysis, the clinical and time course characteristics associated with a favorable outcome (modified Rankin Scale (mRS) 0-2 and 0-3 at 90 days) were examined in patients treated with EVT.

Results

The analysis included 71 patients (median age, 77 years; median NIHSS score on admission, 21). Occlusion sites were the internal carotid artery (48%), M1 segment of the middle cerebral artery (72%) and tandem lesions (20%). Of these patients, 23 (32%) had mRS 0-3 and 12 (17%) had mRS 0-2 at 90 days. In multivariate analysis, there were independent associations of onset to reperfusion time (OR, 0.991; 95% CI, 0.984-0.999, P = 0.01) and puncture to reperfusion time (OR, 0.952; 95% CI, 0.917-0.988, P < 0.001) with mRS 0-3 at 90 days, and of puncture to reperfusion time (OR, 0.930; 95% CI, 0.872-0.991, P = 0.004) with mRS 0-2 at 90 days.

Conclusions

Earlier reperfusion was related to a favorable outcome in patients with acute large vessel occlusion with a large ischemic region. Onset to reperfusion time and especially puncture to reperfusion time were independently associated with a favorable outcome. These results suggest the importance of timing and uninterrupted EVT in this patient population.
Reimbursement for Maxillofacial Surgery: Regional Analysis of the Physician Fee Schedule Reveals Unique Payment Increases in the Western United States From 2010 to 2019
Authors: Tran Angelina Thuy , Diaz Michael Joseph , Batchu Sai
Published: March 2023

Introduction

Medicare Part B reimbursement data has been thoroughly evaluated in several surgical subspecialties to date, with significant ramifications for continued policy research and payment reform discussions. However, trends in maxillofacial surgery payment remain unstudied.

Methods

In this cross-sectional study of Part B reimbursement data, we analyzed regional trends in reimbursement for common maxillofacial repair and reconstruction procedures (N=17). All payment data converted to January 2019 United States dollars.

Results

From 2010 to 2019, fees for maxillofacial surgery evidenced strong region- and procedures-specific changes. After adjusting for inflation, the Southern United States reported an unweighted mean change in Medicare reimbursement of negative 12.59% (SD = 2.63%), while the Western United States reported an unweighted mean change in Medicare reimbursement of +0.08% (SD = 2.82%). In the Midwest, only Part B billing for reconstruction of the mandibular rami and/or body without internal rigid fixation (CPT code 21195) kept up with inflation. In the West, 8 CPT codes (47%) kept up with inflation: 21422, 21246, 21196, 21195, 21194, 21193, 21048, and 21046. In the Northeast and the South, all analyzed procedures reported decreased reimbursement rates after adjusting for inflation.

Conclusion

Reimbursement for maxillofacial surgery has lagged behind inflation with pronounced regional bias.
Public engagement with biomedical science: An analysis of Black, Hispanic, and General Population adults in the United States
Authors: Abeles Adina T. , Hari Kishore , Manento Cory , Block Kyle , Musch Stefan , Schuldt Jonathon P. , Simoncelli Tania
Published: March 2023

The COVID-19 pandemic has highlighted the need to better understand public engagement with biomedical science across groups–especially those that have been historically marginalized by the medical science community. However, common approaches to studying group differences in science attitudes are often limited by small sample sizes or by categorizing individuals based on demographic variables, which may obscure meaningful variability within a given population. We recruited three probability-based samples of Black (N = 963), General Population (N = 957), and Hispanic (N = 964) adults living in the U.S. (October 21 - November 5, 2021). Employing a novel application of a non-negative matrix factorization model to conduct an attitudinal-based segmentation that categorized individuals based on distinct orientations toward biomedical science, our analysis revealed 10 unique mindsets across the three surveyed populations. Overall, our work underscores the value of recruiting independent samples from underserved and marginalized communities by revealing underexplored variation in how different publics orient toward biomedical science.

Teaser

Using a values-based segmentation approach, we uncover 10 unique biomedical mindsets in the general, Black, and Hispanic adult populations in the U.S.
Human assembloids reveal the consequences ofCACNA1Ggene variants in the thalamocortical pathway
Authors: Kim Ji-il , Miura Yuki , Li Min-Yin , Revah Omer , Selvaraj Sridhar , Birey Fikri , Meng Xiangling , Thete Mayuri Vijay , Pavlov Sergey D. , Andersen Jimena , Pașca Anca M. , Porteus Matthew H. , Huguenard John R. , Pașca Sergiu P.
Published: March 2023

Abnormalities in crosstalk between the thalamus and the cerebral cortex are thought to lead to severe neuropsychiatric disorders, such as epilepsy and psychotic disorders. Pathogenic variants in the CACNA1G gene, which encodes the α1G subunit of the thalamus-enriched T-type voltage-gated calcium channel CaV3.1, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit level consequences of these genetic variants in humans remain unknown. Here, we developed an in vitro human assembloid model of the thalamocortical pathway to systematically dissect the contribution of genetic variants in T-type calcium channels. We discovered that a CACNA1G variant (M1531V) associated with seizures led to changes in T-type currents in human thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in thalamo-cortical assembloids. In contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant thalamic axonal projections. Taken together, these results illustrate the utility of organoid and assembloid systems for interrogating human genetic disease risk variants at both cellular and circuit level.
Comprehensive characterization of the complex BAHD acyltransferase family from 218 land plants species: phylogenomic analysis and identification of specificity determinant positions
Authors: Villarreal Fernando , Amalfitano Agustin , Atencio Hugo Marcelo , Stocchi Nicolas , ten Have Arjen
Published: March 2023

Chemodiversity is a fundamental trait acquired by plants during their land’s colonization. This resulted from an evolutionary process leading to the increase in the number of homologues from a distinct set of protein superfamilies, many of them associated to the specialized metabolism, which allowed the expansion of the chemical space to cope with several environmental cues. BAHD acyltransferases are among these important superfamilies, catalyzing a reaction leading to the acylation of acceptor metabolites with Coenzyme A-activated donors. BAHD acyltransferases can use a wide variety of substrates and they often times display substrate permissiveness towards a wide variety of substrates. Together, these factors complicates the reliable identification and functional annotation of BAHD homologues, also due to the (relatively) limited amount of biochemical data on BAHD acyltransferases. In this work, we take a phylogenomics and computational approach to study the BAHD superfamily in land plants. Using a clustered training set with 27 proteomes, followed by the classification of additional 191 proteomes, we obtained a final BAHDome with 15607 homologues. The training set was clustered in 16 groups, that, together with the identification of cluster of orthologues from the complete BAHDome, were partially assigned functionally to different families guided by the characterized activities (in terms of metabolites used) present in each group. However, the function assignation was not direct in several cases, due to large sequence number, taxonomical distribution on the group, and high sequence variability intra-group. Finally, we used the different families (and functional subfamilies) identified to detect specificity determining positions (SDPs), that may account to explain the functional diversity by finding key positions in, for example, substrate interaction. However, only a handful of the SDPs identified in this work are linked to the substrate binding pocket. Together, these results allow to partially annotate functional BAHD families, which have evolved in a complex pattern of taxonomical and functional signals to allow interaction with multiple substrates, more likely associated to protein dynamics rather than direct substrate interaction.
Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism
Authors: Yamashita Akihiro , Ignatenko Olesia , Nguyen Mai , Lambert Raphaëlle , Watt Kathleen , Daneault Caroline , Robillard-Frayne Isabelle , Topisirovic Ivan , Rosiers Christine Des , McBride Heidi M.
Published: March 2023

Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell type-specific manner. However, the mechanisms by which the status of peroxisomes is communicated and integrated into cellular signaling pathways is not yet understood. Herein, we report the cellular responses to acute peroxisomal proteotoxic stress upon silencing the peroxisomal protease/chaperone LONP2. Depletion of LONP2 triggered accumulation of its substrates, alterations in peroxisome size and numbers, and luminal protein import failure. Gene expression changes and lipidomic analysis revealed striking cell specific differences in the response to siLONP2. Specific to COS-7 cells was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway, and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These unexpected consequences of peroxisomal stress provide an important insight for our understanding of the tissue-specific responses seen in peroxisomal disorders.
Decision uncertainty as a context for motor memory
Authors: Ogasa Kisho , Yokoi Atsushi , Okazawa Gouki , Nishigaki Morimichi , Hirashima Masaya , Hagura Nobuhiro
Published: March 2023

The current view of perceptual decision-making suggests that once the decision is made, a single motor program associated with the decision is carried out, irrespective of the degree of uncertainty involved in the decision-making process. As opposed to this view, we show that different levels of decision uncertainty contextualize actions differently, allowing the brain to form different motor memories based on each context. The match between decision uncertainty during learning and retrieval is critical for successful motor memory retrieval. The same movement trajectory can be associated with different motor memories if each memory is linked to a different level of decision uncertainty. Encoding motor memories based on decision contexts may enhance the robustness of control during the varying neural activities induced by different cognitive states.
Human relevant exposure to di-n-butyl phthalate tampers with the ovarian insulin-like growth factor 1 system and disrupts folliculogenesis in young adult mice
Authors: Jauregui Estela J. , McSwain Maile , Liu Xiaosong , Miller Kara , Burns Kimberlie , Craig Zelieann R.
Published: March 2023

Phthalates are compounds used in consumer and medical products worldwide. Phthalate exposure in women has been demonstrated by detection of phthalate metabolites in their urine and ovarian follicular fluid. High urinary phthalate burden has been associated with reduced ovarian reserve and oocyte retrieval in women undergoing assisted reproduction. Unfortunately, no mechanistic explanation for these associations is available. In short term in vivo and in vitro animal studies modeling human relevant exposures to di-n-butyl phthalate (DBP), we have identified ovarian folliculogenesis as a target for phthalate exposures. In the present study, we investigated whether DBP exposure negatively influences insulin-like growth factor 1 (IGF) signaling in the ovary and disrupts ovarian folliculogenesis. CD-1 female mice were exposed to corn oil (vehicle) or DBP (10 or 100 μg/kg/day) for 20-32 days. Ovaries were collected as animals reached the proestrus stage to achieve estrous cycle synchronization. Levels of mRNAs encoding IGF1 and 2 (Igf1andIgf2), IGF1 receptor (Igf1r), and IGF binding proteins 1-6 (Ifgbp1-6) were measured in whole ovary homogenates. Ovarian follicle counts and immunostaining for phosphorylated IGF1R protein (pIGF1R) were used to evaluate folliculogenesis and IGF1R activation, respectively. DBP exposure, at a realistic dose that some women may experience (100 μg/kg/day for 20-32 days), reduced ovarianIgf1andIgf1rmRNA expression and reduced small ovarian follicle numbers and primary follicle pIGF1R positivity in DBP-treated mice. These findings reveal that DBP tampers with the ovarian IGF1 system and provide molecular insight into how phthalates could influence the ovarian reserve in females.
Molecular dynamics simulations illuminate the role of sequence context in the ELF3-PrD-based temperature sensing mechanism in plants
Authors: Lindsay Richard J. , Viegas Rafael Giordano , Leite Vitor B. P. , Wigge Philip A. , Hanson Sonya M.
Published: March 2023

The evening complex (EC) is a tripartite DNA repressor and a core component of the circadian clock that provides a mechanism for temperature-responsive growth and development of many plants. ELF3, a component of the EC, is a disordered scaffolding protein that blocks transcription of growth genes at low temperature. At increased temperature EC DNA binding is disrupted and ELF3 is sequestered in a reversible nuclear condensate, allowing transcription and growth to proceed. The condensation is driven by a low complexity prion-like domain (PrD), and the sensitivity of the temperature response is modulated by the length of a variable polyQ tract, with a longer polyQ tract corresponding to enhanced condensate formation and hypocotyl growth at increased temperature. Here, a series of computational studies provides evidence that polyQ tracts promote formation of temperature-sensitive helices in flanking residues with potential impacts for EC stability under increasing temperature. REST2 simulations uncover a heat-induced population of condensation-prone conformations that results from the exposure of ‘sticky’ aromatic residues by temperature-responsive breaking of long-range contacts. Coarse-grained Martini simulations reveal both polyQ tract length and sequence context modulate the temperature dependence of cluster formation. Understanding the molecular mechanism underlying the ELF3-PrD temperature response in plants has implications for technologies including modular temperature-response elements for heat-responsive protein design and agricultural advances to enable optimization of crop yields and allow plants to thrive in increasingly inhospitable environments.
Identification of mammalian transcription factors that bind to inaccessible chromatin
Authors: Pop Romana T. , Pisante Alessandra , Nagy Dorka , Martin Patrick C. N. , Mikheeva Liudmila A , Hayat Ateequllah , Ficz Gabriella , Zabet Nicolae Radu
Published: March 2023

Transcription factors (TFs) are proteins that affect gene expression by binding to regulatory regions of DNA in a sequence specific manner. The binding of TFs to DNA is controlled by many factors, including the DNA sequence, concentration of TF, chromatin accessibility and co-factors. Here, we systematically investigated the binding mechanism of hundreds of TFs by analysing ChIP-seq data with our explainable statistical model, ChIPanalyser. This tool uses as inputs the DNA sequence binding motif; the capacity to distinguish between strong and weak binding sites; the concentration of TF; and chromatin accessibility. We asked whether TFs preferred to bind to DNA in open or dense chromatin conformation and found that approximately one third of TFs are predicted to bind the genome in a DNA accessibility independent fashion. Our model predicted this to be the case when the TF binds to its strongest binding regions in the genome, and only a small number of TFs have the capacity to bind dense chromatin at their weakest binding regions, such as CTCF USF2 and CEBPB. Our study demonstrated that the binding of hundreds of human and mouse TFs is predicted by ChIPanalyser with high accuracy and showed that many TFs can bind dense chromatin.
NAC1 directs CEP1-CEP3 peptidase expression and modulates root hair growth in Arabidopsis
Authors: Rodríguez-García Diana R. , Guerrero Yossmayer del Carmen Rondón , Ferrero Lucía , Rossi Andrés Hugo , Miglietta Esteban A. , Aptekmann Ariel A. , Marzol Eliana , Pacheco Javier Martínez , Carignani Mariana , Gabarain Victoria Berdion , Lopez Leonel E. , Dominguez Gabriela Díaz , Borassi Cecilia , Sánchez-Serrano José Juan , Xu Lin , Nadra Alejandro D. , Rojo Enrique , Ariel Federico , Estevez José M.
Published: March 2023

Plant genomes encode a unique group of papain-type Cysteine EndoPeptidases (CysEPs) containing a KDEL endoplasmic reticulum (ER) retention signal (KDEL-CysEPs or CEPs). CEPs process the cell-wall scaffolding EXTENSIN proteins (EXTs), which regulatede novocell wall formation and cell expansion. Since CEPs are able to cleave EXTs and EXT-related proteins, acting as cell wall-weakening agents, they may play a role in cell elongation.Arabidopsis thalianagenome encodes three CEPs (AtCPE1-AtCEP3). Here we report that the three Arabidopsis CEPs,AtCEP1-AtCEP3,are highly expressed in root-hair cell files. Single mutants have no evident abnormal root-hair phenotype, butatcep1-3 atcep3-2andatcep1-3 atcep2-2double mutants have longer root hairs (RHs) than wild type (Wt) plants, suggesting that expression ofAtCEPsin root trichoblasts restrains polar elongation of the RH. We provide evidence that the transcription factorNAC1activates AtCEPs expression in roots to limit RH growth. Chromatin immunoprecipitation indicates that NAC1 binds the promoter ofAtCEP1, AtCEP2,and to a lower extent toAtCEP3and may directly regulate their expression. Indeed, inducibleNAC1overexpression increasesAtCEP1 and AtCEP2transcript levels in roots and leads to reduced RH growth while the loss of functionnac1-2mutation reducesAtCEP1-AtCEP3gene expression and enhances RH growth. Likewise, expression of a dominant chimeric NAC1-SRDX repressor construct leads to increased RH length. Finally, we show that RH cell walls in theatcep1-1 atcep3-2double mutant have reduced levels of EXT deposition, suggesting that the defects in RH elongation are linked to alterations in EXT processing and accumulation. Taken together, our results support the involvement of AtCEPs in controlling RH polar growth through EXT-processing and insolubilization at the cell wall.
CanFlyet: Habitat Zone and Diet Trait Dataset for Diptera Species of Canada and Greenland
Authors: Majoros S.E. , Adamowicz S.J.
Published: March 2023

Background

True flies (Diptera) are an ecologically important group that play a role in agriculture, public health and ecosystem functioning. As researchers continue to investigate this order, it is beneficial to link the growing occurrence data to biological traits. However, large-scale ecological trait data are not readily available for fly species. While some databases and datasets include fly data, many ecologically relevant traits for taxa of interest are not included. In this study we create a dataset containing ecological traits (habitat and diet) for fly species of Canada and Greenland having occurrence records on the Barcode of Life Data Systems (BOLD). We present a dataset containing trait information for 981 Diptera species.

New Information

Diptera were chosen for the dataset based on the occurrence records available for Diptera species from Canada and Greenland on the Barcode of Life Data Systems (BOLD). Trait data were then compiled based on literature searches conducted from April 2021 - April 2024 and assigned at the lowest taxonomic level possible. Three biological traits were included: habitat, larval diet, and adult diet. The dataset contains traits for 981 species across 380 genera, 34 subfamilies, and 61 families. This dataset allows for assignment of traits to occurrence data for Diptera species and can be used for further research into the ecology, evolution, and conservation of this order.
Accurate estimation of rare cell type fractions from tissue omics data via hierarchical deconvolution
Authors: Huang Penghui , Cai Manqi , Lu Xinghua , McKennan Chris , Wang Jiebiao
Published: March 2023

Bulk transcriptomics in tissue samples reflects the average expression levels across different cell types and is highly influenced by cellular fractions. As such, it is critical to estimate cellular fractions to both deconfound differential expression analyses and infer cell type-specific differential expression. Since experimentally counting cells is infeasible in most tissues and studies,in silicocellular deconvolution methods have been developed as an alternative. However, existing methods are designed for tissues consisting of clearly distinguishable cell types and have difficulties estimating highly correlated or rare cell types. To address this challenge, we propose Hierarchical Deconvolution (HiDecon) that uses single-cell RNA sequencing references and a hierarchical cell type tree, which models the similarities among cell types and cell differentiation relationships, to estimate cellular fractions in bulk data. By coordinating cell fractions across layers of the hierarchical tree, cellular fraction information is passed up and down the tree, which helps correct estimation biases by pooling information across related cell types. The flexible hierarchical tree structure also enables estimating rare cell fractions by splitting the tree to higher resolutions. Through simulations and real data applications with the ground truth of measured cellular fractions, we demonstrate that HiDecon significantly outperforms existing methods and accurately estimates cellular fractions.
Root system growth and function response to soil temperature in maize (Zea maysL.)
Authors: Clark Randy , Chamberlain Dan , Diepenbrock Christine , Cooper Mark , Messina Carlos D.
Published: March 2023

Crop adaptation to the mixture of environments that defines the target population of environments is the result from a balanced resource allocation between roots, shoots and reproductive organs. Root growth places a critical role in the determination of this balance. Root growth and function responses to temperature can determine the strength of roots as sinks but also influence the crop’s ability to uptake water and nutrients. Surprisingly, this behavior has not been studied in maize since the middle of the last century, and the genetic determinants are unknown. Low temperatures often recorded in deep soil layers limit root growth and soil exploration and may constitute a bottleneck towards increasing drought tolerance, nitrogen recovery, sequestration of carbon and productivity in maize. High throughput phenotyping (HTP) systems were developed to investigate these responses and to examine genetic variability therein across diverse maize germplasm. Here we show that there is: 1) genetic variation of root growth under low temperature and below 10°C, and 2) genotypic variation in water transport under low temperature. Using simulation, we demonstrate that the measured variation for both traits contribute to drought tolerance and explain important components of yield variation in the US corn-belt. The trait set examined herein and HTP platform developed for its characterization reveal a unique opportunity to remove a major bottleneck for crop improvement, and adaptation to climate change.
3DMolMS: Prediction of Tandem Mass Spectra from Three Dimensional Molecular Conformations
Authors: Hong Yuhui , Li Sujun , Welch Christopher J. , Tichy Shane , Ye Yuzhen , Tang Haixu
Published: March 2023

Motivation

Tandem mass spectrometry is an essential technology for characterizing chemical compounds at high sensitivity and throughput, and is commonly adopted in many fields. However, computational methods for automated compound identification from their MS/MS spectra are still limited, especially for novel compounds that have not been previously characterized. In recent years,in silicomethods were proposed to predict the MS/MS spectra of compounds, which can then be used to expand the reference spectral libraries for compound identification. However, these methods did not consider the compounds’ three-dimensional (3D) conformations, and thus neglected critical structural information.

Results

We present the3D Molecular Network forMassSpectra Prediction (3DMolMS), a deep neural network model to predict the MS/MS spectra of compounds from their 3D conformations. We evaluated the model on the experimental spectra collected in several spectral libraries. The results showed that 3DMolMS predicted the spectra with the average cosine similarity of 0.687 and 0.475 with the experimental MS/MS spectra acquired in positive and negative ion modes, respectively. Furthermore, 3DMolMS model can be generalized to the prediction of MS/MS spectra acquired by different labs on different instruments through minor fine-tuning on a small set of spectra. Finally, we demonstrate that themolecular representationlearned by 3DMolMS from MS/MS spectra prediction can be adapted to enhance the prediction of chemical properties such as the elution time (ET) in the liquid chromatography and the Collisional Cross Section (CCS) measured by ion mobility spectrometry (IMS), both of which are often used to improve compound identification.

Contact

hatang@indiana.edu

Supplementary information

The codes of 3DMolMS is available athttps://github.com/JosieHong/3DMolMSand the web service is athttps://spectrumprediction.gnps2.org.
Social association predicts immunological similarity in rewilded mice
Authors: Downie A. E. , Oyesola O. , Barre R. S. , Caudron Q. , Chen Y.-H. , Dennis E. J. , Garnier R. , Kiwanuka K. , Menezes A. , Navarrete D. J. , Mondragón-Palomino O. , Saunders J. B. , Tokita C. K. , Zaldana K. , Cadwell K. , Loke P. , Graham A. L.
Published: March 2023

Environmental influences on immune phenotypes are well-documented, but our understanding of which elements of the environment affect immune systems, and how, remains vague. Behaviors, including socializing with others, are central to an individual’s interaction with its environment. We tracked behavior of rewilded laboratory mice of three inbred strains in outdoor enclosures and examined contributions of behavior, including social associations, to immune phenotypes. We found that the more associated two individuals were, the more similar their immune phenotypes were. Social association was particularly predictive of similar memory T and B cell profiles and was more influential than sibling relationships or worm infection status. These results highlight the importance of social networks for immune phenotype and reveal important immunological correlates of social life.
Phase Separation in Mixtures of Prion-Like Low Complexity Domains is Driven by the Interplay of Homotypic and Heterotypic Interactions
Authors: Farag Mina , Borcherds Wade M. , Bremer Anne , Mittag Tanja , Pappu Rohit V.
Published: March 2023

Prion-like low-complexity domains (PLCDs) are involved in the formation and regulation of distinct biomolecular condensates that form via coupled associative and segregative phase transitions. We previously deciphered how evolutionarily conserved sequence features drive phase separation of PLCDs through homotypic interactions. However, condensates typically encompass a diverse mixture of proteins with PLCDs. Here, we combine simulations and experiments to study mixtures of PLCDs from two RNA binding proteins namely, hnRNPA1 and FUS. We find that 1:1 mixtures of the A1-LCD and FUS-LCD undergo phase separation more readily than either of the PLCDs on their own. The enhanced driving forces for phase separation of mixtures of A1-LCD and FUS-LCD arise partly from complementary electrostatic interactions between the two proteins. This complex coacervation-like mechanism adds to complementary interactions among aromatic residues. Further, tie line analysis shows that stoichiometric ratios of different components and their sequence-encoded interactions jointly contribute to the driving forces for condensate formation. These results highlight how expression levels might be tuned to regulate the driving forces for condensate formationin vivo. Simulations also show that the organization of PLCDs within condensates deviates from expectations based on random mixture models. Instead, spatial organization within condensates will reflect the relative strengths of homotypic versus heterotypic interactions. We also uncover rules for how interaction strengths and sequence lengths modulate conformational preferences of molecules at interfaces of condensates formed by mixtures of proteins. Overall, our findings emphasize the network-like organization of molecules within multicomponent condensates, and the distinctive, composition-specific conformational features of condensate interfaces.

Significance Statement

Biomolecular condensates are mixtures of different protein and nucleic acid molecules that organize biochemical reactions in cells. Much of what we know about how condensates form comes from studies of phase transitions of individual components of condensates. Here, we report results from studies of phase transitions of mixtures of archetypal protein domains that feature in distinct condensates. Our investigations, aided by a blend of computations and experiments, show that the phase transitions of mixtures are governed by a complex interplay of homotypic and heterotypic interactions. The results point to how expression levels of different protein components can be tuned in cells to modulate internal structures, compositions, and interfaces of condensates, thus affording distinct ways to control the functions of condensates.
Remote neuronal activity drives glioma infiltration via Sema4f
Authors: Huang-Hobbs Emmet , Cheng Yi-Ting , Ko Yeunjung , Luna-Figueroa Estefania , Lozzi Brittney , Taylor Kathryn R , McDonald Malcolm , He Peihao , Chen Hsiao-Chi , Yang Yuhui , Maleki Ehson , Lee Zhung-Fu , Murali Sanjana , Williamson Michael , Choi Dongjoo , Curry Rachel , Bayley James , Woo Junsung , Jalali Ali , Monje Michelle , Noebels Jeffrey L , Harmanci Akdes Serin , Rao Ganesh , Deneen Benjamin
Published: March 2023

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput,in vivoscreening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.
Tissue-engineered models of lung cancer premalignancy
Authors: Blomberg Rachel , Sompel Kayla , Hauer Caroline , Peña Brisa , Driscoll Jennifer , Hume Patrick S. , Merrick Daniel T. , Tennis Meredith A. , Magin Chelsea M.
Published: March 2023

Lung cancer is the leading global cause of cancer-related deaths. Although smoking cessation is the best preventive action, nearly 50% of all lung cancer diagnoses occur in people who have already quit smoking. Research into treatment options for these high-risk patients has been constrained to rodent models of chemical carcinogenesis, which are time-consuming, expensive, and require large numbers of animals. Here we show that embedding precision-cut lung slices within an engineered hydrogel and exposing this tissue to a carcinogen from cigarette smoke creates anin vitromodel of lung cancer premalignancy. Hydrogel formulations were selected to promote early lung cancer cellular phenotypes and extend PCLS viability up to six weeks. In this study, hydrogel-embedded lung slices were exposed to the cigarette smoke derived carcinogen vinyl carbamate, which induces adenocarcinoma in mice. At six weeks, analysis of proliferation, gene expression, histology, tissue stiffness, and cellular content revealed that vinyl carbamate induced the formation of premalignant lesions with a mixed adenoma/squamous phenotype. Two putative chemoprevention agents were able to freely diffuse through the hydrogel and induce tissue-level changes. The design parameters selected using murine tissue were validated with hydrogel-embedded human PCLS and results showed increased proliferation and premalignant lesion gene expression patterns. This tissue-engineered model of human lung cancer premalignancy is the starting point for more sophisticatedex vivomodels and a foundation for the study of carcinogenesis and chemoprevention strategies.
HBV rewires liver cancer signaling by altering PP2A complexes
Authors: Pitea Adriana , Turnham Rigney E , Eckhardt Manon , Jang Gwendolyn M , Xu Zhong , Lim Huat C , Choi Alex , Von Dollen John , Levin Rebecca S. , Webber James T , McCarthy Elizabeth , Hu Junjie , Li Xiaolei , Che Li , Chan Gary , Kelley R. Katie , Swaney Danielle , Zhang Wei , Bandyopadhyay Sourav , Theis Fabian J , Chen Xin , Shokat Kevan , Ideker Trey , Krogan Nevan J , Gordan John D
Published: March 2023

Infection by hepatitis B virus (HBV) increases risk for liver cancer by inducing inflammation, cellular stress and cell death. To elucidate the molecular pathways by which HBV promotes cancer development and progression, we used affinity purification mass spectrometry to comprehensively map a network of 145 physical interactions between HBV and human host proteins in hepatocellular carcinoma (HCC). We find that viral proteins target host factors that are preferentially mutated in non-HBV-associated HCC, implicating cancer pathways whose interaction with HBV plays a role in HCC. Focusing on proteins that directly interact with the HBV oncoprotein X (HBx), we show that HBx remodels the PP2A phosphatase complex, altering its effect on tumor signaling. HBx excludes striatin-family regulatory subunits from PP2A, causing Hippo kinase activation and unmasking a requirement for mTOR complex 2 to maintain expression of the YAP oncoprotein in HCC. Thus, HBV rewires HCC to expose potentially targetable signaling dependencies.

Significance

Precision medicine has revolutionized cancer treatment but remains elusive for HCC. We used proteomics to define HBV/host interactions and integrated them with HCC mutations. The results implicate modifiers of HCC behavior via remodeling of host complexes and illuminate new biological mechanisms in advanced disease for therapeutic investigation.
Shaken, not shifted: Genotypic variation tunes how interspecific competition shapes niches
Authors: Costa-Pereira Raul , Fragata Inês , Mira André , de la Masselière Maud Charlery , Hortal Joaquin , Magalhães Sara
Published: March 2023

Individual variation in resource use as well as in the response to competitors has been recognized as playing an important role is species interactions. Still, we have as yet little information on whether such responses have a genetic basis as well as on how they affect each other. Here, we tested whether 20 genetically inbred lines of the spider miteTetranychus evansivary in their response to a gradient of cadmium concentration within plants as well as in their propensity to reshape niches when facing interspecific competition along this gradient. In absence of interspecific competitors, most lines were negatively affected by cadmium, albeit often in a non-linear fashion. Morevoer, half of the lines exhibited changes in the curvature of the relationship between number of females and cadmium concentration when facing competition with the congenericT. urticae. Inbred lines also showed a shallower decay in offspring number along the cadmium gradient in presence of interspecific competition. Our findings provide evidence for large, partly genetic, variation in resource use and in the response to interspecific competition in heterogeneous environments. Moreover, we show that genotype responses to interspecific competition is contingent upon their response to an environmental gradient. Together, our results thus emphasize the importance of considering intraspecific variation in responses to interspecific competition, providing novel insights to link intra- and interspecific levels of biodiversity.
A Novel Silver-Containing Antimicrobial potentiates aminoglycoside activity againstPseudomonas aeruginosa
Authors: Donkor Gracious Yoofi , Anderson Greg M. , Stadler Michael , Tawiah Patrick Ofori , Orellano Carl D. , Edwards Kevin A. , Dahl Jan-Ulrik
Published: March 2023

The rapid dissemination of antibiotic resistance combined with the decline in the discovery of novel antibiotics represents a major challenge for infectious disease control that can only be mitigated by investments into novel treatment strategies. Alternative antimicrobials, including silver, have regained interest due to their diverse mechanisms of inhibiting microbial growth. One such example is AGXX®, a broad-spectrum silver containing antimicrobial that produces highly cytotoxic reactive oxygen species (ROS) to inflict extensive macromolecular damage. Due to connections identified between ROS production and antibiotic lethality, we hypothesized that AGXX® could potentially increase the activity of conventional antibiotics. Using the gram-negative pathogenPseudomonas aeruginosa, we screened possible synergistic effects of AGXX® on several antibiotic classes. We found that the combination of AGXX® and aminoglycosides tested at sublethal concentrations led to a rapid exponential decrease in bacterial survival and restored sensitivity of a kanamycin-resistant strain. ROS production contributes significantly to the bactericidal effects of AGXX®/aminoglycoside treatments, which is dependent on oxygen availability and can be reduced by the addition of ROS scavengers. Additionally,P. aeruginosastrains deficient in ROS detoxifying/repair genes were more susceptible to AGXX®/aminoglycoside treatment. We further demonstrate that this synergistic interaction was associated with significant increase in outer and inner membrane permeability, resulting in increased antibiotic influx. Our study also revealed that AGXX®/aminoglycoside-mediated killing requires an active proton motive force across the bacterial membrane. Overall, our findings provide an understanding of cellular targets that could be inhibited to increase the activity of conventional antimicrobials.

IMPORTANCE

The emergence of drug-resistant bacteria coupled with the decline in antibiotic development highlights the need for novel alternatives. Thus, new strategies aimed at repurposing conventional antibiotics have gained significant interest. The necessity of these interventions is evident especially in gram-negative pathogens as they are particularly difficult to treat due to their outer membrane. This study highlights the effectiveness of the silver containing antimicrobial AGXX® in potentiating aminoglycoside activities againstP. aeruginosa. The combination of AGXX® and aminoglycosides not only reduces bacterial survival rapidly but also significantly re-sensitizes aminoglycoside-resistantP. aeruginosastrains. In combination with gentamicin, AGXX® induces increased endogenous oxidative stress, membrane damage and iron sulfur cluster disruption. These findings emphasize AGXX®’s potential as a route of antibiotic adjuvant development and shed light into potential targets to enhance aminoglycoside activity.