bluuebunny/crossref_metadata_2025 huggingface dataset:
High-resolution MR imaging with gadoxetate disodium for the comprehensive evaluation of potential living liver donors
Authors: Lee Yoonseong , Koh Seok Young , Kim Jae Hyun , Yoo Jeongin , Kang Hyojin , Joo Ijin , Yoon Jeong Hee , Yi Nam-joon , Lee Kwang-Woong , Suh Kyungsuk , Lee Jeong Min
Published: February 2023

Several major transplantation centers have used composite multimodality evaluation for the preoperative evaluation of potential living liver donors. This approach can be time-consuming and, although rare, can cause complications. We aimed to demonstrate the clinical feasibility of our comprehensive preoperative MR protocol for the preoperative assessment of living liver donor candidates instead of composite multimodality evaluation. Thirty-five consecutive living liver donor candidates underwent multiphasic liver CT and comprehensive donor protocol MR examinations for preoperative evaluation in a single large-volume liver transplantation (LT) center. Three blinded abdominal radiologists reviewed the CT and MR images for vascular and biliary variations. The strength of agreement between CT and MR angiography was assessed using the kappa index. The detection rate of biliary anatomical variations was calculated. The sensitivity and specificity for detecting significant steatosis (>5%) were calculated. The estimated total volume and right lobe volumes measured by MR volumetry were compared with the corresponding CT volumetry measurements using the intraclass correlation coefficient (ICC). Among the 35 patients, 26 underwent LT. The measurement of agreement showed a moderate to substantial agreement between CT and MR angiography interpretations (kappa values, 0.47–0.79; p < 0.001). Combining T2-weighted and T1-weighted MR cholangiography techniques detected all biliary anatomical variations in 9 of the 26 patients. MR-proton density fat fraction showed a sensitivity of 100% (3/3) and a specificity of 91.3% (21/23) for detecting pathologically determined steatosis (>5%). MR volumetry reached an excellent agreement with CT volumetry (reviewers 1 and 2: ICC, 0.92; 95% CI, 0.84–0.96). Our one-stop comprehensive liver donor MR imaging protocol can provide complete information regarding hepatic vascular and biliary anatomies, hepatic parenchymal quality, and liver volume for living liver donor candidates and can replace composite multimodality evaluation.
A Qualitative Study of the Pain Experience of Black Individuals With Cancer Taking Long-Acting Opioids
Authors: Yeager Katherine A. , Rosa William E. , Belcher Sarah M. , Lee Stephanie M. , Lee Haerim , Bruner Deborah Watkins , Meghani Salimah H.
Published: February 2023

Background

Little is known about the experience of Black individuals with cancer taking long-acting opioids for cancer pain.

Objective

This study aimed to describe the day-to-day experience of living with pain and the experiences of taking opioids for pain management among Black individuals with cancer prescribed with long-acting opioids.

Methods

This qualitative descriptive study was part of a larger investigation focused on opioid adherence. Participants (N = 14) were interviewed using a semistructured interview guide. Analysis followed conventional content analysis and constant comparison approaches. Sociodemographics, clinical information, and the Brief Pain Inventory form were collected.

Results

The majority of the subsample was female (64.3%), not married (78.6%), and with a median age of 52.5 years. Participants were taking either MS Contin (85.7%) or OxyContin (14.3%). The Brief Pain Inventory median “average” pain severity scores and pain interference scores were 5.1/10 (interquartile range [IQR] = 6.1) and 3.5/10 (IQR = 6.7), respectively. Three themes are reported from the analyses: desire for control, barriers to pain relief, and isolation versus connectedness.

Conclusion

Our findings highlight the persistent nature of moderate to severe cancer pain and how pain and its treatment interfere with patients’ lives. The findings describe ways that patients learn to manage and exert control over pain despite conflicting attitudes and dealing with opioid stigma.

Implication for Practice

Clinicians should partner with patients with cancer, especially people of color, who may experience intersecting stigmas related to their cancer pain and opioid use, to best provide an individualized and culturally sensitive pain treatment plan.
Barking up the wrong tree: the importance of morphology in plant molecular phylogenetic studies
Authors: de Almeida Rafael Felipe , Cheek Martin , Pellegrini Marco O.O. , de Morais Isa L. , Simão-Bianchini Rosangela , Rattanakrajang Pantamith , Simões Ana Rita G.
Published: February 2023

Background and aims

Kerauneais a genus recently described in Convolvulaceae, though it has sat uncomfortably in this family. A recent molecular phylogenetic study suggests that its two morphologically almost identical species actually belong to different families, Malpighiaceae (Superrosids) and Ehretiaceae (Superasterids), although with little-to-no morphological evidence to support it.

Material and methods

Sequences ofmatK, rbcL, and ITS for all the 77 currently accepted genera of Malpighiaceae,K. brasiliensisand Elatinaceae (outgroup) were compiled from Genbank and analysed with Maximum Likelihood and Bayesian Inference criteria for nuclear, plastid and combined datasets. Additional database and herbarium studies were performed to locate and analyse all duplicates of the holotype ofK. brasiliensisto check for misidentified or contaminated materials.

Key results

Our examination of expanded DNA datasets and herbarium sheets of allK. brasiliensisisotypes revealed that an error in tissue sampling was, in fact, what led to this species being placed in Malpighiaceae. Kew’s isotype had a leaf of Malpighiaceae (likely fromMascagnia cordifolia) stored in the fragment capsule, which was unfortunately sampled and sequenced instead of the actual leaves ofK. brasiliensis.

Conclusions

DNA sequences can be helpful in classifying taxa when morphology is conflicting or of a doubtful interpretation, with molecular phylogenetic placement becoming a popular tool that potentially accelerates the discovery of systematic relationships. However, good knowledge of plant morphology is essential for formulating the phylogenetic hypotheses to be tested and for a critical re-interpretation of the results in the context of biological information of the species or families. Thus, these techniques are, much like any others, prone to methodological errors. We highlight the crucial need to observe plant morphology alongside molecular phylogenetic results, particularly when the new hypotheses are in disagreement with the existing classification and at risk of incurring gross taxonomic mistakes.
The effects of adverse childhood experiences on depression and suicidal behaviors are partially mediated by neuroticism, a forme fruste of major depression
Authors: Jirakran Ketsupar , Vasupanrajit Asara , Tunvirachaisakul Chavit , Maes Michael
Published: February 2023

Neuroticism, a personality trait, can predict major depressive disorder (MDD). The current study aims to determine whether a) neuroticism is a feature of the acute state of MDD, including suicidal behaviors (SB); and b) adverse childhood experiences (ACEs) are associated with neuroticism in MDD. This study included 133 participants, 67 normal controls and 66 MDD patients, and assessed the Big 5 Inventory (BFI), ACEs using the ACE Questionnaire, and the phenome of depression using the Hamilton Depression (HAMD) Rating Scale (HAMD), Beck Depression Inventory (BDI), The State-Trait Anxiety Inventory (STAI) and Columbia Suicide Severity Rating Scale (C-SSRS) scores to assess current SB. Neuroticism was significantly higher in MDD than controls, and it explained 64.9% of the variance in the depression phenome (a latent vector extracted from HAMD, BDI, STAI, and current SB scores). The other BFI domains had much less (extraversion, agreeableness) or no effect (openness, conscientiousness). One latent vector could be extracted from the phenome, lifetime dysthymia, lifetime anxiety disorders and neuroticism scores. Neglect (physical and emotional) and abuse (physical, neglect and sexual) account for approximately 30% of the variance in this latent vector. Partial Least Squares analysis showed that the effects of neglect on the phenome were partially mediated by neuroticism, whereas the effects of abuse were completely mediated by neuroticism. Neuroticism (trait) and the MDD phenome (state) are both manifestations of the same latent core, with neuroticism being a less severe manifestation of major depression, which in fact is a multiplicative manifestation of neuroticism.
Metabolic impact of trans 10, cis 12-conjugated linoleic acid on pai transgenic mice
Authors: Rao Yu , Li Shi-Li , Li Mei-Juan , Wang Bao-Zhu , Wang Yang-Yang , Liang Lu-Wen , Yu Shuai , Liu Zong-Ping , Cui Sheng , Gou Ke-Mian
Published: February 2023

Trans10,cis12-conjugated linoleic acid (t10c12-CLA) from ruminant-derived foodstuffs can induce body fat loss in mammals after oral administration, while its mechanism on fat reduction has yet to be clarified fully until now. In the current study, a transgenic mouse that produced t10c12-CLA had been generated by inserting the Propionibacterium acnes isomerase (Pai) expression cassette into the Rosa26 locus, and its male offspring were used to decipher an irreversible long-term impact of t10c12-CLA on health and its mechanism of action. Compared to their wild-type C57BL/6J littermates, comprehensive phenotype profiling of biallelic pai/pai mice indicated that white fat was decreased while brown fat was increased reversely; meanwhile, more heat was released and the central activities were reduced. Besides decreased plasma triglycerides in both pai genotypes and increased serum FGF21 in pai/wt mice, RNA and protein analysis revealed that the fatty acid oxidation and thermogenesis capacity of brown adipose tissues were elevated via CPT1B and UCP1/2 over-expression. The results indicate that the t10c12-CLA-induced fat loss might be caused by the excess FGF21 and the increased mass and extra thermogenesis of brown adipose tissue in transgenic mice.
Deep-Learning Assisted, Single-molecule Imaging analysis (Deep-LASI) of multi-color DNA Origami structures
Authors: Wanninger Simon , Asadiatouei Pooyeh , Bohlen Johann , Salem Clemens-Bässem , Tinnefeld Philip , Ploetz Evelyn , Lamb Don C.
Published: February 2023

Single-molecule experiments have changed the way we investigate the physical world but data analysis is typically time-consuming and prone to human bias. Here, we present Deep-LASI (Deep-Learning Assisted Single-molecule Imaging analysis), a software package consisting of an ensemble of deep neural networks to rapidly analyze single-, two- and three-color single-molecule data, in particular from single-molecule Förster Resonance Energy Transfer (FRET) experiments. Deep-LASI automatically sorts single molecule traces, determines FRET correction factors and classifies the state transitions of dynamic traces, all in ~20-100 ms per trajectory. We thoroughly benchmarked Deep-LASI using ground truth simulations as well as experimental data analyzed manually by an expert user and compared the results with a conventional Hidden Markov Model analysis. We illustrate the capabilities of the technique using a highly tunable L-shaped DNA origami structure and use Deep-LASI to perform titrations, analyze protein conformational dynamics and demonstrate its versatility for analyzing both total internal reflection fluorescence microscopy and confocal smFRET data.
A method for defining tissue injury criteria reveals ligament deformation thresholds are multimodal
Authors: Luetkemeyer Callan M. , Neu Corey P. , Calve Sarah
Published: February 2023

Soft tissue injuries (such as ligament, tendon, and meniscus tears) are the result of extracellular matrix damage from excessive tissue stretching. Deformation thresholds for soft tissues, however, remain largely unknown due to a lack of methods that can measure and compare the spatially heterogeneous damage and deformation that occurs in these materials. Here, we propose a method for definingtissue injury criteria: multimodal strain limits for biological tissues analogous to yield criteria that exist for crystalline materials. Specifically, we developed a method for defining injury criteria for mechanically-driven fibrillar collagen denaturation in soft tissues, using regional multimodal deformation and damage data. We established this new method using the murine medial collateral ligament (MCL) as our model tissue. Our findings revealed that multiple modes of deformation contribute to collagen denaturation in the murine MCL, contrary to the common assumption that collagen damage is driven by strain in the fiber direction alone. Remarkably, our results indicated that hydrostatic strain, or volumetric expansion, may be the best predictor of mechanically-driven collagen denaturation in ligament tissue, suggesting crosslink-mediated stress transfer plays a role in molecular damage accumulation. This work demonstrates that collagen denaturation can be driven by multiple modes of deformation and provides a method for defining deformation thresholds, or injury criteria, from spatially heterogeneous data.
The Cancer Testes Antigen, HORMAD1, is a Tumor-Specific Replication Fork Protection Factor
Authors: Herrera Luis Reza , McGlynn Kathleen , Gibbs Zane A. , Davis Anthony J. , Whitehurst Angelique W.
Published: February 2023

Tumors frequently activate the expression of genes that are only otherwise required for meiosis. HORMAD1, which is essential for meiotic recombination in multiple species, is expressed in over 50% of human lung adenocarcinoma cells (LUAD). We previously found that HORMAD1 promotes DNA double strand break (DSB) repair in LUAD. Here, we report that HORMAD1 takes on an additional role in protecting genomic integrity. Specifically, we find HORMAD1 is critical for protecting stalled DNA replication forks in LUAD. Loss of HORMAD1 leads to nascent DNA degradation, an event which is mediated by the MRE11-DNA2-BLM pathway. Moreover, following exogenous induction of DNA replication stress, HORMAD1 deleted cells accumulate single stranded DNA (ssDNA). We find that these phenotypes are the result of a lack of RAD51 and BRCA2 loading onto stalled replication forks. Ultimately, loss of HORMAD1 leads to increased DSBs and chromosomal aberrations in response to replication stress. Collectively, our data support a model where HORMAD1 expression is selected to mitigate DNA replication stress, which would otherwise induce deleterious genomic instability.
Arginine shortage induces replication stress and confers genotoxic resistance by inhibiting histone H4 translation and promoting PCNA polyubiquitination
Authors: Wang Yi-Chang , Kelso Andrew A. , Karamafrooz Adak , Chen Yi-Hsuan , Chen Wei-Kai , Cheng Chun-Ting , Qi Yue , Gu Long , Malkas Linda , Kung Hsing-Jien , Moldovan George-Lucian , Ciccia Alberto , Stark Jeremy M. , Ann David K
Published: February 2023

The unique arginine dependencies of cancer cell proliferation and survival creates metabolic vulnerability. Here, we investigate the impact of extracellular arginine availability on DNA replication and genotoxic resistance. Using DNA combing assays, we find that when extracellular arginine is limited, cancer cells are arrested at S-phase and DNA replication forks slow or stall instantly until arginine is re-supplied. The translation of new histone H4 is arginine-dependent and impacts DNA replication and the expression of newly synthesized histone H4 is reduced in the avascular nutrient-poor breast cancer xenograft tumor cores. Furthermore, we demonstrate that increased PCNA occupancy and HLTF-catalyzed PCNA K63-linked polyubiquitination protects arginine-starved cells from hydroxyurea-induced, DNA2-catalyzed nascent strand degradation. Finally, arginine-deprived cancer cells are tolerant to genotoxic insults in a PCNA K63-linked polyubiquitination-dependent manner. Together, these findings reveal that extracellular arginine is the “linchpin” for nutrient-regulated DNA replication. Such information could be leveraged to expand current modalities or design new drug targets against cancer.
Alpha-synuclein pre-formed fibrils injected into prefrontal cortex primarily spread to cortical and subcortical structures and lead to isolated behavioral symptoms
Authors: Weber Matthew A. , Kerr Gemma , Thangavel Ramasamy , Conlon Mackenzie M. , Abdelmotilib Hisham A. , Halhouli Oday , Zhang Qiang , Geerling Joel C. , Narayanan Nandakumar S. , Aldridge Georgina M.
Published: February 2023

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. To investigate the consequences of α-syn pathology in the cortex, we injected human α-syn pre-formed fibrils into the PFC of wildtype mice. We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; 3) increased open field exploration; and 4) did not affect susceptibility to an inflammatory challenge. This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.
Danicamtiv increases myosin recruitment and alters the chemomechanical cross bridge cycle in cardiac muscle
Authors: Kooiker Kristina B. , Mohran Saffie , Turner Kyrah L. , Ma Weikang , Flint Galina , Qi Lin , Gao Chengqian , Zheng Yahan , McMillen Timothy S , Mandrycky Christian , Martinson Amy , Mahoney-Schaefer Max , Freeman Jeremy C. , Costales Arenas Elijah Gabriela , Tu An-Yu , Irving Thomas C. , Geeves Michael A. , Tanner Bertrand C.W. , Regnier Michael , Davis Jennifer , Moussavi-Harami Farid
Published: February 2023

Modulating myosin function is a novel therapeutic approach in patients with cardiomyopathy. Detailed mechanism of action of these agents can help predict potential unwanted affects and identify patient populations that can benefit most from them. Danicamtiv is a novel myosin activator with promising preclinical data that is currently in clinical trials. While it is known danicamtiv increases force and cardiomyocyte contractility without affecting calcium levels, detailed mechanistic studies regarding its mode of action are lacking. Using porcine cardiac tissue and myofibrils we demonstrate that Danicamtiv increases force and calcium sensitivity via increasing the number of myosin in the “on” state and slowing cross bridge turnover. Our detailed analysis shows that inhibition of ADP release results in decreased cross bridge turnover with cross bridges staying on longer and prolonging myofibril relaxation. Using a mouse model of genetic dilated cardiomyopathy, we demonstrated that Danicamtiv corrected calcium sensitivity in demembranated and abnormal twitch magnitude and kinetics in intact cardiac tissue.

Significance Statement

Directly augmenting sarcomere function has potential to overcome limitations of currently used inotropic agents to improve cardiac contractility. Myosin modulation is a novel mechanism for increased contraction in cardiomyopathies. Danicamtiv is a myosin activator that is currently under investigation for use in cardiomyopathy patients. Our study is the first detailed mechanism of how Danicamtiv increases force and alters kinetics of cardiac activation and relaxation. This new understanding of the mechanism of action of Danicamtiv can be used to help identify patients that could benefit most from this treatment.
A statistical approach to identify regulatory DNA variations
Authors: Baumgarten Nina , Rumpf Laura , Kessler Thorsten , Schulz Marcel H.
Published: February 2023

Non-coding variations located within regulatory elements may alter gene expression by modifying Transcription Factor (TF) binding sites and thereby lead to functional consequences like various traits or diseases. To understand these molecular mechanisms, different TF models are being used to assess the effect of DNA sequence variations, such as Single Nucleotide Polymorphisms (SNPs). However, few statistical approaches exist to compute statistical significance of results but they often are slow for large sets of SNPs, such as data obtained from a genome-wide association study (GWAS) or allele-specific analysis of chromatin data.

Results

We investigate the distribution of maximal differential TF binding scores for general computational models that assess TF binding. We find that a modified Laplace distribution can adequately approximate the empirical distributions. A benchmark onin vitroandin vivodata sets showed that our new approach improves on an existing method in terms of performance and speed. In applications on large sets of eQTL and GWAS SNPs we could illustrate the usefulness of the novel statistic to highlight cell type specific regulators and TF target genes.

Conclusions

Our approach allows the evaluation of DNA changes that induce differential TF binding in a fast and accurate manner, permitting computations on large mutation data sets. An implementation of the novel approach is freely available athttps://github.com/SchulzLab/SNEEP.

Contact

marcel.schulz@em.uni-frankfurt.de
Depletion-assisted multiplexed cell-free RNA sequencing reveals distinct human and microbial signatures in plasma versus extracellular vesicles
Authors: Wang Hongke , Zhan Qing , Ning Meng , Guo Hongjie , Wang Qian , Zhao Jiuliang , Bao Pengfei , Xing Shaozhen , Chen Shanwen , Zuo Shuai , Li Mengtao , Wang Pengyuan , Lu Zhi John
Published: February 2023

Cell-free long RNAs in human plasma and extracellular vesicles (EVs) have shown promise as biomarkers in liquid biopsy, despite their fragmented nature. To investigate these fragmented cell-free RNAs (cfRNAs), we developed a cost-effective cfRNA sequencing method called DETECTOR-seq (depletion-assisted multiplexedcell-freetotalRNAsequencing). DETECTOR-seq utilized a meticulously tailored set of customized guide RNAs to remove large amounts of unwanted RNAs (i.e., fragmented ribosomal and mitochondrial RNAs) in human plasma. Early barcoding strategy was implemented to reduce costs and minimize plasma requirements. Using DETECTOR-seq, we conducted a comprehensive analysis of cell-free transcriptomes in both whole human plasma and EVs. Our analysis revealed discernible distributions of RNA types in plasma and EVs. Plasma exhibited pronounced enrichment in structured circular RNAs, tRNAs, Y RNAs, and viral RNAs, while EVs showed enrichment in mRNAs and srpRNAs. Functional pathway analysis highlighted RNA splicing-related ribonucleoproteins (RNPs) and antimicrobial humoral response genes in plasma, while EVs demonstrated enrichment in transcriptional activity, cell migration, and antigen receptor-mediated immune signals. Our study indicates the comparable potential of cfRNAs from whole plasma and EVs in distinguishing cancer patients (i.e., colorectal and lung cancer) from healthy donors. And microbial cfRNAs in plasma showed potential in classifying specific cancer types. Our comprehensive analysis of total and EV cfRNAs in paired plasma samples provides valuable insights for determining the need for EV purification in cfRNA-based studies. We envision the cost-effectiveness and efficiency of DETECTOR-seq will empower transcriptome-wide investigations in the fields of extracellular vesicles and liquid biopsy.
Killing them softly with EPO: a new role for erythropoietin in the homeostasis of red blood cells
Authors: Arias Clemente F. , Valente-Leal Nuno , Bertocchini Federica , Marques Sofia , Acosta Francisco J. , Fernandez-Arias Cristina
Published: February 2023

The regulation of red blood cell (RBC) homeostasis is widely assumed to rely on the control of cell production by erythropoietin (EPO) and the destruction of cells at a fixed, species-specific age. In this work, we show that such a regulatory mechanism is a poor homeostatic solution to satisfy the changing needs of the body. Effective homeostatic control requires RBC lifespan to be variable and tightly regulated. We show that EPO controls RBC lifespan by determining CD47 expression in newly formed RBCs and SIRP-αexpression in sinusoidal macrophages. EPO also controls the initiation and intensity of anti-RBC autoimmune responses that curtail RBC lifespan in some circumstances. These mechanisms continuously modulate the rate of RBC destruction depending on oxygen availability. The finding of new homeostatic roles for EPO and autoimmunity critically challenges the current paradigm of RBC homeostasis and sets the grounds for a new approach to this field.
Aberrant circuitry underlying olfaction in the face of severe olfactory bulb degeneration
Authors: Licht Tamar , Yunerman Michael , Maor Ido , Lawabny Naheel , Oz Rokach Renana , Mizrahi Adi , Rokni Dan
Published: February 2023

The olfactory bulb (OB) is a critical component of mammalian olfactory neuroanatomy. Beyond being the first and sole relay station for olfactory information to the rest of the brain, it also contains elaborate stereotypical circuitry that is considered essential for olfaction. Indeed, substantial lesions of the OB in rodents lead to anosmia. Here, we examined the circuitry that underlies olfaction in a mouse model with severe developmental degeneration of the OB. These mice could perform odor-guided tasks and even responded normally to innate olfactory cues. Despite the near total loss of the OB, piriform cortex in these mice responded to odors normally and its neural activity sufficed to decode odor identity. We analyzed the circuitry that supports olfactory function in these mice. We found that sensory neurons express the full repertoire of olfactory receptors and their axons project primarily to the rudimentary OB, but also ectopically, to olfactory cortical regions. Within the OB, the number of principal neurons was greatly reduced and the morphology of their dendrites was abnormal, extending over larger regions within the OB. Glomerular organization was lost. This study shows that olfactory functionality can be preserved despite reduced and aberrant circuitry that is missing many of the elements that are believed to be essential for olfaction, and may explain the retention of olfaction in humans with degenerated OBs.
Self-supervised learning on millions of pre-mRNA sequences improves sequence-based RNA splicing prediction
Authors: Chen Ken , Zhou Yue , Ding Maolin , Wang Yu , Ren Zhixiang , Yang Yuedong
Published: February 2023

RNA splicing is an important post-transcriptional process of gene expression in eukaryotic cells. Predicting RNA splicing from primary sequences can facilitate the interpretation of genomic variants. In this study, we developed a novel self-supervised pre-trained language model, SpliceBERT, to improve sequence-based RNA splicing prediction. Pre-training on pre-mRNA sequences from vertebrates enables SpliceBERT to capture evolutionary conservation information and characterize the unique property of splice sites. SpliceBERT also improves zero-shot prediction of variant effects on splicing by considering sequence context information, and achieves superior performance for predicting branchpoint in the human genome and splice sites across species. Our study highlighted the importance of pre-training genomic language models on a diverse range of species and suggested that pre-trained language models were promising for deciphering the sequence logic of RNA splicing.
Activation of AKT induces EZH2-mediated β-catenin trimethylation in colorectal cancer
Authors: Ghobashi Ahmed H. , Vuong Truc T. , Kimani Jane W. , O’Hagan Heather M.
Published: February 2023

Colorectal cancer (CRC) develops in part through the deregulation of different signaling pathways, including activation of the WNT/β-catenin and PI3K/AKT pathways. Enhancer of zeste homolog 2 (EZH2) is a lysine methyltransferase that is involved in regulating stem cell development and differentiation and is overexpressed in CRC. However, depending on the study EZH2 has been found to be both positively and negatively correlated with the survival of CRC patients suggesting that EZH2’s role in CRC may be context specific. In this study, we explored how PI3K/AKT activation alters EZH2’s role in CRC. We found that activation of AKT by PTEN knockdown or by hydrogen peroxide treatment induced EZH2 phosphorylation at serine 21. Phosphorylation of EZH2 resulted in EZH2-mediated methylation of β-catenin and an associated increased interaction between β-catenin, TCF1, and RNA polymerase II. AKT activation increased β-catenin’s enrichment across the genome and EZH2 inhibition reduced this enrichment by reducing the methylation of β-catenin. Furthermore, PTEN knockdown increased the expression of epithelial-mesenchymal transition (EMT)-related genes, and somewhat unexpectedly EZH2 inhibition further increased the expression of these genes. Consistent with these findings, EZH2 inhibition enhanced the migratory phenotype of PTEN knockdown cells. Overall, we demonstrated that EZH2 modulates AKT-induced changes in gene expression through the AKT/EZH2/ β-catenin axis in CRC with active PI3K/AKT signaling. Therefore, it is important to consider the use of EZH2 inhibitors in CRC with caution as these inhibitors will inhibit EZH2-mediated methylation of histone and non-histone targets such as β-catenin, which can have tumor-promoting effects.
Modelling idiopathic intracranial hypertension in rats: contributions of high fat diet and testosterone to intracranial pressure and cerebrospinal fluid production
Authors: Wardman Jonathan H. , Jensen Mette Nyholm , Andreassen Søren Norge , Styrishave Bjarne , Wilhjelm Jens E. , Sinclair Alexandra J. , MacAulay Nanna
Published: February 2023

Background

Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure (ICP), impaired vision, and headache. Most cases of IIH occur in obese women of childbearing age, though age, BMI, and female sex do not encompass all aspects of IIH pathophysiology. Systemic metabolic dysregulation has been identified in IIH with a profile of androgen excess. However, the mechanistic coupling between obesity/hormonal perturbations and cerebrospinal fluid dynamics remains unresolved.

Methods

Female Wistar rats were either fed a high fat diet (HFD) or exposed to adjuvant testosterone treatment to recapitulate IIH causal drivers. Cerebrospinal fluid (CSF) and blood testosterone levels were determined with mass spectrometry, ICP and CSF dynamics within vivoexperimentation, and the choroid plexus function revealed with transcriptomics and exvivoisotopebased flux assays.

Results

HFD-fed rats presented with increased ICP, which was not accompanied by altered CSF dynamics or modified choroid plexus function. Chronic adjuvant testosterone treatment of lean rats caused elevated CSF secretion rate, in association with increased activity of the choroid plexus Na+,K+,2Cl-cotransporter, NKCC1.

Conclusions

HFD-induced ICP elevation in experimental rats did not originate from an increased rate of CSF secretion. Such modulation of CSF dynamics only came about with adjuvant testosterone treatment, mimicking the androgen excess observed in female IIH patients. Obesity-induced androgen dysregulation may thus play a crucial role in the disease mechanism of IIH.
Modeling the radiative, thermal and chemical microenvironment of 3D scanned corals
Authors: Murthy Swathi , Picioreanu Cristian , Kühl Michael
Published: February 2023

Reef building corals are efficient biological collectors of solar radiation and consist of a thin stratified tissue layer spread over a light scattering calcium carbonate skeleton surface that together construct complex three dimensional (3D) colony structures forming the foundation of coral reefs. They exhibit a vast diversity of structural forms to maximize photosynthesis of their dinoflagellate endosymbionts (Symbiodiniaceae), while simultaneously minimizing photodamage. The symbiosis takes place in the presence of dynamic gradients of light, temperature and chemical species that are affected by the interaction of incident irradiance and water flow with the coral colony.

We developed a multiphysics modelling approach to simulate microscale spatial distribution of light, temperature and O2in coral fragments with accurate morphology determined by 3D scanning techniques.

Model results compared well with spatial measurements of light, O2and temperature under similar flow and light conditions. The model enabled us to infer the effect of coral morphology and light scattering in tissue and skeleton on the internal light environment experienced by the endosymbionts, as well as the combined contribution of light, water flow and ciliary movement on O2and temperature distributions in the coral.

The multiphysics modeling approach is general enough to enable simulation of external and internal light, O2and temperature microenvironments in 3D scanned coral species with varying degrees of branching and morphology under different environmental conditions. This approach is also relevant for simulating structure-function relationships in other benthic systems such as photosynthetic biofilms and aquatic plant tissue, and can also be adapted to other sessile organisms such as symbiont-bearing giant clams, ascidians, jellyfish or foraminifera. The model could also be useful in more applied research such as optimization of 3D bioprinted constructs where different designs can be evaluated and optimized.
Thermal Stimulus Task fMRI in the Cervical Spinal Cord at 7 Tesla
Authors: Seifert Alan C. , Xu Junqian , Kong Yazhuo , Eippert Falk , Miller Karla L. , Tracey Irene , Vannesjo S. Johanna
Published: February 2023

Purpose

Although functional MRI is widely applied in the brain, fMRI of the spinal cord is more technically demanding. Proximity to the vertebral column and lungs results in strong spatial inhomogeneity and temporal fluctuations in B0. Increasing field strength enables higher spatial resolution and improved sensitivity to BOLD signal, but amplifies the effects of B0inhomogeneity. In this work, we present the first task fMRI in the spinal cord at 7 T. Further, we compare the performance of single-shot and multi-shot 2D EPI protocols, which differ in sensitivity to spatial and temporal B0inhomogeneity.

Methods

The cervical spinal cords of 11 healthy volunteers were scanned at 7 T using single-shot 2D EPI at 0.75 mm in-plane resolution and multi-shot 2D EPI at 0.75 and 0.6 mm in-plane resolutions. All protocols used 3 mm slice thickness. For each protocol, the BOLD response to thirteen 10-second noxious thermal stimuli applied to the right thumb was acquired in a 10-minute fMRI run. Image quality, temporal SNR, and BOLD activation (percent signal change and z-stat) at both individual-and group-level were evaluated between the protocols.

Results

Temporal SNR was highest in single-shot and multi-shot 0.75 mm protocols. In group-level analyses, activation clusters appeared in all protocols in the ipsilateral dorsal quadrant at the expected C6 neurological level. In individual-level analyses, activation clusters at the expected level were detected in some, but not all subjects and protocols. Single-shot 0.75 mm generally produced the highest mean z-statistic, while multi-shot 0.60 mm produced the best-localized activation clusters and the least geometric distortion. Larger than expected within-subject segmental variation of BOLD activation along the cord was observed.

Conclusion

Group-level sensory task fMRI of the cervical spinal cord is feasible at 7 T with single-shot or multi-shot EPI. The best choice of protocol will likely depend on the relative importance of sensitivity to activation versus spatial localization of activation for a given experiment.

Highlights

First stimulus task fMRI results in the spinal cord at 7 T

Single-shot 0.75 mm 2D EPI produced the highest mean z-statistic

Multi-shot 0.60 mm 2D EPI provided the best-localized activation and least distortion
Path integration selectively predicts midlife risk of Alzheimer’s disease
Authors: Newton Coco , Pope Marianna , Rua Catarina , Henson Richard , Ji Zilong , Burgess Neil , Rodgers Christopher T. , Stangl Matthias , Dounavi Maria-Eleni , Castegnaro Andrea , Koychev Ivan , Malhotra Paresh , Wolbers Thomas , Ritchie Karen , Ritchie Craig W. , O’Brien John , Su Li , Chan Dennis ,   PREVENT Dementia Research Programme
Published: February 2023

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimer’s disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours.

Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.
A thin-film optogenetic visual prosthesis
Authors: Knudsen Eric B , Zappitelli Kara , Brown Jennifer , Reeder Jonathan , Smith Kevin Sean , Rostov Marat , Choi Jaebin , Rochford Amy , Slager Nate , Miura Satoru K , Rodgers Kyle , Reed Ansel , Lewis Israeli Yonatan R , Shiraga Seton , Seo Kyung Jin , Wolin Corey , Dawson Paul , Eltaeb Mohamed , Dasgupta Arvind , Rothman Max , Yoon Eugene , Chong Paul , Charles Seleipiri , Stewart Jay M. , Silva Ruwan A , Kim Tyson , Kong Yifan , Mardinly Alan R , Hodak Max
Published: February 2023

Retinitis pigmentosa and macular degeneration lead to photoreceptor death and loss of visual perception. Despite recent progress, restorative technologies for photoreceptor degeneration remain largely unavailable. Here, we describe a novel optogenetic visual prosthesis (FlexLED) based on a combination of a thin-film retinal display and optogenetic activation of retinal ganglion cells (RGCs). The FlexLED implant is a 30 µm thin, flexible, wireless µLED display with 8,192 pixels, each with an emission area of 66 µm2. The display is affixed to the retinal surface, and the electronics package is mounted under the conjunctiva in the form factor of a conventional glaucoma drainage implant. In a rabbit model of photoreceptor degeneration, optical stimulation of the retina using the FlexLED elicits activity in visual cortex. This technology is readily scalable to hundreds of thousands of pixels, providing a route towards an implantable optogenetic visual prosthesis capable of generating vision by stimulating RGCs at near-cellular resolution.
Hybridization Mediated Range Expansion and Climate Change Resilience in Two Keystone Tree Species of Boreal Forests
Authors: Karunarathne Piyal , Zhou Qiujie , Lascoux Martin , Milesi Pascal
Published: February 2023

Current global climate change is expected to affect biodiversity negatively at all scales leading to mass biodiversity loss. Many studies have shown that the distribution of allele frequencies across a species’ range is often influenced by specific genetic loci associated with local environmental variables. This association reflects local adaptation and allele changes at those loci could thereby contribute to the evolutionary response to climate change. However, predicting how species will adapt to climate change from this type of data alone remains challenging. In the present study, we combined exome capture sequences and environmental niche reconstruction, to test multiple methods for assessing local adaptation and climate resilience in two widely distributed conifers, Norway spruce and Siberian spruce. Both species are keystone species of the boreal forest and share a vast hybrid zone. We show that local adaptation in conifers can be detected through allele frequency variation, population-level ecological preferences, and historical niche movement. Moreover, we integrated genetic and ecological information into genetic offset predictive models to show that hybridization plays a central role in expanding the niche breadth of the two conifer species and may help both species to cope better with future changing climates. This joint genetic and ecological analysis also identified genetically isolated populations that are at risk under current climate change.
Sensitivity and uncertainty in the Lee-Carter mortality model
Authors: Zuo Wenyun , Damle Anil , Tuljapurkar Shripad
Published: February 2023

BACKGROUND

The Lee-Carter model (LC) is widely used in research and applications for forecasting age specific mortality, and typically performs well regardless of the uncertainty and often the limited quality of mortality data.

OBJECTIVE

Why dose LC perform well regardless of the uncertainty and the limited data quality?

METHODS

We analyze the robustness of LC using sensitivity analyses based on matrix perturbation theory, coupled with simulations that examine the effect of unavoidable randomness in mortality data. The combined effects of sensitivity and uncertainty determine the robustness of LC.

RESULTS

We find that the sensitivity of LC and the uncertainty of death rates both have nonuniform patterns across ages and years. The sensitivities are small in general, with largest sensitivities at both ends of the period. The uncertainty of death rates are high in young ages (5–19) and old ages (90+) with rising in young ages but dropping in old ages.

CONCLUSIONS

The sensitivity and uncertainty analyses indicate that the randomness hardly interrupts the prediction of LC. The divergence of long term prediction in LC is likely due to structural changes in the age-year specific mortality, which is associated with the development of public health policy, medical innovations and chronic disasters.

CONTRIBUTION

Our results reveal that LC is robust against random perturbation and sudden short term changes.
Linking Muscle Mechanics to the Metabolic Cost of Human Hopping
Authors: Jessup Luke N. , Kelly Luke A. , Cresswell Andrew G. , Lichtwark Glen A.
Published: February 2023

Many models have been developed to predict metabolic energy expenditure based on biomechanical proxies of muscle function. However, current models may only perform well for select forms of locomotion, not only because the models are rarely rigorously tested across subtle and broad changes in locomotor task, but also because previous research has not adequately characterised different forms of locomotion to account for the potential variability in muscle function and thus metabolic energy expenditure. To help to address the latter point, the present study imposed frequency and height constraints to hopping and quantified gross metabolic power as well as the activation requirements of medial gastrocnemius, lateral gastrocnemius (GL), soleus (SOL), tibialis anterior, vastus lateralis (VL), rectus femoris (RF) and biceps femoris (BF), and the work requirements GL, SOL and VL. Gross metabolic power increased with a decrease in hop frequency and increase in hop height. There was no hop frequency or hop height effect on the mean electromyography (EMG) of ankle musculature, however, the mean EMG of VL and RF increased with a decrease in hop frequency and that of BF increased with an increase in hop height. With a reduction in hop frequency, GL, SOL and VL fascicle shortening, fascicle shortening velocity and fascicle to MTU shortening ratio increased, whereas with an increase in hop height, only SOL fascicle shortening velocity increased. Therefore, within the constraints that we imposed, decreases in hop frequency and increases in hop height resulted in increases in metabolic power that could be explained by increases in the activation requirements of knee musculature and/or increases in the work requirements of both knee and ankle musculature.

Summary Statement

This study directly measures activation and work requirements of lower-limb musculature and whole-body metabolic energy requirements across a wide variety of human hopping conditions, helping to guide biomechanical models of energy expenditure.
Patient Registry of Upper Limb Outcomes (PRULO) A Protocol for an orthopaedic clinical quality registry to monitor treatment outcomes
Authors: Scholes Corey , Eng Kevin , Harrison-Brown Meredith , Ebrahimi Milad , Brown Graeme , Gill Stephen , Page Richard
Published: February 2023

Introduction

Registries have been widely utilised to track clinical results in observational cohorts for quality improvement. They have been very successful in orthopaedics, particularly in the context of arthroplasties where they have guided and optimised implant choice, patient safety and identified underperforming implants. However, equivalent systems to monitor outcomes in soft-tissue disorders are lacking. This manuscript describes the protocols around design, ethics and implementation of a regional registry focusing on upper limb soft tissue orthopaedic conditions.

Methods and analysis

PRULO (Patient Registry of Upper Limb pathology Outcomes) is a multi-cohort, prospective observational, clinical quality registry collating clinical data and patient-reported outcomes for patients presenting to a specialist orthopaedic clinic with upper limb pathology. PRULO is currently a single-centre study involving three clinician investigators, which aims to determine what patient characteristics, pathology factors and treatment strategies are associated with treatment success within 2 years of surgical or non-surgical treatment of targeted pathology. PRULO captures patient reported outcomes (VAS, EQ5D-5L, QuickDASH, MODEMS-Expectations and Satisfaction, WORC, WOSI), clinical and radiological data. Data points are recorded at initial practice registration, after initial consultation, intraoperatively, as well as 3, 6, 12 and 24 months. Inclusion criteria are patients aged 16 and above offered treatment by speciality trained surgeons, for upper limb orthopaedic pathology. Patient subgroups (cohorts) will include shoulder conditions: conditions affecting predominantly the rotator cuff (tear, tendinopathy), conditions associated with glenohumeral instability, as well as all other conditions presenting in the shoulder elbow, hand and wrist, according to the surgeon-generated diagnosis.

Ethics and dissemination

Ethical approval was obtained by the Barwon Health Research Ethics Committee (approval number 19/70).

Trial Registration

The project was added as a trial to the Australia and New Zealand Clinical Trials Registry (ACTRN12619000770167) 23-May-2019.