bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-Domain Diffuse Optical Tomography for Precision Neuroscience
Authors: Chekin Yaroslav , Decker Dakota , Dehghani Hamid , Dubois Julien , Field Ryan M. , Gopalakrishnan Viswanath , Koch Erin M. , Lerner Gabriel , Aghajan Zahra M. , Miller Naomi , Olvera Isai , Patel Milin J. , Perdue Katherine L. , Schmidt Joshua , Szczepanski Victor
Published: May 2024

Abstract

Recent years have witnessed a rise in research utilizing neuroimaging for precision neuromedicine, but clinical translation has been hindered by scalability and cost. Time Domain functional Near Infrared Spectroscopy (TD-fNIRS), the gold standard of optical neuroimaging techniques, offers a unique opportunity in this domain since it provides superior depth sensitivity and enables resolution of absolute properties unlike its continuous wave counterparts. However, current TD systems have limited commercial availability, slow sampling rates, and sparse head coverage. Our team has overcome the technical challenges involved in developing a whole-head time-domain diffuse optical tomography (TD-DOT) system. Here, we present the system characterization results using standardized protocols and compare them to the state-of-the-art. Furthermore, we showcase the system performance in retrieving cortical activation maps during standard hemodynamic, sensory, and motor tasks. A combination of the system performance, signal quality, and ease-of-use can enable future studies aimed at investigating TD-DOT clinical applications.
Local and global density have distinct and parasite-dependent effects on infection in wild sheep
Authors: Albery Gregory F , Sweeny Amy R , Corripio-Miyar Yolanda , Evans Michael J , Hayward Adam , Pemberton Josephine M , Pilkington Jill G , Nussey Daniel H
Published: May 2024

High density should drive greater parasite exposure. However, evidence linking density with infection generally uses density proxies, rather than of individuals per space within a continuous population.

We used a long-term study of wild sheep to link within-population spatiotemporal variation in host density with individual parasite counts. Although four parasites exhibited strong positive relationships with local density, these relationships were mostly restricted to juveniles and faded in adults. Further, one ectoparasite showed strong negative relationships across all age classes. In contrast, population size – a measure of global density – had limited explanatory power, and its effects did not remove those of spatial density, but were complementary. These results indicate that local and global density can exhibit diverse and contrasting effects on infection within populations. Spatial measures of within-population local density may provide substantial additional insight to temporal metrics based on population size, and investigating them more widely could be highly revealing.
Deciduous forests hold conservation value for birds within South Andaman Island, India
Authors: Jayanth Arpitha , Patel Zankhna , Mubeen Mohammed , Karthikayan M , Naniwadekar Rohit
Published: May 2024

Greater diversity of habitats on islands is often correlated with higher species richness (including endemic and threatened taxa), implying the need to understand species-habitat associations. Such habitat associations would also point towards the role of abiotic filtering and competition in structuring species communities, necessitating the examination of the role of species traits and phylogenetic relationships in intra-island community organisation, an aspect poorly examined in literature. We investigated the composition and structuring of forest bird communities in closely co-occurring evergreen and deciduous forests within South Andaman Island (Indian Ocean), wherein the importance of deciduous forests for birds is undervalued. We sampled 27 transects over two years and compared bird species composition and diversity across the two habitats. We examined species-specific associations with habitat (forest) type, basal area, and distance from human settlements, and tested if these responses were explained by species functional traits and tested for phylogenetic niche conservatism after factoring the effects of environmental predictors. Bird species compositions were markedly distinct across the two habitat types, with deciduous forests having greater taxonomic, but not functional or phylogenetic, diversity of forest birds. The distribution of forest birds, including several endemic and threatened species within the island was largely explained by habitat type (with 39% of the bird species analysed showing higher occurrence probabilities in deciduous forests), followed by distance from human settlements and basal area. We did not find evidence of species traits or phylogenetic relationships mediating these habitat preferences, perhaps due to a relatively impoverished species pool, as is typical on islands. Nevertheless, our results underscore the value of deciduous forests in harbouring high islandic species diversity, and being the preferred habitat of several endemic and threatened bird species. Given the historic focus on evergreen forests and the increasing anthropogenic pressure on the forests of the Andamans, we highlight the critical need to include the rapidly diminishing deciduous forests in existing conservation plans.
Use of human AML cells to study graft-versus-leukemia immunity in xenogeneic mouse models of GVHD
Authors: Faville Charline , Silva Bianca E , Baron Frédéric , Ehx Grégory
Published: May 2024

Allogeneic hematopoietic cell transplantation (allo-HCT) is the main therapeutic approach for patients with high-risk acute myeloid leukemia (AML), but the rate of relapse remains high and is associated with poor outcomes. Discovering new approaches to maximize the graft-versus-leukemia (GVL) effects while mitigating graft-versus-host disease (GVHD) should therefore be pursued. Because of the difficulties in modeling AML in mice, patient-derived xenotransplantations (PDX) in immunodeficient NSG mice are preferred to study the GVL effects. In PDX, AML is typically induced through the intravenous injection of cell lines or leukemic blasts obtained from patients. GVHD and GVL effects are induced by (co)-injecting human T cells or peripheral blood mononuclear cells (PBMCs). While this approach enables the induction of systemic leukemia, notably developing in the spleen and bone marrow of the animals, it can also be associated with difficulties in monitoring the disease, notably by flow cytometry. This can be circumvented by using luciferase-expressing AML cells or transplanting the leukemic cells in Matrigel to generate solid tumors that are easier to monitor. Here, we provide detailed instructions on how to prepare human PBMCs and leukemic cells, transplant them, and monitor the disease in NSG mice.
Partial Fitch Graphs: Characterization, Satisfiability and Complexity∗
Authors: Hellmuth Marc , Korchmaros Annachiara , Ramírez-Rafael José Antonio , Schmidt Bruno , Stadler Peter F. , Thekkumpadan Puthiyaveedu Sandhya
Published: May 2024

Horizontal gene transfer is an important contributor to evolution. Following Walter M. Fitch, two genes are xenologs if at least one HGT separates them. More formally, the directed Fitch graph has a set of genes as its vertices, and directed edges (x, y) for all pairs of genesxandyfor whichyhas been horizontally transferred at least once since it diverged from the last common ancestor ofxandy. Subgraphs of Fitch graphs can be inferred by comparative sequence analysis. In many cases, however, only partial knowledge about the “full” Fitch graph can be obtained. Here, we characterize Fitch-satisfiable graphs that can be extended to a biologically feasible “full” Fitch graph and derive a simple polynomial-time recognition algorithm. We then proceed to show that several versions of finding the Fitch graph with total maximum (confidence) edge-weights are NP-hard. In addition, we provide a greedy-heuristic for “optimally” recovering Fitch graphs from partial ones. Somewhat surprisingly, even if ∼ 80% of information of the underlying input Fitch-graphGis lost (i.e., the partial Fitch graph contains only ∼ 20% of the edges ofG), it is possible to recover ∼ 90% of the original edges ofGon average.
Quantitative cancer-immunity cycle modeling for predicting disease progression in advanced metastatic colorectal cancer
Authors: Li Chenghang , Wei Yongchang , Lei Jinzhi
Published: May 2024

Patients diagnosed with advanced metastatic colorectal cancer (mCRC) often exhibit heterogeneous disease progression and face poor survival prospects. In order to comprehensively analyze the varied treatment responses among individuals and the challenge of tumor recurrence resistant to drugs in advanced mRCR, we developed a novel quantitative cancer-immunity cycle (QCIC) model. The proposed model was meticulously crafted utilizing a blend of differential equations and randomized modeling techniques to quantitatively elucidate the intricate mechanisms governing the cancer-immunity cycle and forecast tumor dynamics under different treatment modalities. Furthermore, by integrating diverse clinical datasets and rigorous model analyses, we introduced two pivotal concepts: the treatment response index (TRI) and the death probability function (DPF). These concepts are crucial tools for translating model predictions into clinically relevant evaluation indexes. Using virtual patient technology, we extrapolated tumor predictive biomarkers from the model to predict survival outcomes for mCRC patients. Our findings underscore the significance of tumor-infiltrating CD8+CTL cell density as a key predictive biomarker for short-term treatment responses in advanced mCRC while emphasizing the potential predict value of the tumor-infiltrating CD4+Th1/Treg ratio in determining patient survival. This study presents a pioneering methodology bridging the divide between diverse clinical data sources and the generation of virtual patients, offering invaluable insights into understanding inter-individual treatment variations and forecasting survival outcomes in mCRC patients.

Author summary

This study introduces a sophisticated modeling approach to delineate the intricate dynamics of tumor-immune interactions within the cancer-immunity cycle. Utilizing a multi-compartmental, multi-scale, multi-dimensional differential equation model, we quantified the complex interplay between tumor cells, immune cells, cytokines, and chemokines. By integrating virtual patient technology, we have conductedin silicoclinical trials that accurately predict disease progression across multiple treatment modalities for cancer patients, particularly in advanced mCRC. Through the combination of differential equations and randomized modeling, we effectively captured the diverse treatment responses and clinical manifestations of drug-resistant tumor recurrence. Furthermore, we explored the pivotal role of predictive biomarkers in determining patients’ survival prognosis, offering insights for tailored therapeutic strategies. Importantly, our computational framework holds promise for the extension to the investigation of patients with other tumor types, thus contributing to the personalized investigation of patients with other tumor types and cancer care.
Unsupervised deep learning enables blur-free super-resolution in two-photon microscopy
Authors: Morita Haruhiko , Hayashi Shuto , Tsuji Takahiro , Kato Daisuke , Wake Hiroaki , Shimamura Teppei
Published: May 2024

We developed an unsupervised deep learning method to simultaneously perform deblurring, super-resolution, and segmentation of two-photon microscopy images. Two-photon microscopy is an excellent technique for non-invasively observing deep biological tissues, but blurring during deep imaging has been a challenge. Conventional deblurring methods have limited performance and are not suitable for deblurring two-photon microscopy images. Moreover, methods that simultaneously perform segmentation, which is usually required in downstream analysis, have not been developed. Therefore, in this method (TENET), we precisely modeled the blur of two-photon microscopy and simultaneously achieved deblurring, super-resolution, and segmentation through unsupervised deep learning. In simulation and experimental data, we achieved deblurring, resolution improvement, and segmentation accuracy surpassing conventional methods. Furthermore, we applied the method to live imaging of microglia, enabling quantitative 3D morphological analysis that was previously difficult. This method allows non-invasive visualization of detailed structures in deep biological tissues, and is expected to lead to a more high-definition understanding of biological phenomena. Future applications to time-series morphological analysis of microglia are anticipated.
Supervised Machine Learning for Bioelectrical Cellular Networks
Authors: Jaundoo Rajeev , Craddock Travis J.A. , Tuszynski Jack A.
Published: May 2024

1.

Cells utilize bioelectricity to form networks as well as regulate and control a variety of processes such as apoptosis, tumor suppression, and voltage-gated ion channels. In-silico modeling of bioelectrical networks can be performed using BETSE, an application that models gap junctions and ion channel activity of networked cells, but its usage of matrix-based differential equations to estimate these properties limits simulations based on the amount of computational resources available. To alleviate this issue, we trained a total of 8 machine learning models to replace three core functions of BETSE, that is, 1) predicting the average transmembrane potential (Vmem) of an entire cellular network, 2) predicting the Vmemof each individual cell within the network, and finally, 3) predicting the average ion concentrations of sodium, potassium, chloride, and calcium within the cell network. For objective 1, the random forest model was shown to be most performant over all 4 scoring metrics, in objective 2 both the decision tree and k-nearest neighbors models scored best in half of all metrics, and for objective 3 the super learner, a meta-learner comprised of multiple base learners, scored best among all scoring metrics. Overall, these models provide a more resource efficient method of predicting properties of bioelectric cellular networks, and future work will include further properties such as temperature and pressure.
The first complete assembly for a lungless urodelan with a "miniaturized" genome, the Northern Dusky Salamander (Plethodontidae: Desmognathus fuscus)
Authors: Myers Edward A , Pyron R. Alexander
Published: May 2024

Salamanders have some of the largest genomes among animals. However, there is a great disparity in total size, ranging from ~8-120GB depending on the lineage. Species in the lungless genus Desmognathus (Plethodontidae) are among the smallest, with estimated genome sizes of 13-15GB. Salamander genomes have exceptional interest in numerous topics ranging from genome-size evolution, the genetic basis of evolutionary differences in life history, and the physiological basis of regeneration, vision, and immunity. However, their large genomes have limited previous attempts at sequencing and assembly, particularly given the difficulties of mapping extensive repeat regions with short-read data. Here we assemble a draft genome of Desmognathus fuscus using PacBio HiFi reads and generate transcriptomic data from two specimens. The combined assembly resulted in a 16.1GB genome in 19,640 contigs and an N/L50 of 2,455/1.75MB, with the longest contig at 27.9MB. The assembly and transcriptome are nearly complete with 93% of the 5,310 BUSCO tetrapod orthologs identified. Attempts to scaffold these data to the existing Ambystoma genome resulted in only 5.8GB of the D. fuscus genome mapping to this reference. This low success suggests substantial syntenic and sequence divergence across salamanders, which may be the result of significant miniaturization in the Desmognathus genome. Identification and annotation of transposable elements reveals that only 26% of the genome is single copy with 74% corresponding to TEs. The most common class of TE in the genome are LTRs (35% of the total genome) and LINEs (~15% of the genome). The relative divergence landscape of these TEs shows an early expansion and slow contraction of LINEs, followed by a quick recent expansion of both LTRs and DNA transposons. This assembly will serve as an important reference for amphibian genomics.
Non-hypermutator cancers access driver mutations through reversals in germline mutational bias
Authors: Tuffaha Marwa Z. , Castellano David , Colome Claudia Serrano , Gutenkunst Ryan N. , Wahl Lindi M.
Published: May 2024

Cancer is an evolutionary disease driven by mutations in asexually-reproducing somatic cells. In asexual microbes, bias reversals in the mutation spectrum can speed adaptation by increasing access to previously undersampled beneficial mutations. By analyzing tumors from 20 tissues, along with normal tissue and the germline, we demonstrate this effect in cancer. Non-hypermutated tumors reverse the germline mutation bias and have consistent spectra across tissues. These spectra changes carry the signature of hypoxia, and they facilitate positive selection in cancer genes. Hypermutated and non-hypermutated tumors thus acquire driver mutations differently: hypermutated tumors by higher mutation rates and non-hypermutated tumors by changing the mutation spectrum to reverse the germline mutation bias.
Virectaria stellata(Sabiceeae-Rubiaceae), a new sandstone cliff species from the Republic of Guinea with stellate hairs recorded for the first time in the Rubiaceae
Authors: Simbiano Faya Julien , Van Der Burgt Xander M. , Darbyshire Iain , Haba Pepe M. , Konomou Gbamon , Cheek Martin , Couch Charlotte , Magassouba Sékou
Published: May 2024

Virectariais a morphologically isolated genus of tropical African herbs or subshrubs, occurring from Senegal to Tanzania.Virectaria stellata, a new species from Guinea, is published. It is a perennial herb, with stems becoming creeping and rooting, to 60 cm long.Virectaria stellatahas stellate hairs, recorded here for the first time in the family Rubiaceae. We hypothesize that the stellate hairs of this species result from horizontal gene flow from an Acanthaceae, most likelyBarleria, due to their common and perhaps unique microstructure.Virectaria stellatais found in Forécariah and Kindia Prefectures in the Republic of Guinea. The species occurs in fissures in vertical sandstone rock at altitudes of 450 to 910 m, in sun or half-shade. An overview of sandstone endemic plant species in the vicinity of the newVirectariais provided. No threats have been observed, therefore,Virectaria stellatais provisionally assessed here as Least Concern (LC).
GIBBERELLIN SIGNALING THROUGH RGA SUPPRESSES GCN5 EFFECT ON STAMEN ELONGATION OF ARABIDOPSIS FLOWERS
Authors: Balouri Christina , Poulios Stylianos , Tsompani Dimitra , Spyropoulou Zoe , Ketikoglou Maria-Christina , Kaldis Athanasios , Doonan John H , Vlachonasios Konstantinos E
Published: May 2024

Histone acetyltransferases (HAT) modify the amino-terminal tails of the core histone proteins via acetylation, regulating chromatin structure and transcription. The GENERAL CONTROL NON-DEREPRESSIBLE 5 (GCN5) is a HAT that specifically acetylates H3K14 residues. GCN5 has been associated with cell division and differentiation, meristem function, root, stem, foliar and floral development, and plant environmental response. The flowers ofgcn5–6plants display reduced length of stamen and exhibit male sterility relative to the wild-type plants. We show these effects may arise from gibberellin (GA) signaling defects. The signaling pathway of bioactive GAs depends on the proteolysis of their repressors, DELLA proteins. The DELLA protein, REPRESSOR OF GA (RGA), represses plant growth, inflorescence, flower and seed development. Our molecular data indicate that GCN5 is required for activation and H3K14 acetylation of genes involved in the late stages of GA biosynthesis and catabolism. We studied the genetic interaction of RGA and GCN5; RGA can partially suppress GCN5 action. The reduced elongation of the stamen filament ofgcn5–6mutants is reversed in therga–t2;gcn5–6double mutants. This mechanism involved suppressing the GCN5 effect on the expression and histone acetylation inGAI-locus by RGA. Interestingly, RGA and RGL2 do not suppress ADA2b function, suggesting that ADA2b acts downstream in GA signaling and is distinct from GCN5 activity. In conclusion, we propose that the action of GCN5 on stamen elongation is mediated partially by RGA and GA signaling.
Two major-effect loci influence assortative mating in females of the sibling species,Drosophila simulansandD. sechellia
Authors: Lu Kenneth , Erezyilmaz Deniz
Published: May 2024

Secondary contact between incompletely isolated species can produce a wide variety of outcomes, including production of new species and adaptive radiations. The vinegar fliesDrosophila simulansandD. sechelliadiverged on islands in the Indian Ocean and are currently separated by partial pre– and postzygotic barriers. The recent discovery of hybridization betweenD. simulansandD. sechelliain the wild presents an opportunity to monitor the prevalence of alleles that influence introgression between these species. We therefore sought to identify those loci that affect assortative mating, and we adapted a two-choice assay to test behavioral isolation in females. Using high-resolution seq-based QTL mapping, we found two major effect loci on the third chromosome that have a profound effect upon assortative mating of females. Each major QTL accounts for 32-37% of the difference in phenotype on its own, which is highly significant for a behavioral trait. The two major QTL of both backcrosses co-localize in one-dimensional analyses, suggesting that they may be alternate alleles of the same loci. The major-effect loci also co-localize with genes that encode enzymes required for female– and species-specific production of the pheromone, 7,11-heptacosadiene, emphasizing the importance of female attractiveness to males in separation of these species. Moreover, the genetic architecture of female assortative mating may be a factor in species separation, since alleles that influence assortative mating in females are linked to major-effect loci that influence assortative mating in males, and to loci that contribute to host fruit adaptation inD. sechellia.
Adaptive Differentiation in the General-Purpose Genotype Invasive PlantErythranthe guttata
Authors: Millar Aaron O , Chapman Hazel M
Published: May 2024

Highly plastic general-purpose genotypes are a frequent occurrence among invasive plants. Yet, it remains uncertain to what extent genetic adaptation can co-occur with such elevated levels of plasticity. Understanding the interplay between these two evolutionary strategies is essential to better predict invasive success and future climate change responses.

We investigated the potential for local adaptation along an altitudinal gradient in introduced New Zealand populations of the highly plastic invasive herb,Erythranthe guttata. We asked a) whether there were phenotypic differences between upland and lowlandE. guttatapopulations along our gradient; b) whether any differences were consistent with known adaptive patterns; and c) whether any adaptive patterns exist alongside high plasticity to elevation.

Samples from 38E. guttatapopulations from upland and lowland Canterbury were grown from cuttings in a lowland and an upland common garden, where we measured a broad range of growth and reproductive traits.

We found significant adaptive differentiation between upland and lowland populations over almost all measured traits. Upland populations had earlier and more intense flowering compared with lowland populations. Lowland plants were taller and had larger leaves with higher photosynthetic rates than upland plants. These differences occurred alongside high levels of unspecialised plasticity to the growing environment.

Synthesis: We found that over a period of less than 150 years the environment along an altitude gradient of 120km has selected for distinct lowland and upland phenotypes ofE. guttata. These changes reflect common selective pressure associated with altitude gradients, increasing reproductive success at higher altitudes and increased competitive ability at lower altitudes. This rapid local adaptation occurred alongside high plasticity within the growing environment, showing that highly plastic invasive species still retain the capacity to genetically adapt to novel environments.
Effective target genes for RNA interference-based management of the cabbage stem flea beetle
Authors: Cedden Doga , Güney Gözde , Debaisieux Xavier , Scholten Stefan , Rostás Michael , Bucher Gregor
Published: May 2024

The cabbage stem flea beetle (CSFB,Psylliodes chrysocephala) is a key pest of oilseed rape. The ban on neonicotinoids in the European Union due to environmental concerns and the emergence of pyrethroid-resistant populations have made the control of CSFB extremely challenging. In search of a solution, we have recently shown that RNA interference (RNAi) has potential in the management of CSFB. However, the previously tested target genes for RNAi-mediated pest control (subsequently calledtarget genes) exhibited moderate and slow-acting lethal effects. In this study, 27 double-stranded RNAs (dsRNAs) were orally delivered to identify highly effective target genes in CSFB adults by leveraging the findings of a genome-wide RNAi screen inTribolium castaneum. Our screen using 500 ng of dsRNA identified 10 moderately effective (> 50% mortality) and 4 highly effective target genes (100% mortality in 8-13 days). The latter mainly included proteasome subunits. RT-qPCR experiments confirmed target gene silencing and dose-response studies revealed LD50values as low as ∼20 ng in 14 days following a single exposure to dsRNA. Four highly effective dsRNAs also inhibited leaf damage (up to ∼75%) and one affected locomotion. The sequences of promising target genes were subjected toin silicotarget prediction in non-target organisms, e.g., beneficials such as honeybees, to design environmentally friendly dsRNAs. Overall, the study provides valuable insights for the development of dsRNA-based insecticides against CSFB.
Fast skeletal myosin binding protein-C expression exacerbates dysfunction in heart failure
Authors: McNamara James W. , Song Taejeong , Alam Perwez , Binek Aleksandra , Singh Rohit R. , Nieman Michelle L. , Koch Sheryl E. , Ivey Malina J. , Lynch Thomas L. , Rubinstein Jack , Jin J-P , Lorenz John N. , Van Eyk Jennifer E. , Kanisicak Onur , Sadayappan Sakthivel
Published: May 2024

During heart failure, gene and protein expression profiles undergo extensive compensatory and pathological remodeling. We previously observed that fast skeletal myosin binding protein-C (fMyBP-C) is upregulated in diseased mouse hearts. While fMyBP-C shares significant homology with its cardiac paralog, cardiac myosin binding protein-C (cMyBP-C), there are key differences that may affect cardiac function. However, it is unknown if the expression of fMyBP-C expression in the heart is a pathological or compensatory response. We aim to elucidate the cardiac consequence of either increased or knockout of fMyBP-C expression. To determine the sufficiency of fMyBP-C to cause cardiac dysfunction, we generated cardiac-specific fMyBP-C over-expression mice. These mice were further crossed into a cMyBP-C null model to assess the effect of fMyBP-C in the heart in the complete absence of cMyBP-C. Finally, fMyBP-C null mice underwent transverse aortic constriction (TAC) to define the requirement of fMyBP-C during heart failure development. We confirmed the upregulation of fMyBP-C in several models of cardiac disease, including the use of lineage tracing. Low levels of fMyBP-C caused mild cardiac remodeling and sarcomere dysfunction. Exclusive expression of fMyBP-C in a heart failure model further exacerbated cardiac pathology. Following 8 weeks of TAC, fMyBP-C null mice demonstrated greater protection against heart failure development. Mechanistically, this may be due to the differential regulation of the myosin super-relaxed state. These findings suggest that the elevated expression of fMyBP-C in diseased hearts is a pathological response. Targeted therapies to prevent upregulation of fMyBP-C may prove beneficial in the treatment of heart failure.

Significance Statement

Recently, the sarcomere – the machinery that controls heart and muscle contraction - has emerged as a central target for development of cardiac therapeutics. However, there remains much to understand about how the sarcomere is modified in response to disease. We recently discovered that a protein normally expressed in skeletal muscle, is present in the heart in certain settings of heart disease. How this skeletal muscle protein affects the function of the heart remained unknown. Using genetically engineered mouse models to modulate expression of this skeletal muscle protein, we determined that expression of this skeletal muscle protein in the heart negatively affects cardiac performance. Importantly, deletion of this protein from the heart could improve heart function suggesting a possible therapeutic avenue.
Glutathione supersulphide regulates T-cell receptor signalling
Authors: Sasaki Yusaku , Numakura Tadahisa , Yamada Mitsuhiro , Sugiura Hisatoshi , Matsunaga Tetsuro , Ida Tomoaki , Morita Masanobu , Suzuki Ayumi , Matsumoto Shuichiro , Kawaguchi Madoka , Kawabe Takeshi , Tayama Shunichi , Okuyama Yuko , Takata Tsuyoshi , Inaba Kenji , Watanabe Satoshi , Suzuki Manami , Sano Hirohito , Kyogoku Yorihiko , Tanaka Rie , Mitsune Ayumi , Ichikawa Tomohiro , Fujino Naoya , Tamada Tsutomu , Ishii Naoto , Ichinose Masakazu , Akaike Takaaki , Motohashi Hozumi
Published: May 2024

Immunometabolism regulates functions and fates of immune cells including T cells. Supersulphides, which are universal metabolites containing catenated sulphur atoms, have various physiological functions based on their unique redox properties. Here we found that activation of T-cell receptor (TCR) signalling was accompanied by supersulphide decrease, which suggests a regulatory contribution of sulphur metabolism to immune function. Consistently, inhibiting supersulphide synthesis facilitated TCR activation and exacerbated allergen-induced type 2 inflammation in mice. Supplementation with glutathione trisulphide (GSSSG), a major endogenous supersulphide, suppressed TCR signalling in naïve CD4+T cells and their differentiation and effectively alleviated the inflammation. Docking simulation revealed interaction of GSSSG with CD3ε chain in the TCR/CD3 complex, which was supported by mass spectrometry detection of persulphidated glutathionylation at a functionally important CXXC motif of CD3ε chain. This study identified a new post-translational modification with supersulfides and demonstrated a critical contribution of sulphur metabolism to TCR signalling regulation.
Transnational adoptees in healthcare: barriers, resources, and needs
Authors: Strand Mattias , Hillerberg Natte
Published: May 2024

Background

After decades of research output, it is well established that transnational adoptees—i.e., individuals who are placed for adoption outside their country of birth—exhibit an increased risk of various negative mental health outcomes. Even so, there is a lack of suggestions for preventive measures or treatment interventions targeting the transnational adoptee population in the literature.

Objective

To explore experiences, opinions, and needs among adult transnational adoptees in Sweden concerning healthcare in general and mental healthcare in particular.

Methods

Sixty-six adult transnational adoptees residing in Sweden, born in 15 different non-European countries, were recruited for individual in-depth interviews about their experiences and opinions regarding psychosocial support and healthcare. The interview data were analyzed employing a codebook thematic analysis approach.

Results

Three overarching themes were identified: a) barriers to adequate treatment, b) helpful resources in dealing with health-related issues, and c) health-related needs and suggestions for the development of adequate support. Identified barriers include a lack of insight into and interest in adoptee health, colorblindness and unwillingness to address racism, expectations of gratitude, steep financial costs, lack of support from adoptive parents, and mistrust of support structures that involve adoptive parents or adoption organizations. Participants also describe helpful resources, such as the community of fellow transnational adoptees. Health-related needs and suggestions include more well-defined and easily accessible structures of support, improved knowledge and competence, a broader psychotherapeutic repertoire that better addresses adoption-related themes, improved support in situations that can be particularly stressful for adoptees (such as during pregnancy and as new parents), routine follow-up during childhood and adolescence, and education targeting adoptive parents. The need for greater attention to the well-being of children of transnational adoptees is also highlighted.

Implications

Based on these findings, a number of recommendations can be made. For example, knowledge about adoptee health should be strengthened, and psychotherapeutic competence in addressing issues related to racism should become a priority. After over 20 years of discussion, one or more national research and knowledge hubs on transnational adoption should be created. Moreover, economic resources should be made available to support transnational adoptees in accessing adequate treatment.
Luminal breast epithelial cells from wildtype andBRCAmutation carriers harbor copy number alterations commonly associated with breast cancer
Authors: Williams Marc J. , Oliphant Michael UJ , Au Vinci , Liu Cathy , Baril Caroline , O’Flanagan Ciara , Lai Daniel , Beatty Sean , Van Vliet Michael , Yiu Jacky CH , O’Connor Lauren , Goh Walter L , Pollaci Alicia , Weiner Adam C. , Grewal Diljot , McPherson Andrew , Moore McKenna , Prabhakar Vikas , Agarwal Shailesh , Garber Judy E. , Dillon Deborah , Shah Sohrab P. , Brugge Joan , Aparicio Samuel
Published: May 2024

Cancer-associated mutations have been documented in normal tissues, but the prevalence and nature of somatic copy number alterations and their role in tumor initiation and evolution is not well understood. Here, using single cell DNA sequencing, we describe the landscape of CNAs in >42,000 breast epithelial cells from women with normal or high risk of developing breast cancer. Accumulation of individual cells with one or two of a specific subset of CNAs (e.g. 1q gain and 16q, 22q, 7q, and 10q loss) is detectable in almost all breast tissues and, in those fromBRCA1orBRCA2mutations carriers, occurs prior to loss of heterozygosity (LOH) of the wildtype alleles. These CNAs, which are among the most common associated with ductal carcinoma in situ (DCIS) and malignant breast tumors, are enriched almost exclusively in luminal cells not basal myoepithelial cells. Allele-specific analysis of the enriched CNAs reveals that each allele was independently altered, demonstrating convergent evolution of these CNAs in an individual breast. Tissues fromBRCA1orBRCA2mutation carriers contain a small percentage of cells with extreme aneuploidy, featuring loss ofTP53, LOH ofBRCA1orBRCA2, and multiple breast cancer-associated CNAs in addition to one or more of the common CNAs in 1q, 10q or 16q. Notably, cells with intermediate levels of CNAs are not detected, arguing against a stepwise gradual accumulation of CNAs. Overall, our findings demonstrate that chromosomal alterations in normal breast epithelium partially mirror those of established cancer genomes and are chromosome- and cell lineage-specific.
Inverse Finite Element Framework Combining Ultrasound Imaging and Inflation Testing of PVA Artery Phantoms
Authors: Guendouz Yasmine , Razif Noor Adeebah Mohamed , Bernasconi Floriane , Brien Gordon O’ , Johnston Robert D. , Lally Caitríona
Published: May 2024

The clinical decision to establish if a patient with carotid disease should undergo surgical intervention is primarily based on the percent stenosis. Whilst this applies for high-grade stenosed vessels (>70%), it falls short for other cases. Due to the heterogeneity of plaque tissue, probing the mechanics of the tissue would likely provide further insights into why some plaques are more prone to rupture. Mechanical characterisation of such tissue is nontrivial, however, due to the difficulties in collecting fresh, intact plaque tissue and using physiologically relevant mechanical testing of such material. The use of polyvinyl alcohol (PVA) is thus highly convenient because of its acoustic properties and tuneable mechanical properties.

Methods

The aim of this study is to demonstrate the potential of polyvinyl alcohol phantoms to simulate atherosclerotic features. In addition, a testing and simulation framework is developed for full PVA vessel material characterization using ring tensile testing and inflation testing combined with non-invasive ultrasound imaging and computational modelling.

Results

Strain stiffening behaviour was observed in PVA through ring tensile tests, particularly at high freeze-thaw cycles. Inflation testing of bi-layered phantoms featuring lipid pool inclusions demonstrated high strains at shoulder regions. The application of an inverse finite element framework successfully recovered boundaries and determined the shear moduli for the PVA wall to lie within the range 27 kPa to 53 kPa.

Conclusion

The imaging-modelling framework presented facilitates the use and characterisation of arterial mimicking phantoms to further explore plaque rupture. It also shows translational potential for non-invasive mechanical characterisation of atherosclerotic plaques to improve the identification of clinically relevant metrics of plaque vulnerability.
Gait signature changes with walking speed are similar among able-bodied young adults despite persistent individual-specific differences
Authors: Winner Taniel S. , Rosenberg Michael C. , Berman Gordon J. , Kesar Trisha M. , Ting Lena H.
Published: May 2024

Understanding individuals’ distinct movement patterns is crucial for health, rehabilitation, and sports. Recently, we developed a machine learning-based framework to show that “gait signatures” describing the neuromechanical dynamics governing able-bodied and post-stroke gait kinematics remain individual-specific across speeds. However, we only evaluated gait signatures within a limited speed range and number of participants, using only sagittal plane (i.e., 2D) joint angles. Here we characterized changes in gait signatures across a wide range of speeds, from very slow (0.3 m/s) to exceptionally fast (above the walk-to-run transition speed) in 17 able-bodied young adults. We further assessed whether 3D kinematic and/or kinetic (ground reaction forces, joint moments, and powers) data would improve the discrimination of gait signatures. Our study showed that gait signatures remained individual-specific across walking speeds: Notably, 3D kinematic signatures achieved exceptional accuracy (99.8%, confidence interval (CI): 99.1-100%) in classifying individuals, surpassing both 2D kinematics and 3D kinetics. Moreover, participants exhibited consistent, predictable linear changes in their gait signatures across the entire speed range. These changes were associated with participants’ preferred walking speeds, balance ability, cadence, and step length. These findings support gait signatures as a tool to characterize individual differences in gait and predict speed-induced changes in gait dynamics.
In-silicostudy of fatty acid biosynthesis pathway enzymes in microalgaScenedesmus
Authors: Sharma Harshit Kumar , Velázquez Ma. Belén , Marchetti Noelia , Busi Ma. Victoria , Barchiesi Julieta , Dasgupta Chitralekha Nag
Published: May 2024

Scenedesmus quadricaudais an important, rapidly growing, freshwater microalga explored as a source of alternative fuel because of its significantly high lipid content. However, the molecular basis of fatty acid biosynthesis is scarcely elucidated not only inS. quadricaudabut also inScenedesmusas a whole. This study aims to understand the 3D model structure of enzymes involved in fatty acid synthesis, and their catalytic sites compared to otherScenedesmusspecies. The first genome sequenceS. quadricaudawas carried initially in our isolate LWG002611 (GenBank ID NNCB00000000). However, till date, no study has been carried out on the 3D modelling and identifying the catalytic sites of fatty acid biosynthesis pathway enzymes. Mining the genome sequence of our isolatedS. quadricaudaLWG002611 as well as otherScenedesmussequences taken from PhycoCosm and NCBI, we identified sequences of the crucial enzymes involved in fatty acid biosynthesis pathways such as acetyl-CoA carboxylase (ACC), malonyl-CoA:ACP transacylase (MAT) and fatty-acyl thioesterases (FAT) for comparative study on homology, catalytic sites, domains, and protein 3D models. Detailed comparative analyses of these identified enzymes were carried out using various bioinformatics tools. Which demonstrated highly significant sequence similarity with homologs of bacteria as well as with homologs of lower groups of eukaryotes suggesting an evolutionary linkage with them. The molecular modeling and 3D structures of the chloroplastic enzymes by AlphaFold Multimer revealed the overall structural orientation and well-conserved catalytic residues. On the other hand, biotin protein ligase and cytosolic acetyl-CoA carboxylase isoforms presented some significant differences with respect to the previously reported protein models. The conserved domain suggests the preservation of the fatty acid biosynthesis pathway inScenedesmaceaefamily. However, some contrasting results, unique sequences and binding sites of some enzymes inS. quadricaudamay have a significant role in higher lipid accumulation than the other species. Our analysis describes some specific features inS. quadricaudafatty acid synthesis enzymes that could open up the scope of further analysis of these enzymes.
VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent tumorigenesis by engaging p300
Authors: Guo Susu , Hu Xiaodi , Cotton Jennifer L. , Ma Lifang , Li Qi , Cui Jiangtao , Wang Yongjie , Thakare Ritesh P. , Tao Zhipeng , Ip Y. Tony , Wu Xu , Wang Jiayi , Mao Junhao
Published: May 2024

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation bothin vitroandin vivo. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.
Clinical Response to Neurofeedback in Major Depression Relates to Subtypes of Whole-Brain Activation Patterns During Training
Authors: Misaki Masaya , Young Kymberly D. , Tsuchiyagaito Aki , Savitz Jonathan , Guinjoan Salvador M.
Published: May 2024

Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. Significant symptom reduction was observed in the active group (t=-4.404,d=-0.704,p<0.001) but not in the control group (t=-1.609,d=-0.430,p=0.111). However, left amygdala activation did not account for the variability in clinical efficacy. To elucidate the brain training process underlying the clinical effect, we examined whole-brain activation patterns during two critical phases of the neurofeedback procedure: activation during the self-regulation period, and transient responses to feedback signal presentations. Using a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified two subtypes of regulation activation and three subtypes of brain responses to feedback signals. These subtypes were significantly associated with the clinical effect (regulation subtype:F=8.735,p=0.005; feedback response subtype:F=5.326,p=0.008; subtypes’ interaction:F=3.471,p=0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity during training is more critical for clinical efficacy than the level of activation in the neurofeedback target region itself. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.
Prefrontal dopamine activity is critical for rapid threat avoidance learning
Authors: Zeidler Zachary , Gomez Marta Fernandez , Gupta Tanya A. , Shari Meelan , Wilke Scott A. , DeNardo Laura A.
Published: May 2024

The medial prefrontal cortex (mPFC) is required for learning associations that determine whether animals approach or avoid potential threats in the environment. Dopaminergic (DA) projections from the ventral tegmental area (VTA) to the mPFC carry information, particularly about aversive outcomes, that may inform prefrontal computations. But the role of prefrontal DA in learning based on aversive outcomes remains poorly understood. Here, we used platform mediated avoidance (PMA) to study the role of mPFC DA in threat avoidance learning in mice. We show that activity in VTA-mPFC dopaminergic terminals is required for avoidance learning, but not for escape, conditioned fear, or to recall a previously learned avoidance strategy. mPFC DA is most dynamic in the early stages of learning, and encodes aversive outcomes, their omissions, and threat-induced behaviors. Computational models of PMA behavior and DA activity revealed that mPFC DA influences learning rates and encodes the predictive relationships between cues and adaptive behaviors. Taken together, these data indicate that mPFC DA is necessary to rapidly learn behaviors required to avoid signaled threats, but not for learning cue-threat associations.