bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractDuring 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 StatementRecently, 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

AbstractImmunometabolism 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

AbstractBackgroundAfter 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.ObjectiveTo explore experiences, opinions, and needs among adult transnational adoptees in Sweden concerning healthcare in general and mental healthcare in particular.MethodsSixty-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.ResultsThree 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.ImplicationsBased 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

AbstractCancer-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

AbstractThe 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.MethodsThe 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.ResultsStrain 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.ConclusionThe 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

AbstractUnderstanding 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

AbstractScenedesmus 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

AbstractStudies 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

AbstractMajor 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

AbstractThe 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.
The genetic architecture and evolutionary consequences of the human pelvic form
Authors: Xu Liaoyi , Kun Eucharist , Pandey Devansh , Wang Joyce Y. , Brasil Marianne F. , Singh Tarjinder , Narasimhan Vagheesh M. 
Published: May 2024

AbstractHuman pelvic shape has undergone significant evolutionary change since the divergence from the chimpanzee lineage. This transformation, involving the reduction of the pelvic canal size to support bipedal locomotion, is thought to give rise to the obstetrical dilemma, a hypothesis highlighting the mismatch between the large brain size of infants and the narrowed birth canal in females. Empirical evidence for this classic hypothesis has been equivocal, largely due to a lack of sample size and appropriate types of data. To elucidate the genetic underpinnings of pelvic morphology, we applied a deep learning model to 31,115 dual-energy X-ray absorptiometry (DXA) from the UK Biobank, extracting a set of seven pelvic proportion (PP) phenotypes, including measures of the birth canal. All PPs were found to be highly heritable (∼25-40%) and a genome-wide association study of these traits identified 179 independent loci. Unlike other skeletal proportions including long bone lengths, the subpubic angle associated with the birth canal exhibits a genetic correlation between sexes significantly less than 1, in line with sex-specific reproductive function. PPs were also left-right asymmetric but not heritable and instead associated with handedness. We conducted phenotypic and genetic association analyses to link PPs to 3 facets of the dilemma: locomotion, pelvic floor function and childbirth. Larger birth canal phenotypes were associated with reduced walking pace, decreased risk of back pain, and increased risk of hip osteoarthritis - phenotypes linked to locomotor efficiency. We also observed that a narrower birth canal width was associated with a reduced risk of pelvic floor disorders. When examining childbirth-related outcomes, narrower birth canal phenotypes were associated with increased risk of emergency cesarean sections and obstructed labor due to insufficient dilation, but not obstructed labor due to positioning of the fetus. Finally, we examined whether the dilemma might have been alleviated through evolution. We found no association between any PPs and gestational duration, contrary to the initial prediction by Washburn in 1960. However, we found that the birth weight of the child, a proxy for skull and brain size, was genetically correlated with birth canal width but not with other PPs. Collectively, our study offers fresh insight on a 60-year-old debate in human evolutionary studies. Our results support the idea that the obstetrical dilemma has played a central role in the co-evolution of the human brain and pelvis, while also highlighting the potential role of associated factors such as pelvic floor health.