bluuebunny/crossref_metadata_2025 huggingface dataset:
CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses
Authors: Hebbar Subramanyam Sudheendra , Hriczko Judit , Look Thomas , Goodarzi Tannaz , Clarner Tim , Verjans Eva , Boell Svenja , Neullens Christopher , Costa Ivan , Gan Lin , Denecke Bernd , Schippers Angela , Floess Stefan , Huehn Jochen , Schmitt Edgar , Bopp Tobias , Wasmuth Hermann , Winograd Ron , Beyaert Rudi , Lambrecht Bart , Boor Peter , Zenke Martin , Wagner Norbert , Ohl Kim , Tenbrock Klaus
Published: July 2024

Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. The cAMP response element binding protein CREB binds the TSDR and influences Foxp3 expression. To understand the functional consequences, we generated mice with a Foxp3-specific knockout of CREB. CREB deficient Tregs expand in vivo but show a reduced Foxp3 expression combined with an enhanced expression of IL-5, IL-13, IL-10, ST2 and CREM. This renders such Tregs highly suppressive in vitro and prevents disease activity in the Th1 model of T cell mediated transfer colitis in an IL-10 dependent way while it enhanced ovalbumin mediated asthma severity. While TSDR methylation was unchanged in CREB deficient Tregs, CREB and CREM directly interact with Foxp3 and deficiency of CREB alters chromatin accessibility at the IL13 and ST2 locus. Additional genetic CREM deficiency reverses the ST2 phenotype. Our data suggest that CREB expression in Tregs is important for the regulation of ST2 mediated balance between type 1 and type 2 immune responses.
Integrative Imaging of Lung Micro Structure: Amplifying Classical Histology by Paraffin Block μCT and same-slide Scanning Electron Microscopy
Authors: Reiser Johanna , Albers Jonas , Svetlove Angelika , Mertiny Mara , Kommoss Felix K.F. , Schwab Constantin , Schneemann Anna , Tromba Giuliana , Wacker Irene , Curticean Ronald E. , Schroeder Rasmus R. , Kauczor Hans-Ulrich , Wielpütz Mark O. , Dullin Christian , Wagner Willi L.
Published: July 2024

Classical histopathology of formalin fixed and paraffin embedded (FFPE) tissue using light microscopy (LM) remains the undisputed gold standard in biomedical microstructural lung tissue analysis. To extend this method, we developed an integrative imaging and processing pipeline which adds 3D context and screening capabilities by micro-CT (μCT) imaging of the entire paraffin block and adds ultrastructural information by correlative same-slide scanning electron microscopy (SEM). The different modalities are integrated by elastic registration to provide hybrid image datasets.

Without compromising standard light microscopic readout, we overcome the limitations of conventional histology by combining and integrating several imaging modalities. The biochemical information contained in histological and immunohistological tissue staining is embedded into the 3D tissue configuration and is amplified by adding ultrastructural visualization of features of interest. By combining μCT and conventional histological processing, specimens can be screened, and specifically preselected areas of interest can be targeted in the subsequent sectioning process.

While most of the μCT data shown in the manuscript was acquired at a Synchrotron, we further demonstrate that our workflow can also by applied using X-ray microscopy.
The role of LEDGF in transcription is exploited by HIV-1 to position integration
Authors: Pathak Rakesh , Esnault Caroline , Radhakrishnan Rajalingam , Singh Parmit K , Zhang Hongen , Dale Ryan , Anand Abhishek , Bedwell Gregory J , Engelman Alan N , Rabi Ali , Hormoz Sahand , Singh Priyanka , Levin Henry L
Published: July 2024

HIV-1 integration occurs across actively transcribed genes due to the interaction of integrase with host chromatin factor LEDGF. Although LEDGF was originally isolated as a co-activator that stimulates promoter activity in purified systems, this role is inconsistent with LEDGF-mediated integration across gene bodies and with data indicating LEDGF is a histone chaperone that promotes transcriptional elongation. We found LEDGF is enriched in pronounced peaks that match the enrichments of H3K4me3 and RNA Pol II at transcription start sites (TSSs) of active promoters. Our genome-wide chromatin mapping revealed that MLL1 had a dominant role in recruiting LEDGF to promoters and the presence of LEDGF recruits RNA Pol II. Enrichment of LEDGF at TSSs correlates strongly with levels of integration across the transcribed sequences, indicating that LEDGF at TSSs contributed to integration across gene bodies. Although the N-terminal Pro-Trp-Trp-Pro (PWWP) domain of LEDGF interacts with nucleosomes containing H3K36me3, a modification thought to recruit LEDGF to chromatin, we found H3K36me3 does not contribute to gene specificity of integration. These data support a dual role model of LEDGF where it is tethered to promoters by MLL1 and recruits RNA Pol II. Subsequently, LEDGF travels across genes to effect HIV-1 integration. Our data also provides a mechanistic context for the contribution made by LEDGF to MLL1-based infant acute leukemia and acute myeloid leukemia in adults.
GeneLLM: A Large cfRNA Language Model for Cancer Screening from Raw Reads
Authors: Deng Siwei , Sha Lei , Jin Yongcheng , Zhou Tianyao , Wang Chengen , Liu Qianpu , Guo Hongjie , Xiong Chengjie , Xue Yangtao , Li Xiaoguang , Li Yuanming , Gao Yaping , Hong Mengyu , Xu Junjie , Chen Shanwen , Wang Pengyuan
Published: July 2024

Plasma cell-free RNA (cfRNA) has recently emerged as a promising biomarker for non-invasive early cancer detection and treatment monitoring [8, 28, 31, 32, 38, 40]. Here, we introduce GeneLLM, a novel large language model de-signed to interpret cfRNA sequences directly, bypassing the need for genome annotations. GeneLLM significantly advances the detection accuracy of various cancer types. Our study demonstrates that this method achieves higher accuracy than traditional biomarkers and effectively handles large datasets from different centres, even with low sequencing depth. By avoiding the use of bioinformatics tools to count known genes, GeneLLM also discovered cfRNAs from previously unknown genes, referred to as ‘dark matters’ in the genome, as cancer detec-tion ‘pseudo-biomarkers’. Our results showcase the potential of GeneLLM to revolutionise cancer detection, making it more accessible and cost-effective. By offering a method that does not depend on bioinformatics tools to count known genes, GeneLLM opens new avenues for biomarker discovery and enhances our understanding of intercellular communication through novel RNA molecules.
StarSignDNA: Signature tracing for accurate representation of mutational processes
Authors: Bope christian Domilongo , Kalyanasundaram Sumana , Rand Knut D , Nakken Sigve , Lingjaerde Ole Christian , Hovig Eivind
Published: July 2024

All cell lineages accumulate mutations over time, increasing the probability that some lineages eventually become malignant. Many of the processes responsible for generating mutations are leaving a characteristic footprint in the genome that allows their presence to be detected. However, the mutational pattern in a tumor is usually the combined result of multiple mutational processes being at work simultaneously, and the problem of disentangling the different footprints and their relative impact then becomes a deconvolution problem. Several algorithms have been developed for this purpose, most of them involving a factorization of the mutation count matrix into two nonnegative matrices, representing respectively the underlying mutational signatures and the relative weighting of (or exposure to) these signatures. Here, we introduce the StarSignDNA algorithm for mutational signature analysis, which offers efficient refitting and de novo mutational signature extraction. StarSignDNA is capable of deciphering well-differentiated signatures linked to known mutagenic mechanisms and suggesting clinically relevant predictions for a single patient. The package offers a command line-based interface and data visualization routines.
Combined HDAC and eIF4A inhibition: A novel epigenetic therapy for pancreatic adenocarcinoma
Authors: Safari Maryam , Scotto Luigi , Basseville Agnes , Litman Thomas , Xue Haoran , Petrukhin Luba , Zhou Ping , Morales Diana V. , Damoci Christopher , Zhu Mingzhao , Hull Kenneth , Olive Kenneth P. , Fojo Tito , Romo Daniel , Bates Susan E.
Published: July 2024

Pancreatic ductal adenocarcinoma-(PDAC) needs innovative approaches due to its 12% 5-year survival despite current therapies. We show marked sensitivity of pancreatic cancer cells to the combination of a novel eIF4A inhibitor, des-methyl pateamine A (DMPatA), and a histone deacetylase inhibitor, romidepsin, inducing epigenetic reprogramming as an innovative therapeutic strategy. Exploring the mechanistic activity of this combination showed that with a short duration of romidepsin at low doses, robust acetylation persisted up to 48h with the combination, while histone acetylation rapidly faded with monotherapy. This represents an unexpected mechanism of action against PDAC cells that triggers transcriptional overload, metabolic stress, and augmented DNA damage. Structurally different class I HDAC inhibitors exhibit the same hyperacetylation patterns when co-administered with DMPatA, suggesting a class effect. We show efficacy of this combination regimen against tumor growth in a MIA PaCa-2 xenograft model of PDAC with persistent hyperacetylation confirmed in tumor samples.

STATEMENT OF SIGNIFICANCE

Pancreatic ductal adenocarcinoma, a significant clinical challenge, could benefit from the latent potential of epigenetic therapies like HDAC inhibitors-(HDIs), typically limited to hematological malignancies. Our study shows that a synergistic low dose combination of HDIs with an eIF4A-inhibitor in pancreatic cancer models results in marked pre-clinical efficacy, offering a promising new treatment strategy.
Hierarchical population genetic structure and signatures of adaptation inLates calcarifer
Authors: Campbell Matthew A. , Becker Joy A.
Published: July 2024

Context

Lates calcariferis a widespread Indo-Pacific fish that is important in aquaculture, recreational and commercial fisheries. Genetic divergences from different data sources and sampling schemes have been reported.

Aims

To conduct phylogenetic and population genetic analyses from a geographically and phylogenetically representative data set to identify hierarchical divisions withinL. calcarifer. We further test the evolutionary significance of genetic units in terms of signatures of adaptation.

Methods

Using a whole-genome sequence data set of 61 fish including an outgroup, we conducted phylogenetic and population genetic analyes. We also generated measures of Fst, nucleotide diversity (π) and Tajima’s D (D).

Key Results

We identify three main lineages ofL. calcarifercorresponding to the Indian subcontinent, Southeast Asia and Australasia. Subdivision within each of the three main lineages is also identified and characterized. Adaptively significant differences are indicated within and between the three main lineages.

Conclusions

L. calcariferexhibits genetic divergences at different levels that originate before and during the Pleistocene. These divergences are associated with adaptive divergence but unclear phenotypic changes.

Implications

This study highlights the need for comprehensive sampling and integrative study of genotypes and phenotypes across the range ofL. calcarifer.
Exploring individual codon influence on protein expression: a predictive approach
Authors: Zaytsev Konstantin , Bogatyreva Natalya , Fedorov Alexey
Published: July 2024

An important role of a particular synonymous codon composition of a gene on its expression level is well-known. There are a number of algorithms optimising codon usage of recombinant genes to maximise their expression in host cells. Nevertheless, the problem has not been solved yet and remains relevant. In the realm of modern biotechnology, directing protein production to a specific level is crucial for metabolic engineering, genome rewriting, and a growing number of other applications. In this study, we propose two new simple statistical and empirical methods for predicting the protein expression level from the nucleotide sequence of the corresponding gene: Codon Expression Index Score (CEIS) and Codon Productivity Score (CPS). Both of these methods are based on the influence of each individual codon in the gene on the overall expression level of the encoded protein and the frequencies of isoacceptors in the species. Our predictions achieve a correlation with experimentally measured quantitative proteome data ofEscherichia coliup to a level of r=0.7, which is superior to any previously proposed methods. Our work helps to understand how codons determine translation rates; based on our methods, it is possible to design proteins optimised for expression in a particular organism.
Myelin-informed forward models for M/EEG source reconstruction
Authors: Helbling S , Meyer SS , Weiskopf N
Published: July 2024

Magnetoencephalography (MEG) and Electroencephalography (EEG) provide direct electrophysiological measures at an excellent temporal resolution, but the spatial resolution of source-reconstructed current activity is limited to several millimetres. Here we show, using simulations of MEG signals and Bayesian model comparison, that non-invasive myelin estimates from high-resolution quantitative magnetic resonance imaging (MRI) can enhance MEG/EEG source reconstruction. Our approach assumes that MEG/EEG signals primarily arise from the synchronised activity of pyramidal cells, and since most of the myelin in the cortical sheet originates from these cells, myelin density can predict the strength of cortical sources measured by MEG/EEG. Leveraging recent advances in quantitative MRI, we exploit this structure-function relationship and scale the leadfields of the forward model according to the local myelin density estimates from in vivo quantitative MRI to inform MEG/EEG source reconstruction. Using Bayesian model comparison and dipole localisation errors (DLEs), we demonstrate that adapting local forward fields to reflect increased local myelination at the site of a simulated source explains the simulated data better than models without such leadfield scaling. Our model comparison framework proves sensitive to myelin changes in simulations with exact coregistration and moderate-to-high sensor-level signal-to-noise ratios (≥10 dB) for the multiple sparse priors (MSP) and empirical Bayesian beamformer (EBB) approaches. Furthermore, we sought to infer the microstructure giving rise to specific functional activation patterns by comparing the myelin-informed model which was used to generate the activation with a set of test forward models incorporating different myelination patterns. We found that the direction of myelin changes, however not their magnitude, can be inferred by Bayesian model comparison. Finally, we apply myelin-informed forward models to MEG data from a visuo-motor experiment. We demonstrate improved source reconstruction accuracy using myelin estimates from a quantitative longitudinal relaxation (R1) map and discuss the limitations of our approach.

Highlights

We use quantitative MRI to implement myelin-informed forward models for M/EEG

Local myelin density was modelled by adapting the local leadfields

Myelin-informed forward models can improve source reconstruction accuracy

We can infer the directionality of myelination patterns, but not their strength

We apply our approach to MEG data from a visuo-motor experiment
Phylogenetic and non-phylogenetic patterns in the richness, frequency and composition of links in a herbivore-parasitoid interaction network
Authors: Sinclair Frazer H , Tang Chang-Ti , Bailey Richard A , Csoka Gyorgy L , Melika George , Nicholls James A , Nieves-Aldrey Jose-Luis , Reiss Alexander , Zhang Yuanmeng Miles , Phillimore Albert , Schonrogge Karsten , Stone Graham N
Published: July 2024

Revealing processes that structure species interactions is central to understanding community assembly and dynamics. Species interact via their phenotypes, but identifying and quantifying the traits that structure species-specific interactions (links) can be challenging. Where these traits show phylogenetic signal, however, link properties may be predictable using models that incorporate phylogenies in place of trait data. We analysed variation in link richness, frequency, and species identity in a multi-site dataset of interactions between oak cynipid galls and parasitoid natural enemies, using a Bayesian mixed modelling framework allowing concurrent fitting of phylogenetic effects of both trophic levels. In both link incidence (presence/absence) and link frequency datasets, we identified strong signatures of cophylogeny (related parasitoids attack related host galls) alongside patterns independent of either phylogeny. Our results are robust to simulations of substantially reduced sample completeness, and are consistent with the structuring of trophic interactions by a combination of phylogenetically conserved and convergently evolving traits in both trophic levels. We discuss our results in light of phenotypic traits thought to structure gall-parasitoid interactions and consider wider applications of this approach, including inference of underlying community assembly processes and prediction of economically important trophic interactions.
Functional monocentricity with holocentric characteristics and chromosome-specific centromeres in a stick insect
Authors: Toubiana William , Dumas Zoé , Van Patrick Tran , Parker Darren J. , Mérel Vincent , Schubert Veit , Aury Jean-Marc , Bournonville Lorène , Cruaud Corinne , Houben Andreas , Istace Benjamin , Labadie Karine , Noel Benjamin , Schwander Tanja
Published: July 2024

Centromeres are specialized genomic regions that are critical for chromosome segregation in eukaryotes. However, how the diversity of centromeres evolved, ranging from localized centromeres in monocentric species to complex chromosome-wide distributed centromere regions in holocentric species, remains elusive. Our cellular and genomic analyses inTimemastick insects reveal that within cell variation of the major centromere protein CenH3 recapitulates the variation typically observed across species. While CenH3-containing nucleosomes are distributed in a monocentric fashion on autosomes and bind tandem repeat sequences specific to individual or small groups of chromosomes, they exhibit a holocentric-like distribution on the sex chromosome and bind to more complex intergenic regions. Despite this contrasting distribution, all chromosomes, including the sex chromosome, attach to spindle microtubules at a single location, marking the first instance of a functionally monocentric species with holocentric-like attributes. Together, our findings highlight the potential for gradual transitions towards holocentricity or CenH3-independent centromere determination, and help to understand the rapid centromere sequence divergence between species.
Towards a simplified model of primary visual cortex
Authors: Du Fengtong , Núñez-Ochoa Miguel Angel , Pachitariu Marius , Stringer Carsen
Published: July 2024

Artificial neural networks (ANNs) have been shown to predict neural responses in primary visual cortex (V1) better than classical models. However, this performance comes at the expense of simplicity because the ANN models typically have many hidden layers with many feature maps in each layer. Here we show that ANN models of V1 can be substantially simplified while retaining high predictive power. To demonstrate this, we first recorded a new dataset of over 29,000 neurons responding to up to 65,000 natural image presentations in mouse V1. We found that ANN models required only two convolutional layers for good performance, with a relatively small first layer. We further found that we could make the second layer small without loss of performance, by fitting a separate “minimodel” to each neuron. Similar simplifications applied for models of monkey V1 neurons. We show that these relatively simple models can nonetheless be useful for tasks such as object and visual texture recognition and we use the models to gain insight into how texture invariance arises in biological neurons.
Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration
Authors: Xie Manling , Miller Alessandra S. , Pallegar Praveen N. , Umpierre Anthony , Liang Yue , Wang Na , Zhang Shuwen , Nagaraj Nagaswaroop Kengunte , Fogarty Zachary C. , Ghayal Nikhil B. , Oskarsson Björn , Zhao Shunyi , Zheng Jiaying , Qi Fangfang , Nguyen Aivi , Dickson Dennis W. , Wu Long-Jun
Published: July 2024

Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinalin vivocalcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.
Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance
Authors: Boe Ryan H , Triandafillou Catherine G , Lazcano Rossana , Wargo Jennifer A , Raj Arjun
Published: July 2024

Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.
The Mammalian KU70 C-terminus SAP Domain Is Required to Repair Exogenous DNA Damage
Authors: Wang Yuan , Czap Michael S. , Kim Hailey , Lu Huimei , Liu Jingmei , Chang Yokechen , Romanienko Peter J. , Montagna Cristina , Shen Zhiyuan
Published: July 2024

The mammalian non-homologous end joining (NHEJ) is required for V(D)J recombination as well as coping with exogenously induced DNA double strand breaks (DSBs). Initiated by the binding of KU70/KU80 (KU) dimer to DNA ends and the subsequent recruitment of the DNA- dependent protein kinase catalytic subunit (DNA-PKcs), NHEJ plays a key role in DNA repair. While there has been significant structural understandings of how KU70 participates in NHEJ, the specific function of its highly conserved C-terminal SAP domain remains elusive. In this study, we developed a novel mouse model by deleting the SAP domain but preserving the KU70 nuclear localization and its dimerization ability with KU80. We found that the KU70 SAP deletion did not affect the V(D)J recombination or animal development but significantly impaired the animals and cells in repairing exogenously induced DSBs. We further showed an inability of KU70-ΔSAP cells to retain the DNA Ligase IV (LIG4) and other NHEJ co-factors on chromatin, and a spreading pattern of DSB marker γH2AX in KU70-ΔSAP cells after DNA damage. Our findings suggest that a specific inhibition of the SAP function may offer an opportunity to modulate cell sensitivity to therapeutic DSB-inducing agents without interfering with the developmental function of KU70.

KeyPoints

Generation of a novel transgenic mouse line lacking the C-terminal conserved KU70-SAP domain

KU70-SAP defends against exogenous DSBs, but unessential for development and V(D)J recombination

KU70-SAP aids in recruiting and retaining NHEJ components, such as LIG4, to DSB sites
Temporal Image Sandwiches Enable Link between Functional Data Analysis and Deep Learning for Single-Plant Cotton Senescence
Authors: DeSalvio Aaron J. , Adak Alper , Arik Mustafa A. , Shepard Nicholas R. , DeSalvio Serina M. , Murray Seth C. , García-Ramos Oriana , Badavath Himabindhu , Stelly David M.
Published: July 2024

Senescence is a highly ordered degenerative biological process that affects yield and quality in annuals and perennials. Images from 14 unoccupied aerial system (UAS, UAV, drone) flights captured the senescence window across two experiments while functional principal component analysis (FPCA) effectively reduced the dimensionality of temporal visual senescence ratings (VSRs) and two vegetation indices: RCC and TNDGR.

Convolutional neural networks (CNNs) trained on temporally concatenated, or “sandwiched,” UAS images of individual cotton plants (Gossypium hirsutumL.), allowed single-plant analysis (SPA). The first functional principal component scores (FPC1) served as the regression target across six CNN models (M1-M6).

Model performance was strongest for FPC1 scores from VSR (R2= 0.857 and 0.886 for M1 and M4), strong for TNDGR (R2= 0.743 and 0.745 for M3 and M6), and strong-to- moderate for RCC (R2= 0.619 and 0.435 for M2 and M5), with deep learning attention of each model confirmed by activation of plant pixels within saliency maps.

Single-plant UAS image analysis across time enabled translatable implementations of high-throughput phenotyping by linking deep learning with functional data analysis (FDA). This has applications for fundamental plant biology, monitoring orchards or other spaced plantings, plant breeding, and genetic research.
Morphological simulation tests the limits on phenotype discovery in 3D image analysis
Authors: Roston Rachel A. , Whikehart Sophie M. , Rolfe Sara M. , Maga Murat
Published: July 2024

In the past few decades, advances in 3D imaging have created new opportunities for reverse genetic screens. Rapidly growing datasets of 3D images of genetic knockouts require high-throughput, automated computational approaches for identifying and characterizing new phenotypes. However, exploratory, discovery-oriented image analysis pipelines used to discover these phenotypes can be difficult to validate because, by their nature, the expected outcome is not knowna priori. Introducingknownmorphological variation through simulation can help distinguish between real phenotypic differences and random variation; elucidate the effects of sample size; and test the sensitivity and reproducibility of morphometric analyses. Here we present a novel approach for 3D morphological simulation that uses open-source, open-access tools available in 3D Slicer, SlicerMorph, and Advanced Normalization Tools in R (ANTsR). While we focus on diffusible-iodine contrast-enhanced micro-CT (diceCT) images, this approach can be used on any volumetric image. We then use our simulated datasets to test whether tensor-based morphometry (TBM) can recover our introduced differences; to test how effect size and sample size affect detectability; and to determine the reproducibility of our results. In our approach to morphological simulation, we first generate a simulated deformation based on a reference image and then propagate this deformation to subjects using inverse transforms obtained from the registration of subjects to the reference. This produces a new dataset with a shifted population mean while retaining individual variability because each sample deforms more or less based on how different or similar it is from the reference. TBM is a widely-used technique that statistically compares local volume differences associated with local deformations. Our results showed that TBM recovered our introduced morphological differences, but that detectability was dependent on the effect size, the sample size, and the region of interest (ROI) included in the analysis. Detectability of subtle phenotypes can be improved both by increasing the sample size and by limiting analyses to specific body regions. However, it is not always feasible to increase sample sizes in screens of essential genes. Therefore, methodical use of ROIs is a promising way to increase the power of TBM to detect subtle phenotypes. Generating known morphological variation through simulation has broad applicability in developmental, evolutionary, and biomedical morphometrics and is a useful way to distinguish between a failure to detect morphological difference and a true lack of morphological difference. Morphological simulation can also be applied to AI-based supervised learning to augment datasets and overcome dataset limitations.
IgM plays a prominent role in naturally acquired immunity againstPlasmodium falciparumgametocytes
Authors: Chan Jo-Anne , Lisboa-Pinto Ashley , Lu Shirley , Harris Alexander , Dixon Matthew WA , Thomas Adam , Drew Damien R , Jayakrishnan Niva , Larcher Katrina , Naghizadeh Mohammad , Opi D Herbert , Reiling Linda , Theisen Michael , Chelimo Kiprotich , Ome-Kaius Maria , Mantila Daisy , Laman Moses , Robinson Leanne J , Mueller Ivo , King Christopher L , Dent Arlene , Kazura James W , Beeson James G
Published: July 2024

The development of transmission-blocking vaccines againstPlasmodium falciparummalaria could facilitate malaria elimination. However, limitations in the knowledge of the human immune responses againstP. falciparumtransmission stages, known as gametocytes, represent a critical roadblock to vaccine development. We evaluated human antibodies acquired through natural malaria exposure to whole gametocytes and recombinant antigens expressed by transmission stages, including the major transmission-blocking vaccine candidates Pfs230 and Pfs48/45 and other transmission stages, Pf38, Pf12 and Pf41. Among individuals residing in Kenya and Papua New Guinea, we found substantial antibody responses to whole gametocytes and to all recombinant transmission stage antigens with high levels of IgG, IgG subclasses and IgM. Complement fixation by antibodies to gametocytes is key for effective transmission-blocking activity. We found that purified IgM was substantially more potent than IgG at mediating complement fixation and activation. Higher antibody levels were generally observed in individuals positive forP. falciparuminfection, including gametocyte positive individuals, and these antibodies generally increased with age. Our findings reveal that IgM is a prominent feature of antibody responses to gametocytes and that antibodies target multiple antigens. The further demonstration that IgM has high functional activity against gametocytes suggests IgM plays an important role in immunity to transmission stages. Our data provide new insights to inform the development of potent transmission-blocking vaccines.
Forecasting trade and biosecurity risk under climate change
Authors: Camac James S , Cantele Matthew , Ha Pham Van , Li Christine , Robinson Andrew , Kompas Tom
Published: July 2024

It is well known that the increasing globalisation of human movement and trade has led to substantial range expansions of many taxa, and as a consequence, is increasingly exposing countries to novel biosecurity threats. This increased exposure to novel threats is expected to be exacerbated by a changing climate as trade patterns and species distributions change. In many countries biosecurity regulators are already struggling to contend with the increased exposure to pests and diseases, and as such, must shift towards a pro-active strategy of anticipating risk. However, to anticipate risk, regulators must make better use of the data they collect (e.g. border interceptions) and develop models capable of forecasting biosecurity propagule pressure and establishment exposure as a function of changing trade, human population, and species distributions. In this project, we develop a highly innovative model framework that simulates annual changes in international trade patterns (imports & exports) as a function of climate change impacts on crop productivity, labour productivity (via heat stress) and the amount of arable land. These simulated changes in global trade are then coupled with border interception data, and annual predicted changes in the geographic distributions of both human populations and threat climate suitability to estimate climate-induced changes in: 1) contamination rates for imports from different trading partners, 2) the total amount of biosecurity risk material arriving at Australia's borders, and 3) its exposure to an establishment event (Figure 1.1). Here, we provide an in-depth description of both the trade and biosecurity risk sub-models. We then illustrate the model's implementation and outputs under two different climate scenarios (RCP 4.5 and RCP 8.5) for the purposes of forecasting temporal changes in: 1) global and regional economic trade; and 2) the amount of biosecurity risk material arriving at Australia's border (i.e. propagule pressure) and what it may mean for establishment exposure. In illustrating the biosecurity risk, we focused on five plant pests deemed by the Department of Agriculture, Fisheries and Forestry (DAFF) as an exemplar of different hitch-hiking functional groups.
The Cambridge Questionnaire for Apathy and Impulsivity Traits (CamQUAIT): a novel assessment tool for frontotemporal lobar degeneration-related syndromes
Authors: Lansdall CJ , Williams R , Coyle-Gilchrist I , Murley AG , Rouse MA , Bateman A , Rowe JB
Published: July 2024

State of the Art

Apathy and impulsivity are common in syndromes associated with frontotemporal lobar degeneration (FTLD). They are associated with high carer distress and poor patient outcomes. There are limited treatment options and progress has been hindered by a lack of appropriate outcome measures. This study aimed to develop a carer-rated questionnaire oriented to people with syndromes associated with FTLD.

Methodology

Principal component and Rasch analysis were conducted on carer-, clinician- and patient-reported questionnaires and performance-based tests of behavioural change in the “Pick’s Disease and Progressive Supranuclear Palsy Prevalence and Incidence” (PiPPIN) study. We identified two key components which informed subsequent item development for a novel scale which we call the Cambridge Questionnaire for Apathy and Impulsivity Traits (CamQUAIT). The resulting scale comprised two subscales assessing “motivation and support” (CamQUAIT-M) and “impulsivity and challenging behaviours” (CamQUAIT-C). An independent sample of 132 carers for people with FTLD-associated syndromes completed the CamQUAIT, along with a battery of existing measures. The CamQUAIT was reduced to 15 items following Rasch analysis.

Results

Both subscales showed good construct validity as assessed by high Person separation index (CamQUAIT-M=0.9; CamQUAIT-C=0.7) and Cronbach’s alpha (CamQUAIT-M=0.9; CamQUAIT-C=0.8). The subscales correlated moderately with each other (r=0.376, p<0.001), and with existing measures of behavioural change.

Conclusion

The CamQUAIT is a targeted measurement tool to assess apathy, impulsivity, and related behavioural change in the context of FTLD-related syndromes. The scale demonstrates good measurement properties and is sensitive to group differences, providing a suitable outcome measure to evaluate novel symptomatic treatments.
The complex interplay between risk tolerance and the spread of infectious diseases
Authors: Nguyen Maximilian , Freedman Ari , Cheung Matthew , Saad-Roy Chadi , Espinoza Baltazar , Grenfell Bryan , Levin Simon
Published: July 2024

Abstract

Risk-driven behavior provides a feedback mechanism through which individuals both shape and are collectively affected by an epidemic. We introduce a general and flexible compartmental model to study the effect of heterogeneity in the population with regards to risk tolerance. The interplay between behavior and epidemiology leads to a rich set of possible epidemic dynamics. Depending on the behavioral composition of the population, we find that increasing heterogeneity in risk tolerance can either increase or decrease the epidemic size. We find that multiple waves of infection can arise due to the interplay between transmission and behavior, even without the replenishment of susceptibles. We find that increasing protective mechanisms such as the effectiveness of interventions, the number of risk-averse people in the population, and the duration of intervention usage reduces the epidemic overshoot. When the protection is pushed past a critical threshold, the epidemic dynamics enter an underdamped regime where the epidemic size exactly equals the herd immunity threshold and overshoot is eliminated. Lastly, we can find regimes where epidemic size does not monotonically decrease with a population that becomes increasingly risk-averse.
MAGNITUDE OF NEONATAL HYPOGLYCEMIA AND ITS ASSOCIATED FACTORS AMONG NEONATES ADMITTED TO NEONATAL INTENSIVE CARE UNIT AT HAWASSA CITY PUBLIC HOSPITALS, ETHIOPIA, 2023
Authors: Tadele Selam , Jembere Wegene , Aschale Mastewal , Mulugeta Tewodros , Jigso Samuel , Ayehu Mequanint , Sibhat Migbar
Published: July 2024

Background

Neonatal hypoglycemia is one of the most common metabolic abnormalities seen in newborns. It is a major contributing factor to neonatal morbidity and mortality. Globally, it affects around 5–15% of all babies and approximately 50% of at-risk babies.. In Ethiopia, neonatal hypoglycemia is frequently diagnosed and one of the commonest causes of admission to the neonatal intensive care unit. Nevertheless, documented records regarding its magnitude and factors associated with hypoglycemia are scarce in the study area. Therefore we aimed to assess the magnitude of neonatal hypoglycemia and its associated factors among neonates admitted to the neonatal intensive care unit at Hawassa City Public Hospitals, Ethiopia.

Method

Institution-based cross-sectional study was conducted from April 20 – June 20, 2023among 293 neonates. A systematic random sampling technique was used to reach the study subjects. The data was collected through face-to-face interviews and card review by using structured pretested questionnaire and analyzed using SPSS software version 25. A multivariable logistic regression model was used to determine factors significantly associated with neonatal hypoglycemia with adjusted odds ratio, p-values <0.05 at 95% confidence interval (CI).

Result

The magnitude of neonatal hypoglycemia was found 16.6%. Variables significantly associated with the occurrence of neonatal hypoglycemia were: Diabetes mellitus [AOR=9.8, 95%CI (3.08-31.37)], perinatal asphyxia [AOR=2.87, 95%CI (1.07-7.72)], delayed initiation of breastfeeding [AOR=2.63, 95%CI (1.04-6.6)] and hypothermia [AOR=3.8, 95%CI (1.6-9.1)].

Conclusion

In this study the magnitude of neonatal hypoglycemia among neonates was high. Neonates with hypothermia, perinatal asphyxia, and delayed initiation of breastfeeding and maternal history of diabetes mellitus have an increased risk of developing hypoglycemia. Hence, Health care providers who are working on delivery and neonatal care should focus on early identification and management of these identified factors.
DIFFERENT PHENOTYPES OF CHRONIC CONSTIPATION IN MALES AND FEMALES
Authors: Gardner Jerry D. , Triadafilopoulos George
Published: July 2024

INTRODUCTION

Patients with chronic constipation exhibit symptoms and motility abnormalities that occur in combinations, but the nature of these combinations has not been characterized.

METHODS

We calculated prevalences of combinations of symptoms (abdominal pain, infrequent defecation, incomplete evacuation, straining), abnormal motility test results (prolonged colonic transit time, low anal basal pressure, low anal squeeze pressure, poor rectal sensation, absent balloon expulsion), or both using data from 75 females and 91 males with chronic constipation. We calculated the “Cluster Factor” as observed prevalence of a combination of symptoms, abnormal test results or both divided by the prevalence of the combination due to chance. We calculated the conditional probabilities of combinations of symptoms, abnormal motility test results or both given the prevalence of other members of the same combination.

RESULTS

Combinations of symptoms alone or abnormal motility test results alone in both males and females, and for combinations of symptoms plus abnormal motility test results in females, failed to cluster together beyond that attributable to chance alone. Males, however, showed significant clustering. Significant conditional probabilities with symptoms, and with symptoms plus abnormal motility test results was higher in males than females. Significant conditional probabilities with abnormal motility test results were not different between males and females.

CONCLUSIONS

Gender-related differences in prevalences of combinations of symptoms and abnormal motility test results, of significant Cluster Factors, and of conditional probabilities indicate that chronic constipation in males reflects a fundamentally different disorder from that in females.
Coherent Raman microscopy detects nucleolar defects through amide I peak shifts originating from β-sheets: an application to visualizing ongoing cellular senescence
Authors: Ishibashi Shigeo , Inoko Akihito , Oka Yuki , Leproux Philippe , Kano Hideaki
Published: July 2024

Cellular senescence occurs through the accumulation of many kinds of stresses. Senescent cells in tissues also cause various age-related disorders. Therefore, detecting them without labeling is beneficial. However, existing biomarkers have limitations of requiring fixation and labeling, or their molecular backgrounds are uncertain. Coherent anti-Stokes Raman scattering (CARS) spectroscopic imaging is a novel option because it can assess and visualize molecular structures based on their molecular fingerprint. Here, we present a new label-free method to visualize cellular senescence by obtaining molecular fingerprint signals in nucleoli using a CARS microspectroscopic system. We found the peak of the nucleolar amide I band shifted to a higher wavenumber in binuclear senescent cells, which reflects changes in the protein secondary structure from predominant α-helices to β-sheets originating from amyloid-like aggregates. Following this, we developed a procedure that can visualize the senescent cells by providing the ratios and subtractions of these two components. We also confirmed that the procedure can visualize nucleolar aggregates due to unfolded/misfolded proteins produced by proteasome inhibition. Finally, we found that this method can help visualize the nucleolar defects in naïve cells even before binucleation. Thus, our method is beneficial to evaluate ongoing cellular senescence through label-free imaging of nucleolar defects.
Single-cell transcriptomic changes in oligodendroglial lineage cells derived from Parkinson’s disease patient-iPSCs with LRRK2-G2019S mutation
Authors: Dehestani Mohammad , Kessler Wiebke , Karmali Nasser , Sun Wenhua , Volos Polina , Tsitkov Stanislav , Dhingra Ashutosh , Rodriguez-Nieto Salvador , Tietz Julia , Schafflick David , Fernandes Noémia , Fitzgerald Julia , Fraenkel Ernest , Gasser Thomas , Rafiq Nisha Mohd , Kuhlmann Tanja , Bansal Vikas
Published: July 2024

Despite extensive research, the contribution of the LRRK2 p.G2019S mutation to Parkinson’s disease (PD) remains unclear. Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression ofLRRK2. We induced PD patient-iPSCs with the LRRK2 p.G2019S mutation into oligodendroglial lineages and performed single-cell RNA sequencing. Cell type composition analysis revealed an increase in OPCs, proliferating OPCs and ciliated ependymal cells in LRRK2 lines, all of which are characterized byLRRK2expression. Differential expression analysis revealed transcriptomic changes in several pathways, including down-regulation of genes related to myelin assembly in ODCs, semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs. Cell-cell communication analysis identified significant alterations in several signaling pathways including a deactivation of PSAP signaling and an activation of MIF signaling in LRRK2 lines. Additionally, we observed an overall increase in SEMA6 signaling communication in LRRK2 cell lines; however, OPCs derived from these LRRK2 lines specifically lost SEMA6 signaling due to a down-regulation ofSEMA6AandPLXNA2. Pseudotemporal trajectory analysis revealed thatSHHhad significantly altered expression along the pseudotime, accompanied by higher expression levels in LRRK2 lines. We propose that dysfunctional semaphorin-plexin signaling, along with cilia movement and SHH signaling, might represent early events in PD pathology.
Orthogonalization of spontaneous and stimulus-driven activity by hierarchical neocortical areal network in primates
Authors: Matsui Teppei , Hashimoto Takayuki , Murakami Tomonari , Uemura Masato , Kikuta Kohei , Kato Toshiki , Ohki Kenichi
Published: July 2024

Understanding how biological neural networks perform reliable information processing in the presence of intensive spontaneous activity (1-3) is an essential question in biological computation. Stimulus-evoked and spontaneous activities show orthogonal (dissimilar) patterns in the primary visual cortex (V1) of mice (4-6), which is likely to be beneficial for separating sensory signals from internally generated noise (5, 7-12); however, those in V1 of carnivores and primates show highly similar patterns (3, 13-17). Consequently, the mechanism of segregation of stimulus information and internally generated noise in carnivores and primates remain unclear. To address this question, we used primate-optimized functional imaging (18) to precisely compare spontaneous and stimulus-evoked activities in multiple areas of the marmoset visual cortical pathway (19). In marmoset V1, but not in mouse V1, spontaneous and stimulus-evoked activity shared similar activity patterns, suggesting a function of spontaneous activity specific to mammals with functional columns. However, in the higher-order visual areas of marmosets, spontaneous and stimulus-evoked activities exhibited dissimilar patterns. Analysis of neural activity geometry further revealed progressive orthogonalization of the two types of activities along the cortical hierarchy in marmosets, which reached a level comparable to that of mouse V1. Thus, orthogonalization of spontaneous and stimulus-evoked activity is a general principle of cortical computation, which, in primates, is implemented by the hierarchical areal network.