bluuebunny/crossref_metadata_2025 huggingface dataset:
Solute Transporter OCTN1/Slc22a4 Affects Disease Severity and Response to Infliximab in Experimental Colitis: Role of Gut Microbiota and Immune Modulation
Authors: Del Chierico Federica , Masi Letizia , Petito Valentina , Baldelli Valerio , Puca Pierluigi , Benvenuto Roberta , Fidaleo Marco , Palucci Ivana , Lopetuso Loris Riccardo , Caristo Maria Emiliana , Carrozza Cinzia , Giustiniani Maria Cristina , Nakamichi Noritaka , Kato Yukio , Putignani Lorenza , Gasbarrini Antonio , Pani Giovambattista , Scaldaferri Franco
Published: June 2024

Background

Inflammatory bowel diseases are chronic disabling conditions with a complex and multifactorial etiology, still incompletely understood. OCTN1, an organic cation transporter, could have a role in modulating the inflammatory response, and some genetic polymorphisms of this molecule have been associated with increased risk of inflammatory bowel diseases. Until now, limited information exists on its potential in predicting/modulating patient’s response to therapies. The aim of this study was to evaluate the role of OCTN1 in modifying gut microbiota and mucosal immunity in response to infliximab therapy in murine colitis.

Methods

A dextran sodium sulphate model of colitis was used to assess the clinical efficacy of infliximab administered intravenously in ocnt1 gene knockout mice and their C57BL/6 controls. Stool, colon, and mesenteric lymph node samples were collected to evaluate differences in gut microbiota composition, histology, and T cell populations, respectively.

Results

Octn1 -/- influences the microbiota profile and is associated with a worse dysbiosis in mice with colitis. Infliximab treatment attenuates colitis-associated dysbiosis, with an increase of bacterial richness and evenness in both strains. In comparison with wild type, octn1-/- mice have milder disease and a higher baseline percentage of Treg, Tmemory, Th2 and Th17 cells.

Conclusions

Our data support the murine model to study OCTN1 genetic contribution to inflammatory bowel diseases. This could be the first step towards the recognition of this membrane transporter as a biomarker in inflammatory conditions and a predictor of response to therapies.
Detecting Temporal shape changes with the Euler Characteristic Transform
Authors: Marsh Lewis , Zhou Felix Y , Qin Xiao , Lu Xin , Byrne Helen M , Harrington Heather A
Published: July 2024

Organoids are multi-cellular structures that are cultured in vitro from stem cells to resemble specific organs (e.g., brain, liver) in their three-dimensional composition. Dynamic changes in the shape and composition of these model systems can be used to understand the effect of mutations and treatments in health and disease. In this paper, we propose a new technique in the field of topological data analysis for DEtecting Temporal shape changes with the Euler Characteristic Transform (DETECT). DETECT is a rotationally invariant signature of dynamically changing shapes. We demonstrate our method on a data set of segmented videos of mouse small intestine organoid experiments and show that it outperforms classical shape descriptors. We verify our method on a synthetic organoid data set and illustrate how it generalizes to 3D. We conclude that DETECT offers rigorous quantification of organoids and opens up computationally scalable methods for distinguishing different growth regimes and assessing treatment effects.
Affine Springer Fibers and Generalized Haiman Ideals (with an Appendix by Eugene Gorsky and Joshua P. Turner)
Authors: Turner Joshua P
Published: July 2024

We compute the Borel–Moore homology of unramified affine Springer fibers for $\textrm{Gr}_n$ under the assumption that they are equivariantly formal and relate them to certain ideals discussed by Haiman. For $n=3$, we give an explicit description of these ideals, compute their Hilbert series, generators, and relations, and compare them to generalized $(q,t)$-Catalan numbers. We also compare the homology to the Khovanov–Rozansky homology of the associated link, and prove a version of a conjecture of Oblomkov, Rasmussen, and Shende in this case.
Fast and Greener Ultrasound-Assisted Acid Extraction for the Determination of Potentially Toxic Elements in Fluorescent Lamp Waste Using ICP OES
Authors: Duarte Vitor Busto , Gonçalves Felippe Ceraso , Guimarães Júlia Concordido , Braz Bernardo Ferreira , Carneiro Manuel Castro , Santelli Ricardo Erthal , Paulino Jéssica Frontino , Pontes Fernanda Veronesi Marinho
Published: July 2024

Background

Understanding the chemical composition of fluorescent lamp residue, particularly potentially toxic elements, is crucial for reducing environmental impacts and human health risks after disposal. However, the challenge lies in effectively analyzing these heterogeneous solid samples. Techniques involving quantitative dissolution become imperative, playing a fundamental role in quantifying trace elements.

Objective

The aim of this work is to develop and present a new, faster, and more efficient and environmentally friendly method using ultrasound-assisted acid extraction to quantify potentially toxic elements (Cu, Mn, Ni, Sr, and Zn) present in fluorescent lamp waste using the inductively coupled plasma-optical emission spectrometry technique.

Methods

An ultrasound-assisted acid extraction method for the quantification of potentially toxic elements in fluorescent lamp waste was developed and applied as a greener alternative to conventional digestion methods. For variable optimization, a full factorial design with two levels and two variables (time and temperature) was used to determine which factors significantly affected the observed response.

Results

The results obtained for the developed extraction method were compared with a reference method employing a heating acid digestion (with a mixture of HCl, HClO4, and HF) using statistical tools. The best results were obtained using an extraction time of 10 min and a temperature of 25°C. Inductively coupled plasma optical emission spectrometry was applied for element quantification.

Conclusion

The proposed extraction method showed good results for Cu, Mn, Ni, Sr, and Zn. Furthermore, the proposed method based on ultrasound radiation presents additional criteria that align with the concepts of green analytical chemistry.

Highlights

A greener alternative method for the determination of Cu, Mn, Ni, Sr, and Zn in fluorescent lamp waste was developed. Optimal conditions for ultrasound extraction of potentially toxic elements were achieved in 10 min at a temperature of 25°C. Environmentally friendly aspects of ultrasound align with the requirements of green analytical chemistry.
Why and How Consumers Perform Online Reviewing Differently
Authors: de Kerviler Gwarlann , Demangeot Catherine , Dolbec Pierre-Yann
Published: July 2024

Reviewing products and services is a widespread consumer activity in which millions engage. Why and how do consumers review differently from one another? Prior work assumes that consumers commonly understand what reviewing is. Consequently, it attributes differences in reviewing to individual variations in psychological, motivational, and sociodemographic characteristics, consumption experiences, and expertise. This central assumption is problematic because it fails to consider that differences in how consumers understand reviewing may explain why they approach and perform reviewing differently. To address this gap, we analyze a large qualitative dataset composed of reviews and interviews with their authors. Our insights complement prior work by theorizing the sociocultural shaping of reviewing. We answer why consumers review differently by inductively theorizing the concept of reviewing orientation—a cultural model comprising a set of interconnected characteristics that shapes how consumers review and translates into a distinct reviewer voice—a reviewer’s standpoint expressed within a review. We answer how consumers review differently by developing three reviewing orientations: communal sharing, systemic evaluation, and competitive punditry. Finally, we discuss the transferability of the findings, the role of institutional dynamics in reviewing, and recommendations for online review platforms and marketers.
Harvesting insect pests for animal feed: potential to capture an unexploited resource
Authors: Cohnstaedt Lee W , Lado Paula , Ewing Robert , Cherico Jason , Brabec Daniel , Shults Phillip , Arsi Komala , Donoghue Ann M , Wagner Roy , Chaskopoulou Alexandra
Published: July 2024

The demand for animal protein grows as the human population increases. Technological and genetic advances in traditional animal agriculture will not produce enough protein to meet future needs without significant innovations such as the use of insects as protein sources. Insect farming is growing insects, whereas insect harvesting is collecting insects from their natural habitats to produce high-quality protein for animal feed or human food. Intensive agricultural environments produce tremendous quantities of pestiferous insects and with the right harvest technologies these insects can be used as a protein supplement in traditional animal daily rations. An avenue to exploit these insects is to use traps such as the United States Department of Agriculture-Biomass Harvest Trap (USDA-BHT) to efficiently attract, harvest, and store insects from naturally abundant agricultural settings. The modular design allows for a low cost, easy to build and fix device that is user friendly and has customizable attractants to target various pest species. Although insect harvesting faces substantial challenges, including insect biomass quantity, seasonal abundance and preservation, food safety, and economic and nutritional evaluation, the potential for utilizing these pests for protein shows tremendous promise. In this forum, insect harvesting is discussed, including its potential, limitations, challenges, and research needs. In addition, the use of a mass trapping device is discussed as a tool to increase the biomass of insects collected from the environment.
A cargo sorting receptor mediates chloroplast protein trafficking through the secretory pathway
Authors: Liu Jinling , Chen Hong , Liu Li , Meng Xiangzhao , Liu Qianwen , Ye Qinyi , Wen Jiangqi , Wang Tao , Dong Jiangli
Published: July 2024

Nucleus-encoded chloroplast proteins can be transported via the secretory pathway. The molecular mechanisms underlying the trafficking of chloroplast proteins between the intracellular compartments are largely unclear, and a cargo sorting receptor has not previously been identified in the secretory pathway. Here, we report a cargo sorting receptor that is specifically present in Viridiplantae and mediates the transport of cargo proteins to the chloroplast. Using a forward genetic analysis, we identified a gene encoding a transmembrane protein (MtTP930) in barrel medic (Medicago truncatula). Mutation of MtTP930 resulted in impaired chloroplast function and a dwarf phenotype. MtTP930 is highly expressed in the aerial parts of the plant and is localized to the endoplasmic reticulum (ER) exit sites and Golgi. MtTP930 contains typical cargo sorting receptor motifs, interacts with Sar1, Sec12, and Sec24, and participates in coat protein complex II vesicular transport. Importantly, MtTP930 can recognize the cargo proteins plastidial N-glycosylated nucleotide pyrophosphatase/phosphodiesterase (MtNPP) and α-carbonic anhydrase (MtCAH) in the ER and then transport them to the chloroplast via the secretory pathway. Mutation of a homolog of MtTP930 in Arabidopsis (Arabidopsis thaliana) resulted in a similar dwarf phenotype. Furthermore, MtNPP-GFP failed to localize to chloroplasts when transgenically expressed in Attp930 protoplasts, implying that these cargo sorting receptors are conserved in plants. These findings fill a gap in our understanding of the mechanism by which chloroplast proteins are sorted and transported via the secretory pathway.
Impaired myoblast differentiation and muscle IGF‐1 receptor signaling pathway activation after N‐glycosylation inhibition
Authors: Annibalini Giosuè , Di Patria Laura , Valli Giacomo , Bocconcelli Matteo , Saltarelli Roberta , Ferri Lorenzo , Barberi Laura , Fanelli Fabiana , Morrone Amelia , Barone Rita , Guerrini Renzo , Musarò Antonio , Stocchi Vilberto , Barbieri Elena
Published: July 2024

The role of N‐glycosylation in the myogenic process remains poorly understood. Here, we evaluated the impact of N‐glycosylation inhibition by Tunicamycin (TUN) or by phosphomannomutase 2 (PMM2) gene knockdown, which encodes an enzyme essential for catalyzing an early step of the N‐glycosylation pathway, on C2C12 myoblast differentiation. The effect of chronic treatment with TUN on tibialis anterior (TA) and extensor digitorum longus (EDL) muscles of WT and MLC/mIgf‐1 transgenic mice, which overexpress muscle Igf‐1Ea mRNA isoform, was also investigated. TUN‐treated and PMM2 knockdown C2C12 cells showed reduced ConA, PHA‐L, and AAL lectin binding and increased ER‐stress‐related gene expression (Chop and Hspa5 mRNAs and s/uXbp1 ratio) compared to controls. Myogenic markers (MyoD, myogenin, and Mrf4 mRNAs and MF20 protein) and myotube formation were reduced in both TUN‐treated and PMM2 knockdown C2C12 cells. Body and TA weight of WT and MLC/mIgf‐1 mice were not modified by TUN treatment, while lectin binding slightly decreased in the TA muscle of WT (ConA and AAL) and MLC/mIgf‐1 (ConA) mice. The ER‐stress‐related gene expression did not change in the TA muscle of WT and MLC/mIgf‐1 mice after TUN treatment. TUN treatment decreased myogenin mRNA and increased atrogen‐1 mRNA, particularly in the TA muscle of WT mice. Finally, the IGF‐1 production and IGF1R signaling pathways activation were reduced due to N‐glycosylation inhibition in TA and EDL muscles. Decreased IGF1R expression was found in TUN‐treated C2C12 myoblasts which was associated with lower IGF‐1‐induced IGF1R, AKT, and ERK1/2 phosphorylation compared to CTR cells. Chronic TUN‐challenge models can help to elucidate the molecular mechanisms through which diseases associated with aberrant N‐glycosylation, such as Congenital Disorders of Glycosylation (CDG), affect muscle and other tissue functions.
Surgical Management of Spontaneous Lateral Skull Base Cerebrospinal Fluid Leaks: The Middle Cranial Fossa Approach
Authors: Gewirtz Jordan , Tiano Benjamin N. , Bendok Bernard R. , Deep Nicholas L.
Published: June 2024

This article provides the reader with a comprehensive overview of the middle cranial fossa approach for the surgical management of spontaneous lateral skull base cerebrospinal fluid (CSF) leaks. The relationship of spontaneous CSF leaks being related to obesity has been established, and there has been an increase in their frequency of late secondary to the increasing prevalence of obesity in the United States. These leaks require surgical intervention due to their associated morbidity. The selection of a specific surgical approach to repair the skull base must be personalized for the individual patient and is based on the location and size of the leak and the number of defects.
Case Study on Analysing the Early Disease Detection of Pancreatic Ductal Adenocarcinoma in Korean Association for Clinical Oncology
Authors: Ponnarassery Chandran Sijithra , Santhi N.
Published: July 2024

Objectives:

Pancreatic ductal adenocarcinoma (PDAC) is the most pervasive sort of pancreatic malignant growth. Due to the lack of early symptoms and effective methods for early detection and screening, the majority of patients (80% to 85%) are diagnosed with advanced metastatic or locally advanced disease, resulting in a low 5-year survival rate of 12%. The case study represents a comprehensive investigation into the intricate landscape of pancreatic cancer diagnosis within the Korean population.

Methods:

Grounded in epidemiological bits of knowledge, the review plans to disentangle the particular examples, commonness, and segment attributes of PDAC in Korea. By scrutinizing current diagnostic modalities, including conventional imaging techniques, molecular markers, and emerging technologies, the research seeks to evaluate the strengths and limitations of existing approaches within the Korean clinical context. Central to the study is an exploration of the collaborative initiatives spearheaded by the Association of Clinical Oncology in Korea in the domain of PDAC early detection. Analysing research projects, clinical trials, and interdisciplinary collaborations, the case study sheds light on the association’s pivotal role in driving innovation and progress in oncology.

Results:

The goal is to offer a detailed analysis of how the association helps in furthering knowledge and enhancing results in the management of PDAC. The case study delves into the implications of early PDAC detection for patient outcomes, emphasizing the significance of timely interventions and tailored treatment strategies. By outlining the potential benefits and challenges associated with early diagnosis, the study aims to inform health care policies, shape clinical guidelines, and guide future research priorities.

Conclusion:

Through a holistic approach, the case study endeavours to offer important experiences into the multifaceted landscape of PDAC early detection within the Korean health care system, contributing to the broader discourse on effective oncological practices and patient care.
An Investigation of Moxibustion Treatment for Abscesses in the Song Dynasty: Focusing on the "Jiu Ai Tu"
Authors: Wang Li
Published: July 2024

Jiu Ai Tu（灸艾图 The Moxa Treatment）from the Song dynasty is the earliest surviving painting that focuses on the subject of acupuncture and moxibustion. This paper takes the medical activities depicted in the artwork as its research object and systematically analyzes the external treatment methods for abscesses during the Song dynasty reflected in Jiu Ai Tu. By examining the understanding of abscesses during that period, the paper explores the level of development in external medicine techniques. By analyzing the medical awareness and behaviors of patients when facing such severe illnesses, it aims to explore the societal cognition and experiences regarding health and disease. The paper attempts to present the folk medical ecology of the Song dynasty represented by Jiu Ai Tu.
Assessing cachexia in obesity: contradiction or perfectly possible?
Authors: Baracos Vickie E.
Published: July 2024

Purpose of review

Existing definitions of clinically important weight loss in patients with cancer do not specifically address weight loss in patients who are obese at presentation. This review explores the clinical impact of weight loss and depletion of the skeletal muscle mass (i.e., criteria defining cancer cachexia), in patients with obesity.

Recent findings

Overweight and obese BMI values are shown by many recent studies to pose a survival advantage in patients with cancers of advanced stage, when compared with BMI in normal and underweight ranges. The classification of cancer-associated weight loss has evolved, and current grading schemes evaluate the impact of weight across the range of BMI values. Weight loss is associated with mortality in patients with BMI more than 30 kg/m2, however this is to a much lesser degree than in patients with lower BMI values. Diagnostic imaging permits the precise assessment of skeletal muscle index (SMI) in patients with cancer, and it has been clearly shown that while usually quite muscular, obese patients can have profound muscle depletion (i.e., sarcopenia), independent of the presence of weight loss. Muscle depletion associates strongly with mortality in obese patients, as well as with complications of cancer surgery and systemic therapy.

It would seem contradictory to diagnose concurrent obesity and cachexia, as these terms represent opposite ends of the weight spectrum. Weight loss can occur in anyone with cancer, however its priority for clinical management may be lesser in obese versus low body weight individuals. Sarcopenic obesity is strongly associated with a poor clinical outcome and deserves further research, diagnosis in clinical practice, and new strategies for mitigation.
Internal dosimetry and biodistribution of indigenously prepared 177Lu-DOTA-rituximab in lymphoma and other hematological malignancies treated with rituximab
Authors: Edamadaka Yeshwanth , Parghane Rahul V. , Sahu Sudeep , Lad Sangita , Kamaldeep  , Wanage Gaurav , Shanmukhaiah Chandrakala , Kulkarni Vrinda , Basu Sandip
Published: July 2024

Objective

The aim of this study was to evaluate the biodistribution and dosimetry of lutetium-177-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (177Lu-DOTA)-rituximab in CD20+ non-Hodgkin’s lymphoma and other hematological malignancies treated with rituximab.

Methods

The standard dosimetry protocol was used, with cold rituximab infusion, then a diagnostic activity of 177Lu-DOTA-rituximab. Planar images were acquired at multiple time points. Normal organs and tumor dosimetry were performed by using organ and tumor-specific regions of interest and whole-body counts were obtained serially after pixel matched, background, scatter, and attenuation correction. The mean radiation absorbed doses were obtained from OLINDA/EXM v2.1.1 and ORIGIN software.

Results

A total of 22 patients were included in this study. Prolonged blood pool clearance of 177Lu-DOTA-rituximab with long residence time in the blood pool and normal organs were observed. The whole body effective half-life was 104.5 ± 22 h. The mean total body radiation absorbed dose was 0.208 ± 0.03 mGy/MBq and the mean total body effective dose was 0.196 ± 0.05 mGy/MBq of 177Lu-DOTA-rituximab. The mean radiation absorbed doses of 0.613 ± 0.21, 1.68 ± 2, 1.01 ± 0.42, and 0.136 ± 0.02mGy/MBq were seen for the liver, spleen, kidneys, and bone marrow, respectively. Tumor lesion uptake was noticed in two patients with tumor radiation absorbed doses were 0.842 mGy/MBq in one and 9.9 mGy/MBq in the other patient. A strong correlation was obtained between the cumulative activities of radiation-absorbed doses derived from ORIGIN and OLINDA software methods at a significant P value less than 0.001.

Conclusion

The results of our study demonstrated favorable biodistribution and dosimetry of indigenously produced 177Lu-DOTA-rituximab in patients with CD20+ lymphoma. These results can be used for future studies of radioimmunotherapy employing 177Lu-DOTA-rituximab.
Are maximum magnitudes of induced earthquakes controlled by pressure diffusion?
Authors: Langenbruch Cornelius , Moein Mohammad J. A. , Shapiro Serge A.
Published: June 2024

There is an ongoing discussion about how to forecast the maximum magnitudes of induced earthquakes based on operational parameters, subsurface conditions and physical process understanding. Although the occurrence of damage caused by induced earthquakes is rare, some cases have caused significant economic loss, injuries and even loss of life. We analysed a global compilation of earthquakes induced by hydraulic fracturing, geothermal reservoir stimulation, water disposal, gas storage and reservoir impoundment. Our analysis showed that maximum magnitudes scale with the characteristic length of pressure diffusion in the brittle Earth’s crust. We observed an increase in the nucleation potential of larger-magnitude earthquakes with time and explained it by diffusion-controlled growth of the pressure-perturbed part of faults. Numerical and analytical fault size modelling supported our findings. Finally, we derived magnitude scaling laws to manage induced seismic hazard of upcoming energy projects prior to operation.

This article is part of the theme issue ‘Induced seismicity in coupled subsurface systems’.
The relationship between microbial population ATP and quantitative PCR bioburdens in diesel fuel microcosms
Authors: Passman Frederick J. , Schmidt Jordan , Nicoletti Danika
Published: July 2024

Historically, fuel microbiology studies have relied on culture data. Potentially relevant but unculturable bacteria were not detected. Although ATP can quantify total microbial bioburdens in fuels, it cannot differentiate among the taxa present. Quantitative PCR (qPCR) testing promises to fill this gap by quantifying targeted amplicon sequences thereby detecting both culturable and non-culturable taxa and quantifying specifically targeted taxa. In this study, fluid samples drawn from the fuel, interface and water phases of fuel over water microcosms were tested for cellular ATP concentration ([cATP]) and qPCR bioburdens. Additionally, surface swab samples from steel corrosion coupon surfaces exposed to each of these three phases were collected and tested for total ATP concentration ([tATP]) and qPCR bioburdens. Statistical relationships between ATP and qPCR bioburdens were examined. Correlation coefficients between the two variables were matrix dependent and ranged from negligible (|r|=0.2) to strong (|r|=0.7). When results were categorized into negligible, moderate and heavy bioburdens, parameter agreement was again matrix dependent. Percentage agreement between [ATP] and qPCR gene copies ranged from 11 % to 89 % – with qPCR-bioburden ratings typically being greater than ATP-bioburden ratings.
STAN, a computational framework for inferring spatially informed transcription factor activity
Authors: Zhang Linan , Sagan April , Qin Bin , Kim Elena , Hu Baoli , Osmanbeyoglu Hatice Ulku
Published: June 2024

Transcription factors (TFs) drive significant cellular changes in response to environmental cues and intercellular signaling. Neighboring cells influence TF activity and, consequently, cellular fate and function. Spatial transcriptomics (ST) captures mRNA expression patterns across tissue samples, enabling characterization of the local microenvironment. However, these datasets have not been fully leveraged to systematically estimate TF activity governing cell identity. Here, we present STAN (Spatially informedTranscription factorActivityNetwork), a linear mixed-effects computational method that predicts spot-specific, spatially informed TF activities by integrating curated TF-target gene priors, mRNA expression, spatial coordinates, and morphological features from corresponding imaging data. We tested STAN using lymph node, breast cancer, and glioblastoma ST datasets to demonstrate its applicability by identifying TFs associated with specific cell types, spatial domains, pathological regions, and ligand‒receptor pairs. STAN augments the utility of STs to reveal the intricate interplay between TFs and spatial organization across a spectrum of cellular contexts.
Graph neural networks best guide phenotypic virtual screening on cancer cell lines
Authors: Vishwakarma Sachin , Hernandez-Hernandez Saiveth , Ballester Pedro J.
Published: June 2024

Artificial intelligence is increasingly driving early drug design, offering novel approaches to virtual screening. Phenotypic virtual screening (PVS) aims to predict how cancer cell lines respond to different compounds by focusing on observable characteristics rather than specific molecular targets. Some studies have suggested that deep learning may not be the best approach for PVS. However, these studies are limited by the small number of tested molecules as well as not employing suitable performance metrics and dissimilar-molecules splits better mimicking the challenging chemical diversity of real-world screening libraries. Here we prepared 60 datasets, each containing approximately 30,000 to 50000 molecules tested for their growth inhibitory activities on one of the NCI-60 cancer cell lines. We evaluated the performance of five machine learning algorithms for PVS on these 60 problem instances. To provide a comprehensive evaluation, we employed two model validation types: the random split and the dissimilar-molecules split. The models were primarily evaluated using hit rate, a more suitable metric in VS contexts. The results show that all models are more challenged by test molecules that are substantially different from those in the training data. In both validation types, the D-MPNN algorithm, a graph-based deep neural network, was found to be the most suitable for building predictive models for this PVS problem.
InterLabelGO+: Unraveling label correlations in protein function prediction
Authors: Liu Quancheng , Zhang Chengxin , Freddolino Lydia
Published: June 2024

Motivation

Accurate protein function prediction is crucial for understanding biological processes and advancing biomedical research. However, the rapid growth of protein sequences far outpaces the experimental characterization of their functions, necessitating the development of automated computational methods.

Results

We present InterLabelGO+, a hybrid approach that integrates a deep learning-based method with an alignment-based method for improved protein function prediction. InterLabelGO+ incorporates a novel loss function that addresses label dependency and imbalance and further enhances performance through dynamic weighting of the alignment-based component. A preliminary version of InterLabelGO+ achieved a strong performance in the CAFA5 challenge, ranking 6th out of 1,625 participating teams. Comprehensive evaluations on large-scale protein function prediction tasks demonstrate InterLabelGO+’s ability to accurately predict Gene Ontology terms across various functional categories and evaluation metrics.

Availability and Implementation

The source code and datasets for InterLabelGO+ are freely available on GitHub athttps://github.com/QuanEvans/InterLabelGO. The software is implemented in Python and PyTorch, and is supported on Linux and macOS.

Contact

lydsf@umich.edu(LF) andzcx@umich.edu(CZ)
Origin and evolution of Auxin Efflux Carrier family: PIN, PILS, GPR155 and the others
Authors: Vosolsobě Stanislav , Kurtović Katarina , Schmidt Vojtěch , Skokan Roman , Petrášek Jan
Published: June 2024

The resolution of the 3D structure of PIN proteins and the ability to universally predict protein structures using AlphaFold allowed us to reconsider the classification of Auxin efflux carriers within the BART superfamily, and we propose to merge members of this superfamily, possessing a characteristic fold with a helical crossover, with other families carrying this fold (BASS, NhaA, CPA and others) into a newly proposed superfamily named X-Helices Carriers (XHC). We further demonstrate a profound divergence between PIN and PILS proteins and monophyly of eukaryotic PINs with the animal cholesterol receptor GPR155/LYCHOS. We hypothesise that its signalling capacity is derived from a general feature of PIN proteins to interact with membrane lipids within the core membrane fold. Finally, we discuss the auxin-transport ability of PIN and PILS proteins in the context of the described properties of bacterial homologs that act as organic acid permeases.

Disclaimer

This version is a draft and it will be updated during the next few weeks.

Highlights

PINs are in plants and fragmentary in many algae and protists, but never in fungi

Eukaryotic PINs are monophyletic together with animal cholesterol receptor GPR155

PILS are frequently present in protists and in all fungi, but not in animals

PINs/PILS split is occurred very early in Prokaryota

AECs belongs to proposed superfamily of transporter with helical crossover
Cell-type-specific alternative splicing in the cerebral cortex of a Schinzel-Giedion Syndrome patient variant mouse model
Authors: Jones Emma F. , Howton Timothy C. , Soelter Tabea M. , Crumley Anthony B. , Lasseigne Brittany N.
Published: June 2024

Schinzel-Giedion Syndrome (SGS) is an ultra-rare Mendelian disorder caused by gain-of-function mutations in theSETBP1gene. While previous studies determined multiple roles for howSETBP1and associated pathways may cause disease manifestation, they have not assessed whether cell-type-specific alternative splicing (AS) plays a role in SGS. We used STARsolo to quantify gene and splice junction (SJ) expression for 51,465 nuclei previously generated from the cerebral cortex of atypicalSetbp1S858RSGS patient variant mice (n = 3) and wild-type control mice (n = 3). After cell type annotation, we performed pseudobulk differential gene expression and SJ usage (SJU) analyses across cell types and conditions. We identified 34 genes with statistically significant alterations in SJU. Oligodendrocytes had the most genes with changes in SJU, followed by astrocytes, excitatory, and inhibitory neurons. One gene,Son, a splicing cofactor known to cause the neurodevelopmental disorder ZTTK Syndrome, had SJU changes in all six non-vascular cell types we measured inSetbp1S858Rcompared to controls. This is the first research to report AS changes in the cerebral cortex of an SGS model and the first study to link SGS to perturbations inSon.
Barking Up the Right Tree: Immune Checkpoint Signatures of Human and Dog Cancers
Authors: Kocikowski Mikolaj , Yébenes Mayordomo Marcos , Alfaro Javier , Parys Maciej
Published: June 2024

In the quest for improved therapeutics targeting immune checkpoints (ICs), we turn to spontaneously developing dog (canine) cancers, which are unique models that genetically and clinically mirror human equivalents. Despite its potential, canine cancer immunology remains largely unexplored. Here, we examine the RNA-seq-based expression of 44 ICs across 14 canine cancer types and an extensive human dataset. We unveil diverse canine IC expression patterns and unique human IC signatures that reflect the histological type and primary site of cancer. We uncover a striking similarity between canine brain cancers, osteosarcoma, and their human counterparts, identifying them as prospective immunotherapy models. Four ICs—CD160, A2AR, NKG2A, and OX40—are key to the differences observed between species. Moreover, individual patient IC signatures exhibit varying alignment with their respective cancer types, a finding with profound implications for personalized human therapy. This exploration illuminates new aspects of canine and human cancer immunology, setting the stage for discoveries at their crossroads.
Evolution of the Batoidea Pectoral Fin Skeleton: Convergence, Modularity, and Integration Driving Disparity Trends
Authors: López-Romero Faviel A. , Villalobos-Segura Eduardo , Türtscher Julia , Berio Fidji , Stumpf Sebastian , Dearden Richard P. , Kriwet Jürgen , Maldonado Ernesto
Published: June 2024

Batoids (skates and rays) are the most speciose group of cartilaginous fishes. Their body plan represents diverse ecologies and swimming modes. Early skeletal fossil remains, and recent phylogenetic analyses suggest that convergence has occurred within the batoids several times independently. The drivers for such disparity patterns and possible association with modularity and phenotypic integration among batoids are not fully understood. Here we used geometric morphometrics and phylogenetic comparative methods to characterize the evolutionary trends of the basal fin skeleton of batoids and sharks. Our analyses show that the morphological variation has a strong phylogenetic signal. Interestingly, the most speciose orders of batoids display low morphological disparity. Reef and freshwater species, show increased evolutionary rates. Meanwhile, the swimming mode shows different rates depending on the fin structure analyzed. A higher modularity and integration signal suggest that the pectoral fin of batoids has experienced mosaic evolution. The low morphological disparity might be associated with high integration. We find support for convergence between Jurassic, Cretaceous, and Extant guitarfishes, however, not completely between sharks and batoids. Our findings suggest that habitats and swimming mode have shaped the pectoral fin evolution among batoids, and at the same time batoids have constrained their basal fin skeleton.
EEG Electrodes and Where to Find Them: Automated Localization From 3D Scans
Authors: Tveter Mats , Tveitstøl Thomas , Nygaard Tønnes , Pérez T Ana S. , Kulashekhar Shrikanth , Bruña Ricardo , Hammer Hugo L. , Hatlestad-Hall Christoffer , Haraldsen Ira R. J. Hebold
Published: June 2024

Objective

The accurate localization of electroencephalography (EEG) electrode positions is crucial for accurate source localization. Recent advancements have proposed alternatives to labor-intensive, manual methods for spatial localization of the electrodes, employing technologies such as 3D scanning and laser scanning. These novel approaches often integrate Magnetic Resonance Imaging (MRI) as part of the pipeline in localizing the electrodes. The limited global availability of MRI data restricts its use as a standard modality in several clinical scenarios. This limitation restricts the use of these advanced methods.

Approach

In this paper, we present a novel, versatile approach that utilizes 3D scans to localize EEG electrode positions with high accuracy. Importantly, while our method can be integrated with MRI data if available, it is specifically designed to be highly effective even in the absence of MRI, thus expanding the potential for advanced EEG analysis in various resource-limited settings. Our solution implements a two-tiered approach involving landmark/fiducials localization and electrode localization, creating an end-to-end framework.

Main results

The efficacy and robustness of our approach have been validated on an extensive dataset containing over 400 3D scans from 278 subjects. The framework identifies pre-auricular points and achieves correct electrode positioning accuracy in the range of 85.7% to 91.0%. Additionally, our framework includes a validation tool that permits manual adjustments and visual validation if required.

Significance

This study represents, to the best of the authors’ knowledge, the first validation of such a method on a substantial dataset, thus ensuring the robustness and generalizability of our innovative approach. Our findings focus on developing a solution that facilitates source localization, contributing to the critical discussion on balancing cost effectiveness with methodological accuracy to promote wider adoption in both research and clinical settings.
Evolutionary bursts drive morphological novelty in the world’s largest skinks
Authors: Brennan Ian G. , Chapple David G. , Scott Keogh J. , Donnellan Stephen
Published: June 2024

Animal phenotypes evolve and diverge as a result of differing selective pressures and drift. These processes leave unique signatures in patterns of trait evolution, impacting the tempo and mode of morphological macroevolution. While there is a broad understanding of the history of some organismal traits (e.g. body size), there is little consensus about the evolutionary mode of most others. This includes the relative contribution of prolonged (Darwinian gradualist) and episodic (Simpsonian jump) changes towards the evolution of novel morphologies. Here we use new exon-capture and linear morphological datasets to investigate the tempo and mode of morphological evolution in Australo-Melanesian Tiliquini skinks. We generate a well-supported time-calibrated phylogenomic tree from ∼400 nuclear markers for more than 100 specimens including undescribed diversity, and provide unprecedented resolution of the rapid Miocene diversification of these lizards. By collecting a morphological dataset that encompasses the lizard body plan (19 traits across the head, body, limb, and tail) we are able to identify that most traits evolve conservatively but infrequent evolutionary bursts result in morphological novelty. These phenotypic discontinuities occur via rapid rate increases along individual branches, inconsistent with both gradualistic and punctuated equilibrial evolutionary modes. Instead, this ‘punctuated gradualism’ has resulted in the rapid evolution of blue-tongued giants and armored dwarves in the ∼20 million years since colonizing Australia. These results outline the evolutionary pathway towards new morphologies and highlight the heterogeneity of evolutionary tempo and mode, even within individual traits.
Improved detection of microbiome-disease associations via population structure-aware generalized linear mixed effects models (microSLAM)
Authors: Goldman Miriam , Zhao Chunyu , Pollard Katherine S.
Published: June 2024

Microbiome association studies typically link host disease or other traits to summary statistics measured in metagenomics data, such as diversity or taxonomic composition. But identifying disease-associated species based on their relative abundance does not provide insight into why these microbes act as disease markers, and it overlooks cases where disease risk is related to specific strains with unique biological functions. To bridge this knowledge gap, we developed microSLAM, a mixed-effects model and an R package that performs association tests that connect host traits to the presence/absence of genes within each microbiome species, while accounting for strain genetic relatedness across hosts. Traits can be quantitative or binary (such as case/control). MicroSLAM is fit in three steps for each species. The first step estimates population structure across hosts. Step two calculates the association between population structure and the trait, enabling detection of species for which a subset of related strains confer risk. To identify specific genes whose presence/absence across diverse strains is associated with the trait, step three models the trait as a function of gene occurrence plus random effects estimated from step two. Applying microSLAM to 710 gut metagenomes from inflammatory bowel disease (IBD) samples, we discovered 49 species whose population structure correlates with IBD. In addition, after controlling for population structure, we found 57 microbial genes that are significantly more common in healthy individuals and 26 that are more common in IBD patients, including a seven-gene operon in Faecalibacterium prausnitzii that is involved in utilization of fructoselysine from the gut environment. Overall, microSLAM detected IBD associations for 45 species that were not detected using relative abundance tests, and it identified specific strains and genes underlying IBD associations for 13 other species. These findings highlight the importance of accounting for within-species genetic variation in microbiome studies.
Widespread destabilization ofC. elegansmicroRNAs by the E3 ubiquitin ligase EBAX-1
Authors: Stubna Michael W. , Shukla Aditi , Bartel David P.
Published: June 2024

MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to form complexes that direct mRNA repression. miRNAs are also the subject of regulation. For example, some miRNAs are destabilized through a pathway in which pairing to specialized transcripts recruits the ZSWIM8 E3 ubiquitin ligase, which polyubiquitinates AGO, leading to its degradation and exposure of the miRNA to cellular nucleases. Here, we found that 22 miRNAs inC. elegansare sensitive to loss of EBAX-1, the ZSWIM8 ortholog in nematodes, implying that these 22 miRNAs might be subject to this pathway of target-directed miRNA degradation (TDMD). The impact of EBAX-1 depended on the developmental stage, with the greatest effect on the miRNA pool (14.5%) observed in L1 larvae and the greatest number of different miRNAs affected (17) observed in germline-depleted adults. The affected miRNAs included the miR-35–42 family, as well as other miRNAs among the least stable in the worm, suggesting that TDMD is a major miRNA-destabilization pathway in the worm. The excess miR-35–42 molecules that accumulated inebax-1mutants caused increased repression of their predicted target mRNAs and underwent 3′ trimming over time. In general, however, miRNAs sensitive to EBAX-1 loss had no consistent pattern of either trimming or tailing. Replacement of the 3′ region of miR-43 substantially reduced EBAX-1 sensitivity, a result that differed from that observed previously for miR-35. Together, these findings broaden the implied biological scope of TDMD-like regulation of miRNA stability in animals, and indicate that a role for miRNA 3′ sequences is variable in the worm.
Gut microbial profiling of COVID-19 patients in Uganda
Authors: Kateete David Patrick , Lubega Christopher , Galiwango Ronald , Nasinghe Emmanuel , Mbabazi Monica , Jjingo Daudi , Elliott Alison
Published: June 2024

Background:

While COVID-19 spread globally, the role of the gut microbiota in patient outcomes has remained an area of exploration especially in resource limited settings. This study aimed to comprehensively profile the gut microbiome among Ugandan COVID-19 patients and infer potential implications.

Methods:

Nasopharyngeal swabs, stool, clinical and demographic data were collected from COVID-19 confirmed cases at the COVID-19 isolation and treatment centers in Kampala and Entebbe, Uganda, during the first and second waves of the pandemic in Uganda (i.e., 2020 and 2021, respectively). SARS-CoV-2 presence in the swab samples was confirmed by quantitative real-time RT-PCR assays. 16S rRNA metagenomic next-generation sequencing was performed on the DNA extracted from the stool samples, followed by bioinformatics analysis. Machine learning was used to determine microbes that were associated with disease severity.

Results:

We observed varied gut microbial composition between COVID-19 patients and healthy controls. Potentially pathogenic bacteria such as Klebsiella oxytoca, Salmonella enterica and Serratia marcescens had an increased presence in COVID-19 disease states, especially severe cases. Enrichment of opportunistic pathogens, such as Enterococcus species, and depletion of beneficial microbes, like Alphaproteobacteria, was observed between mild and severe cases. Machine learning identified age and microbes such as Ruminococcaceae, Bacilli, Enterobacteriales, porphyromonadaceae, and Prevotella copri as predictive of severity.

Conclusion:

These findings suggest that the microbiome plays a role in the dynamics of SARS-CoV-2 infection in African patients. The shift in abundance of specific microbes can moderately predict severity of COVID-19 in this population. Their direct or indirect roles in determining severity should be investigated further for potential therapeutic interventions.