bluuebunny/crossref_metadata_2025 huggingface dataset:
On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging
Authors: Dang Hope , Castro-Portuguez Raul , Espejo Luis , Backer Grant , Freitas Samuel , Spence Erica , Meyers Jeremy , Shuck Karissa , Gardea Emily A. , Chang Leah M. , Balsa Jonah , Thorns Niall , Corban Caroline , Liu Teresa , Bean Shannon , Sheehan Susan , Korstanje Ron , Sutphin George L.
Published: December 2023

Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes—tdo-2, kynu-1, and acsd-1—for which decreasing expression extends lifespan in invertebrates. Here we report that knockdown of haao-1, a fourth gene encoding the enzyme 3-hydroxyanthranilic acid (3HAA) dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated health decline in Caenorhabditis elegans. Lifespan extension is mediated by increased physiological levels of the HAAO substrate 3HAA. 3HAA increases oxidative stress resistance and activates the Nrf2/SKN-1 oxidative stress response. In pilot studies, female Haao knockout mice or aging wild type male mice fed 3HAA supplemented diet were also long-lived. HAAO and 3HAA represent potential therapeutic targets for aging and age-associated disease.
Bioinspired mechanical mineralization of organogels
Authors: Ayarza Jorge , Wang Jun , Kim Hojin , Huang Pin-Ruei , Cassaidy Britteny , Yan Gangbin , Liu Chong , Jaeger Heinrich M. , Rowan Stuart J. , Esser-Kahn Aaron P.
Published: December 2023

Mineralization is a long-lasting method commonly used by biological materials to selectively strengthen in response to site specific mechanical stress. Achieving a similar form of toughening in synthetic polymer composites remains challenging. In previous work, we developed methods to promote chemical reactions via the piezoelectrochemical effect with mechanical responses of inorganic, ZnO nanoparticles. Herein, we report a distinct example of a mechanically-mediated reaction in which the spherical ZnO nanoparticles react themselves leading to the formation of microrods composed of a Zn/S mineral inside an organogel. The microrods can be used to selectively create mineral deposits within the material resulting in the strengthening of the overall resulting composite.
Molecular basis and cellular functions of vinculin-actin directional catch bonding
Authors: Chirasani Venkat R. , Khan Mohammad Ashhar I. , Malavade Juilee N. , Dokholyan Nikolay V. , Hoffman Brenton D. , Campbell Sharon L.
Published: December 2023

The ability of cells and tissues to respond differentially to mechanical forces applied in distinct directions is mediated by the ability of load-bearing proteins to preferentially maintain physical linkages in certain directions. However, the molecular basis and biological consequences of directional force-sensitive binding remain unclear. Vinculin (Vcn) is a load-bearing linker protein that exhibits directional catch bonding due to interactions between the Vcn tail domain (Vt) and filamentous (F)-actin. We developed a computational approach to predict Vcn residues involved in directional catch bonding and produced a set of associated Vcn variants with unaltered Vt structure, actin binding, or phospholipid interactions. Incorporation of the variants did not affect Vcn activation but reduced Vcn loading and altered exchange dynamics, consistent with the loss of directional catch bonding. Expression of Vcn variants perturbed the coordination of subcellular structures and cell migration, establishing key cellular functions for Vcn directional catch bonding.
The bacterial replication origin BUS promotes nucleobase capture
Authors: Pelliciari Simone , Bodet-Lefèvre Salomé , Fenyk Stepan , Stevens Daniel , Winterhalter Charles , Schramm Frederic D. , Pintar Sara , Burnham Daniel R. , Merces George , Richardson Tomas T. , Tashiro Yumiko , Hubbard Julia , Yardimci Hasan , Ilangovan Aravindan , Murray Heath
Published: December 2023

Genome duplication is essential for the proliferation of cellular life and this process is generally initiated by dedicated replication proteins at chromosome origins. In bacteria, DNA replication is initiated by the ubiquitous DnaA protein, which assembles into an oligomeric complex at the chromosome origin (oriC) that engages both double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA) to promote DNA duplex opening. However, the mechanism of DnaA specifically opening a replication origin was unknown. Here we show that Bacillus subtilis DnaAATP assembles into a continuous oligomer at the site of DNA melting, extending from a dsDNA anchor to engage a single DNA strand. Within this complex, two nucleobases of each ssDNA binding motif (DnaA-trio) are captured within a dinucleotide binding pocket created by adjacent DnaA proteins. These results provide a molecular basis for DnaA specifically engaging the conserved sequence elements within the bacterial chromosome origin basal unwinding system (BUS).
Profiling ubiquitin signalling with UBIMAX reveals DNA damage- and SCFβ-Trcp1-dependent ubiquitylation of the actin-organizing protein Dbn1
Authors: Colding-Christensen Camilla S. , Kakulidis Ellen S. , Arroyo-Gomez Javier , Hendriks Ivo A. , Arkinson Connor , Fábián Zita , Gambus Agnieszka , Mailand Niels , Duxin Julien P. , Nielsen Michael L.
Published: December 2023

Ubiquitin widely modifies proteins, thereby regulating most cellular functions. The complexity of ubiquitin signalling necessitates unbiased methods enabling global detection of dynamic protein ubiquitylation. Here, we describe UBIMAX (UBiquitin target Identification by Mass spectrometry in Xenopus egg extracts), which enriches ubiquitin-conjugated proteins and quantifies regulation of protein ubiquitylation under precise and adaptable conditions. We benchmark UBIMAX by investigating DNA double-strand break-responsive ubiquitylation events, identifying previously known targets and revealing the actin-organizing protein Dbn1 as a major target of DNA damage-induced ubiquitylation. We find that Dbn1 is targeted for proteasomal degradation by the SCFβ-Trcp1 ubiquitin ligase, in a conserved mechanism driven by ATM-mediated phosphorylation of a previously uncharacterized β-Trcp1 degron containing an SQ motif. We further show that this degron is sufficient to induce DNA damage-dependent protein degradation of a model substrate. Collectively, we demonstrate UBIMAX’s ability to identify targets of stimulus-regulated ubiquitylation and reveal an SCFβ-Trcp1-mediated ubiquitylation mechanism controlled directly by the apical DNA damage response kinases.
Polygenic risk alters the penetrance of monogenic kidney disease
Authors: Khan Atlas , Shang Ning , Nestor Jordan G. , Weng Chunhua , Hripcsak George , Harris Peter C. , Gharavi Ali G. , Kiryluk Krzysztof
Published: December 2023

Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.
Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation
Authors: Martinez-Campanario M. C. , Cortés Marlies , Moreno-Lanceta Alazne , Han Lu , Ninfali Chiara , Domínguez Verónica , Andrés-Manzano María J. , Farràs Marta , Esteve-Codina Anna , Enrich Carlos , Díaz-Crespo Francisco J. , Pintado Belén , Escolà-Gil Joan C. , García de Frutos Pablo , Andrés Vicente , Melgar-Lesmes Pedro , Postigo Antonio
Published: December 2023

Accumulation of lipid-laden macrophages within the arterial neointima is a critical step in atherosclerotic plaque formation. Here, we show that reduced levels of the cellular plasticity factor ZEB1 in macrophages increase atherosclerotic plaque formation and the chance of cardiovascular events. Compared to control counterparts (Zeb1WT/ApoeKO), male mice with Zeb1 ablation in their myeloid cells (Zeb1∆M/ApoeKO) have larger atherosclerotic plaques and higher lipid accumulation in their macrophages due to delayed lipid traffic and deficient cholesterol efflux. Zeb1∆M/ApoeKO mice display more pronounced systemic metabolic alterations than Zeb1WT/ApoeKO mice, with higher serum levels of low-density lipoproteins and inflammatory cytokines and larger ectopic fat deposits. Higher lipid accumulation in Zeb1∆M macrophages is reverted by the exogenous expression of Zeb1 through macrophage-targeted nanoparticles. In vivo administration of these nanoparticles reduces atherosclerotic plaque formation in Zeb1∆M/ApoeKO mice. Finally, low ZEB1 expression in human endarterectomies is associated with plaque rupture and cardiovascular events. These results set ZEB1 in macrophages as a potential target in the treatment of atherosclerosis.
Proximity extracellular protein-protein interaction analysis of EGFR using AirID-conjugated fragment of antigen binding
Authors: Yamada Kohdai , Shioya Ryouhei , Nishino Kohei , Furihata Hirotake , Hijikata Atsushi , Kaneko Mika K. , Kato Yukinari , Shirai Tsuyoshi , Kosako Hidetaka , Sawasaki Tatsuya
Published: December 2023

Receptor proteins, such as epidermal growth factor receptor (EGFR), interact with other proteins in the extracellular region of the cell membrane to drive intracellular signalling. Therefore, analysis of extracellular protein-protein interactions (exPPIs) is important for understanding the biological function of receptor proteins. Here, we present an approach using a proximity biotinylation enzyme (AirID) fusion fragment of antigen binding (FabID) to analyse the proximity exPPIs of EGFR. AirID was C-terminally fused to the Fab fragment against EGFR (EGFR-FabID), which could then biotinylate the extracellular region of EGFR in several cell lines. Liquid Chromatography-Mass Spectrometry (LC-MS/MS) analysis indicated that many known EGFR interactors were identified as proximity exPPIs, along with many unknown candidate interactors, using EGFR-FabID. Interestingly, these proximity exPPIs were influenced by treatment with EGF ligand and its specific kinase inhibitor, gefitinib. These results indicate that FabID provides accurate proximity exPPI analysis of target receptor proteins on cell membranes with ligand and drug responses.
Remodeling of the ribosomal quality control and integrated stress response by viral ubiquitin deconjugases
Authors: Liu Jiangnan , Nagy Noemi , Ayala-Torres Carlos , Aguilar-Alonso Francisco , Morais-Esteves Francisco , Xu Shanshan , Masucci Maria G.
Published: December 2023

The strategies adopted by viruses to reprogram the translation and protein quality control machinery and promote infection are poorly understood. Here, we report that the viral ubiquitin deconjugase (vDUB)—encoded in the large tegument protein of Epstein-Barr virus (EBV BPLF1)—regulates the ribosomal quality control (RQC) and integrated stress responses (ISR). The vDUB participates in protein complexes that include the RQC ubiquitin ligases ZNF598 and LTN1. Upon ribosomal stalling, the vDUB counteracts the ubiquitination of the 40 S particle and inhibits the degradation of translation-stalled polypeptides by the proteasome. Impairment of the RQC correlates with the readthrough of stall-inducing mRNAs and with activation of a GCN2-dependent ISR that redirects translation towards upstream open reading frames (uORFs)- and internal ribosome entry sites (IRES)-containing transcripts. Physiological levels of active BPLF1 promote the translation of the EBV Nuclear Antigen (EBNA)1 mRNA in productively infected cells and enhance the release of progeny virus, pointing to a pivotal role of the vDUB in the translation reprogramming that enables efficient virus production.
Mechanically tunable organogels from highly charged polyoxometalate clusters loaded with fluorescent dyes
Authors: Zhang Fenghua , Li Zhong , Wang Xun
Published: December 2023

Inorganic nanowires-based organogel, a class of emerging organogel with convenient preparation, recyclability, and excellent mechanical properties, is in its infancy. Solidifying and functionalizing nanowires-based organogels by designing the gelator structure remains challenging. Here, we fabricate Ca2-P2W16 and Ca2-P2W15M nanowires utilizing highly charged [Ca2P2W16O60]10− and [Ca2P2W15MO60]14−/13− cluster units, respectively, which are then employed for preparing organogels. The mechanical performance and stability of prepared organogels are improved due to the enhanced interactions between nanowires and locked organic molecules. Compressive stress and tensile stress of Ca2-P2W16 nanowires-based organogel reach 34.5 and 29.0 kPa, respectively. The critical gel concentration of Ca2-P2W16 nanowires is as low as 0.28%. Single-molecule force spectroscopy confirms that the connections between cluster units and linkers can regulate the flexibility of nanowires. Furthermore, the incorporation of fluorophores into the organogels adds fluorescence properties. This work reveals the relationships between the microstructures of inorganic gelators and the properties of organogels, guiding the synthesis of high-performance and functional organogels.
Viruses under the Antarctic Ice Shelf are active and potentially involved in global nutrient cycles
Authors: Lopez-Simon Javier , Vila-Nistal Marina , Rosenova Aleksandra , De Corte Daniele , Baltar Federico , Martinez-Garcia Manuel
Published: December 2023

Viruses play an important role in the marine ecosystem. However, our comprehension of viruses inhabiting the dark ocean, and in particular, under the Antarctic Ice Shelves, remains limited. Here, we mine single-cell genomic, transcriptomic, and metagenomic data to uncover the viral diversity, biogeography, activity, and their role as metabolic facilitators of microbes beneath the Ross Ice Shelf. This is the largest Antarctic ice shelf with a major impact on global carbon cycle. The viral community found in the cavity under the ice shelf mainly comprises endemic viruses adapted to polar and mesopelagic environments. The low abundance of genes related to lysogenic lifestyle (<3%) does not support a predominance of the Piggyback-the-Winner hypothesis, consistent with a low-productivity habitat. Our results indicate a viral community actively infecting key ammonium and sulfur-oxidizing chemolithoautotrophs (e.g. Nitrosopumilus spp, Thioglobus spp.), supporting a “kill-the-winner” dynamic. Based on genome analysis, these viruses carry specific auxiliary metabolic genes potentially involved in nitrogen, sulfur, and phosphorus acquisition. Altogether, the viruses under Antarctic ice shelves are putatively involved in programming the metabolism of ecologically relevant microbes that maintain primary production in these chemosynthetically-driven ecosystems, which have a major role in global nutrient cycles.
Elucidating the structure-stability relationship of Cu single-atom catalysts using operando surface-enhanced infrared absorption spectroscopy
Authors: Zhang Li , Yang Xiaoju , Yuan Qing , Wei Zhiming , Ding Jie , Chu Tianshu , Rong Chao , Zhang Qiao , Ye Zhenkun , Xuan Fu-Zhen , Zhai Yueming , Zhang Bowei , Yang Xuan
Published: December 2023

Understanding the structure-stability relationship of catalysts is imperative for the development of high-performance electrocatalytic devices. Herein, we utilize operando attenuated total reflectance surface-enhanced infrared absorption spectroscopy (ATR-SEIRAS) to quantitatively monitor the evolution of Cu single-atom catalysts (SACs) during the electrochemical reduction of CO2 (CO2RR). Cu SACs are converted into 2-nm Cu nanoparticles through a reconstruction process during CO2RR. The evolution rate of Cu SACs is highly dependent on the substrates of the catalysts due to the coordination difference. Density functional theory calculations demonstrate that the stability of Cu SACs is highly dependent on their formation energy, which can be manipulated by controlling the affinity between Cu sites and substrates. This work highlights the use of operando ATR-SEIRAS to achieve mechanistic understanding of structure-stability relationship for long-term applications.
Mapping combinatorial drug effects to DNA damage response kinase inhibitors
Authors: Zhang Hanrui , Kreis Julian , Schelhorn Sven-Eric , Dahmen Heike , Grombacher Thomas , Zühlsdorf Michael , Zenke Frank T. , Guan Yuanfang
Published: December 2023

One fundamental principle that underlies various cancer treatments, such as traditional chemotherapy and radiotherapy, involves the induction of catastrophic DNA damage, leading to the apoptosis of cancer cells. In our study, we conduct a comprehensive dose-response combination screening focused on inhibitors that target key kinases involved in the DNA damage response (DDR): ATR, ATM, and DNA-PK. This screening involves 87 anti-cancer agents, including six DDR inhibitors, and encompasses 62 different cell lines spanning 12 types of tumors, resulting in a total of 17,912 combination treatment experiments. Within these combinations, we analyze the most effective and synergistic drug pairs across all tested cell lines, considering the variations among cancers originating from different tissues. Our analysis reveals inhibitors of five DDR-related pathways (DNA topoisomerase, PLK1 kinase, p53-inducible ribonucleotide reductase, PARP, and cell cycle checkpoint proteins) that exhibit strong combinatorial efficacy and synergy when used alongside ATM/ATR/DNA-PK inhibitors.
Sphingosine-1-phosphate suppresses GLUT activity through PP2A and counteracts hyperglycemia in diabetic red blood cells
Authors: Thomas Nadine , Schröder Nathalie H. , Nowak Melissa K. , Wollnitzke Philipp , Ghaderi Shahrooz , von Wnuck Lipinski Karin , Wille Annalena , Deister-Jonas Jennifer , Vogt Jens , Gräler Markus H. , Dannenberg Lisa , Buschmann Tobias , Westhoff Philipp , Polzin Amin , Kelm Malte , Keul Petra , Weske Sarah , Levkau Bodo
Published: December 2023

Red blood cells (RBC) are the major carriers of sphingosine-1-phosphate (S1P) in blood. Here we show that variations in RBC S1P content achieved by altering S1P synthesis and transport by genetic and pharmacological means regulate glucose uptake and metabolic flux. This is due to S1P-mediated activation of the catalytic protein phosphatase 2 (PP2A) subunit leading to reduction of cell-surface glucose transporters (GLUTs). The mechanism dynamically responds to metabolic cues from the environment by increasing S1P synthesis, enhancing PP2A activity, reducing GLUT phosphorylation and localization, and diminishing glucose uptake in RBC from diabetic mice and humans. Functionally, it protects RBC against lipid peroxidation in hyperglycemia and diabetes by activating the pentose phosphate pathway. Proof of concept is provided by the resistance of mice lacking the S1P exporter MFSD2B to diabetes-induced HbA1c elevation and thiobarbituric acid reactive substances (TBARS) generation in diabetic RBC. This mechanism responds to pharmacological S1P analogues such as fingolimod and may be functional in other insulin-independent tissues making it a promising therapeutic target.
Visible light-induced switching of soft matter materials properties based on thioindigo photoswitches
Authors: Walden Sarah L. , Nguyen Phuong H. D. , Li Hao-Kai , Liu Xiaogang , Le Minh T. N. , Xian Jun Loh , Barner-Kowollik Christopher , Truong Vinh X.
Published: December 2023

Thioindigos are visible light responsive photoswitches with excellent spatial control over the conformational change between their trans- and cis- isomers. However, they possess limited solubility in all conventional organic solvents and polymers, hindering their application in soft matter materials. Herein, we introduce a strategy for the covalent insertion of thioindigo units into polymer main chains, enabling thioindigos to function within crosslinked polymeric hydrogels. We overcome their solubility issue by developing a thioindigo bismethacrylate linker able to undergo radical initiated thiol-ene reaction for step-growth polymerization, generating indigo-containing polymers. The optimal wavelength for the reversible trans-/cis- isomerisation of thioindigo was elucidated by constructing a detailed photochemical action plot of their switching efficiencies at a wide range of monochromatic wavelengths. Critically, indigo-containing polymers display significant photoswitching of the materials’ optical and physical properties in organic solvents and water. Furthermore, the photoswitching of thioindigo within crosslinked structures enables visible light induced modulation of the hydrogel stiffness. Both the thioindigo-containing hydrogels and photoswitching processes are non-toxic to cells, thus offering opportunities for advanced applications in soft matter materials and biology-related research.
Type I collagen and fibromodulin enhance the tenogenic phenotype of hASCs and their potential for tendon regeneration
Authors: Tu Tian , Shi Yuan , Zhou Boya , Wang Xiaoyu , Zhang Wenjie , Zhou Guangdong , Mo Xiumei , Wang Wenbo , Wu Jinglei , Liu Wei
Published: December 2023

Our previous work demonstrated the tendon-derived extracellular matrix (ECM) extracts as vital niches to specifically direct mesenchymal stem cells towards tenogenic differentiation. This study aims to further define the effective ECM molecules capable of teno-lineage induction on human adipose-derived stem cells (hASCs) and test their function for tendon engineering. By detecting the teno-markers expression levels in hASCs exposed to various substrate coatings, collagen I (COL1) and fibromodulin (FMOD) were identified to be the key molecules as a combination and further employed to the modification of poly(L-lactide-co-ε-caprolactone) electrospun nanoyarns, which showed advantages in inducting seeded hASCs for teno-lineage specific differentiation. Under dynamic mechanical loading, modified scaffold seeded with hASCs formed neo-tendon in vitro at the histological level and formed better tendon tissue in vivo with mature histology and enhanced mechanical properties. Primary mechanistic investigation with RNA sequencing demonstrated that the inductive mechanism of these two molecules for hASCs tenogenic differentiation was directly correlated with positive regulation of peptidase activity, regulation of cell-substrate adhesion and regulation of cytoskeletal organization. These biological processes were potentially affected by LOC101929398/has-miR-197-3p/TENM4 ceRNA regulation axis. In summary, COL1 and FMOD in combination are the major bioactive molecules in tendon ECM for likely directing tenogenic phenotype of hASCs and certainly valuable for hASCs-based tendon engineering.
Does students’ awareness of school-track-related stereotypes exacerbate inequalities in education?
Authors: Bardach Lisa , Neuendorf Claudia , Murayama Kou , Fahrbach Thorsten , Knigge Michel , Nagengast Benjamin , Trautwein Ulrich
Published: December 2023

Early ability tracking increases inequalities in education. It has been proposed that the awareness of negative school-track-related stereotypes contributes to educational inequalities, as stereotype awareness interferes with students’ abilities to thrive, particularly those in lower, stigmatized tracks. The present study tested this assumption in a sample of 3880 German secondary school students from three tracks, who were assessed four times on stereotype awareness regarding their own school track and academic outcomes (achievement, engagement, self-concept) between Grades 5 and 8. Students in the lowest track reported higher levels of stereotype awareness than higher track students or students attending a combined track. Stereotype awareness increased across time in all tracks. Contrary to our preregistered hypotheses, however, the results from multigroup models revealed that (changes in) stereotype awareness were not more strongly related to (changes in) most outcomes in the lowest track in comparison with the other two tracks.
Machine learning and topological data analysis identify unique features of human papillae in 3D scans
Authors: Andreeva Rayna , Sarkar Anwesha , Sarkar Rik
Published: December 2023

The tongue surface houses a range of papillae that are integral to the mechanics and chemistry of taste and textural sensation. Although gustatory function of papillae is well investigated, the uniqueness of papillae within and across individuals remains elusive. Here, we present the first machine learning framework on 3D microscopic scans of human papillae ($$n=2092$$

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), uncovering the uniqueness of geometric and topological features of papillae. The finer differences in shapes of papillae are investigated computationally based on a number of features derived from discrete differential geometry and computational topology. Interpretable machine learning techniques show that persistent homology features of the papillae shape are the most effective in predicting the biological variables. Models trained on these features with small volumes of data samples predict the type of papillae with an accuracy of 85%. The papillae type classification models can map the spatial arrangement of filiform and fungiform papillae on a surface. Remarkably, the papillae are found to be distinctive across individuals and an individual can be identified with an accuracy of 48% among the 15 participants from a single papillae. Collectively, this is the first evidence demonstrating that tongue papillae can serve as a unique identifier, and inspires a new research direction for food preferences and oral diagnostics.
The longitudinal biochemical profiling of TBI in a drop weight model of TBI
Authors: Yilmaz Ali , Liraz-Zaltsman Sigal , Shohami Esther , Gordevičius Juozas , Kerševičiūtė Ieva , Sherman Eric , Bahado-Singh Ray O. , Graham Stewart F.
Published: December 2023

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine, creatinine, adenine, dimethylamine, histidine, N-Acetyl aspartate, and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p < 0.05, Pearson correlation). This study highlights the metabolic changes associated with underlying TBI severity and secondary injury. While comprehensive, future studies should investigate whether: (a) the biochemical pathways highlighted here are recapitulated in the brain of TBI sufferers and (b) if the panel of biomarkers are also as effective in less invasively harvested biomatrices, for objective and rapid identification of TBI severity and prognosis.
Real-life use of tolvaptan in ADPKD: a retrospective analysis of a large Canadian cohort
Authors: Calvaruso Luca , Yau Kevin , Akbari Pedram , Nasri Fatemah , Khowaja Saima , Wang Bill , Haghighi Amirreza , Khalili Korosh , Pei York
Published: December 2023

Tolvaptan is the first disease-modifying drug proven to slow eGFR decline in high-risk patients with ADPKD. However, barriers from the patient perspective to its use in real-life settings have not been systemically examined in a large cohort. This was a single-center, retrospective study of 523 existing or new patients with ADPKD followed at the Center for Innovative Management of PKD in Toronto, Ontario, between January 1, 2016 to December 31, 2018. All patients underwent clinical assessment including total kidney volume measurements and Mayo Clinic Imaging Class (MCIC). Those who were deemed to be at high risk were offered tolvaptan with their preference (yes or no) and reasons for their choices recorded. Overall, 315/523 (60%) patients had MCIC 1C-1E; however, only 96 (30%) of them were treated with tolvaptan at their last follow-up. Among these high-risk patients, those not treated versus treated with tolvaptan were more likely to have a higher eGFR (82 ± 26 vs. 61 ± 27 ml/min/1.73 m2), CKD stages 1–2 (79% vs. 41%), and MCIC 1C (63% vs. 31%). The most common reasons provided for not taking tolvaptan were lifestyle preference related to the aquaretic effect (51%), older age ≥ 60 (12%), and pregnancy/family planning (6%). In this real-world experience, at least 60% of patients with ADPKD considered to be at high risk for progression to ESKD by imaging were not treated with tolvaptan; most of them had early stages of CKD with well-preserved eGFR and as such, were prime targets for tolvaptan therapy to slow disease progression. Given that the most common reason for tolvaptan refusal was the concern for intolerability of the aquaretic side-effect, strategies to mitigate this may help to reduce this barrier to tolvaptan therapy.
Leveraging a KRAS-based signature to predict the prognosis and drug sensitivity of colon cancer and identifying SPINK4 as a new biomarker
Authors: Huo Jian-Ting , Tuersun Abudumaimaitijiang , Yu Su-Yue , Zhang Yu-Chen , Feng Wen-Qing , Xu Zhuo-Qing , Zhao Jing-Kun , Zong Ya-Ping , Lu Ai-Guo
Published: December 2023

KRAS is one of the leading mutations reported in colon cancer. However, there are few studies on the application of KRAS related signature in predicting prognosis and drug sensitivity of colon cancer patient. We identified KRAS related differentially expressed genes (DEGs) using The Cancer Genome Atlas (TCGA) database. A signature closely related to overall survival was recognized with Kaplan–Meier survival analysis and univariate cox regression analysis. Then we validated this signature with overall expression score (OE score) algorithm using both scRNA-seq and bulk RNA-seq data. Based on this signature, we performed LASSO cox regression to establish a prognostic model, and corresponding scores were calculated. Differences in genomic alteration, immune microenvironment, drug sensitivity between high- and low-KRD score groups were investigated. A KRAS related signature composed of 80 DEGs in colon cancer were recognized, among which 19 genes were selected to construct a prognostic model. This KRAS related signature was significantly correlated with worse prognosis. Furthermore, patients who scored lower in the prognostic model presented a higher likelihood of responding to chemotherapy, targeted therapy and immunotherapy. Furthermore, among the 19 selected genes in the model, SPINK4 was identified as an independent prognostic biomarker. Further validation in vitro indicated the knockdown of SPINK4 promoted the proliferation and migration of SW48 cells. In conclusion, a novel KRAS related signature was identified and validated based on clinical and genomic information from TCGA and GEO databases. The signature was proved to regulate genomic alteration, immune microenvironment and drug sensitivity in colon cancer, and thus might serve as a predictor for individual prognosis and treatment.
A fine pore-preserved deep neural network for porosity analytics of a high burnup U-10Zr metallic fuel
Authors: Wang Haotian , Xu Fei , Cai Lu , Salvato Daniele , Di Lemma Fidelma Giulia , Capriotti Luca , Yao Tiankai , Xian Min
Published: December 2023

U-10 wt.% Zr (U-10Zr) metallic fuel is the leading candidate for next-generation sodium-cooled fast reactors. Porosity is one of the most important factors that impacts the performance of U-10Zr metallic fuel. The pores generated by the fission gas accumulation can lead to changes in thermal conductivity, fuel swelling, Fuel-Cladding Chemical Interaction (FCCI) and Fuel-Cladding Mechanical Interaction (FCMI). Therefore, it is crucial to accurately segment and analyze porosity to understand the U-10Zr fuel system to design future fast reactors. To address the above issues, we introduce a workflow to process and analyze multi-source Scanning Electron Microscope (SEM) image data. Moreover, an encoder-decoder-based, deep fully convolutional network is proposed to segment pores accurately by integrating the residual unit and the densely-connected units. Two SEM 250 × field of view image datasets with different formats are utilized to evaluate the new proposed model’s performance. Sufficient comparison results demonstrate that our method quantitatively outperforms two popular deep fully convolutional networks. Furthermore, we conducted experiments on the third SEM 2500 × field of view image dataset, and the transfer learning results show the potential capability to transfer the knowledge from low-magnification images to high-magnification images. Finally, we use a pre-trained network to predict the pores of SEM images in the whole cross-sectional image and obtain quantitative porosity analysis. Our findings will guide the SEM microscopy data collection efficiently, provide a mechanistic understanding of the U-10Zr fuel system and bridge the gap between advanced characterization to fuel system design.
PACT - Prediction of amyloid cross-interaction by threading
Authors: Wojciechowski Jakub W. , Szczurek Witold , Szulc Natalia , Szefczyk Monika , Kotulska Malgorzata
Published: December 2023

Amyloid proteins are often associated with the onset of diseases, including Alzheimer’s, Parkinson’s and many others. However, there is a wide class of functional amyloids that are involved in physiological functions, e.g., formation of microbial biofilms or storage of hormones. Recent studies showed that an amyloid fibril could affect the aggregation of another protein, even from a different species. This may result in amplification or attenuation of the aggregation process. Insight into amyloid cross-interactions may be crucial for better understanding of amyloid diseases and the potential influence of microbial amyloids on human proteins. However, due to the demanding nature of the needed experiments, knowledge of such interactions is still limited. Here, we present PACT (Prediction of Amyloid Cross-interaction by Threading) - the computational method for the prediction of amyloid cross-interactions. The method is based on modeling of a heterogeneous fibril formed by two amyloidogenic peptides. The resulting structure is assessed by the structural statistical potential that approximates its plausibility and energetic stability. PACT was developed and first evaluated mostly on data collected in the AmyloGraph database of interacting amyloids and achieved high values of Area Under ROC (AUC=0.88) and F1 (0.82). Then, we applied our method to study the interactions of CsgA - a bacterial biofilm protein that was not used in our in-reference datasets, which is expressed in several bacterial species that inhabit the human intestines - with two human proteins. The study included alpha-synuclein, a human protein that is involved in Parkinson’s disease, and human islet amyloid polypeptide (hIAPP), which is involved in type 2 diabetes. In both cases, PACT predicted the appearance of cross-interactions. Importantly, the method indicated specific regions of the proteins, which were shown to play a central role in both interactions. We experimentally confirmed the novel results of the indicated CsgA fragments interacting with hIAPP based on the kinetic characteristics obtained with the ThT assay. PACT opens the possibility of high-throughput studies of amyloid interactions. Importantly, it can work with fairly long protein fragments, and as a purely physicochemical approach, it relies very little on scarce training data. The tool is available as a web server at https://pact.e-science.pl/pact/. The local version can be downloaded from https://github.com/KubaWojciechowski/PACT.
Non-destructive and efficient method for obtaining miRNA information in cells by artificial extracellular vesicles
Authors: Maeda Fumio , Adachi Shungo , Natsume Tohru
Published: December 2023

In recent years, research has explored the use of microRNA (miRNA) analysis in extracellular vesicles (EVs) as a minimally invasive strategy for the diagnosis and prediction of diseases. This is because miRNAs in EVs partly reflect the miRNA information and cellular status of the origin cells. However, not all intracellular miRNAs are internalized into EVs. Therefore, the miRNA information obtained from EVs is limited. To get more miRNA information, we aimed to produce artificial EVs (aEVs) encapsulating Argonaute 2 (Ago2) miRNA-binding protein, which actively incorporate miRNAs within themselves. In this study, we utilized the protein EPN-01, which is capable of releasing aEVs encapsulating it and associated proteins. This system enables us to obtain more miRNA species and increase each miRNA’s yield in the EV fraction. Furthermore, we examined whether miRNAs in the EV fraction using our system reflect the cellular condition. In cells treated with CoCl2, a reagent for inducing a hypoxia-mimic state, we detected a change in the level of hypoxia marker miR-210 with aEVs. To the best of our knowledge, this is the first report on a method to increase the yield and variety of endogenous miRNAs in the EV fraction. This approach leads to improved accuracy of cell status assessment using miRNAs in EVs.
Tiny stresses are capable of triggering earthquakes and tremors in Arunachal Himalaya
Authors: Saini Tony , Bansal Abhey Ram , Rao N. Purnachandra , Pasricha Rajat , Vempati Venkatesh
Published: December 2023

The Arunachal Himalaya has been hosting some notable events in the recent past. The tectonic history of Arunachal Himalaya is complex and has been influenced by several major tectonic events, including the 1950 Mw8.6 Assam-Tibet earthquake. In this study, we explored the effect of dynamic stresses generated by teleseismic events on the triggering of seismicity in the region. We analyzed 34 large teleseismic events since 2010 and found triggering during six events. The change in seismicity was also confirmed by analysis with the STA/LTA method. The triggering in the region occurred in the form of earthquakes and tremors. The dynamic stress as low as 1 kPa was found capable of triggering. The back-azimuth angle does not play an important role in the triggering. The angle direction of incoming waves with respect to the fault ~ 60° and ~ 120° is the possible reason for triggering in the region. The triggering occurred in the Mishmi and Main Central Thrust regions. The largest triggered event, ML2.3, was triggered 7.5 h after the 2012 Indian Ocean earthquake of Mw8.6. The region is tectonically very sensitive and tiny stresses are capable of triggering seismicity in Arunachal Pradesh.
Tree size diversity is the major driver of aboveground carbon storage in dryland agroforestry parklands
Authors: Noulèkoun Florent , Mensah Sylvanus , Kim HyungSub , Jo Heejae , Gouwakinnou Gérard N. , Houéhanou Thierry D. , Mensah Michael , Naab Jesse , Son Yowhan , Khamzina Asia
Published: December 2023

Despite the importance of agroforestry parkland systems for ecosystem and livelihood benefits, evidence on determinants of carbon storage in parklands remains scarce. Here, we assessed the direct and indirect influence of human management (selective harvesting of trees), abiotic factors (climate, topography, and soil) and multiple attributes of species diversity (taxonomic, functional, and structural) on aboveground carbon (AGC) stocks in 51 parklands in drylands of Benin. We used linear mixed-effects regressions and structural equation modeling to test the relative effects of these predictors on AGC stocks. We found that structural diversity (tree size diversity, HDBH) had the strongest (effect size β = 0.59, R2 = 54%) relationship with AGC stocks, followed by community-weighted mean of maximum height (CWMMAXH). Taxonomic diversity had no significant direct relationship with AGC stocks but influenced the latter indirectly through its negative effect on CWMMAXH, reflecting the impact of species selection by farmers. Elevation and soil total organic carbon content positively influenced AGC stocks both directly and indirectly via HDBH. No significant association was found between AGC stocks and tree harvesting factor. Our results suggest the mass ratio, niche complementarity and environmental favorability as underlying mechanisms of AGC storage in the parklands. Our findings also highlight the potential role of human-driven filtering of local species pool in regulating the effect of biodiversity on AGC storage in the parklands. We conclude that the promotion of AGC stocks in parklands is dependent on protecting tree regeneration in addition to enhancing tree size diversity and managing tall-stature trees.
A novel post-weld treatment using nanostructured metallic multilayer for superior fatigue strength
Authors: Brunow Jakob , Spalek Niclas , Mohammadi Fawad , Rutner Marcus
Published: December 2023

Welded joints exhibit fatigue failure potential from weld geometry and characteristics of the heat affected zone. In order to counteract fatigue, structures and components require larger thicknesses resulting in heavier designs exhausting the finite natural resources. We hereby introduce a novel post-weld treatment, which postpones or even prevents fatigue failure of the welded connection. A Cu/Ni nanostructured metallic multilayer (NMM) is applied via electrodeposition and a 300–600% increase in usable lifetime compared to the untreated weld is observed. A FAT class 190 with a slope of k = 6 is proposed for the design of NMM treated butt welds. Material mechanisms responsible for the fatigue strength increase are introduced herein. A case study shows that the design of offshore wind turbine support structures applying NMM post-weld treatment enables a lifetime extension as well as a 28% weight reduction compared to the structure without post-weld treatment.
Highly dynamic inflammatory and excitability transcriptional profiles in hippocampal CA1 following status epilepticus
Authors: Galvis-Montes Daniel S. , van Loo Karen M. J. , van Waardenberg Ashley J. , Surges Rainer , Schoch Susanne , Becker Albert J. , Pitsch Julika
Published: December 2023

Transient brain insults including status epilepticus (SE) can initiate a process termed ‘epileptogenesis’ that results in chronic temporal lobe epilepsy. As a consequence, the entire tri-synaptic circuit of the hippocampus is fundamentally impaired. A key role in epileptogenesis has been attributed to the CA1 region as the last relay station in the hippocampal circuit and as site of aberrant plasticity, e.g. mediated by acquired channelopathies. The transcriptional profiles of the distinct hippocampal neurons are highly dynamic during epileptogenesis. Here, we aimed to elucidate the early SE-elicited mRNA signature changes and the respective upstream regulatory cascades in CA1. RNA sequencing of CA1 was performed in the mouse pilocarpine-induced SE model at multiple time points ranging from 6 to 72 h after the initial insult. Bioinformatics was used to decipher altered gene expression, signalling cascades and their corresponding cell type profiles. Robust transcriptomic changes were detected at 6 h after SE and at subsequent time points during early epileptogenesis. Major differentially expressed mRNAs encoded primarily immediate early and excitability-related gene products, as well as genes encoding immune signalling factors. Binding sites for the transcription factors Nfkb1, Spi1, Irf8, and two Runx family members, were enriched within promoters of differentially expressed genes related to major inflammatory processes, whereas the transcriptional repressors Suz12, Nfe2l2 and Rest were associated with hyperexcitability and GABA / glutamate receptor activity. CA1 quickly responds to SE by inducing transcription of genes linked to inflammation and excitation stress. Transcription factors mediating this transcriptomic switch represent targets for new highly selected, cell type and time window-specific anti-epileptogenic strategies.
Superconducting transition edge bolometer for high-flux neutron detection
Authors: Brock Mette Bybjerg , Østergaard Emil Visby , Busi Matteo , Wulff Anders C. , Abrahamsen Asger Bech , Kuhn Luise Theil
Published: December 2023

Needs for neutron detection and monitoring in high neutron flux environments are increasing in several different fields. A completely solid-state, current mode bolometric detector is constructed as a solid substrate transition edge sensor based on a high-T$$_c$$csuperconducting meander. The detector consists of four individual pixels of which three pixels include$${^{10}{\hbox {B}}_{4}\hbox {C}}$$10B4Cneutron absorption layers. The absorbed energy per neutron absorption reaction is modelled and compared to experimental data. The response of the tested detector is directly correlated to a cold neutron beam with a flux of$${1.8\times 10^{8}}\,{\hbox {n}/{\hbox {cm}}^2/\hbox {s}}$$1.8×108n/cm2/smodulated by a slit. The signal is found to be an order of magnitude higher than the thermal background. The dynamics described by the temporal saturation constants is governed by a modulation frequency less than$${1}\hbox { Hz}$$1Hz. The thermal response is dynamic and never fully saturates for$${50}\hbox { s}$$50sexposures. The efficiency for this proof-of-principle design is 1–2%. Possibilities for optimization are identified, that will increase the efficiency to become comparable to existing solid boron-10 detectors. The existing detectors with event-based read-out have limited functionality in high flux environments. The superconducting bolometer described in this work using current-mode readout will pave the way for high flux applications.