bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lignin isolated by microwave-assisted acid-catalyzed solvolysis induced cell death on mammalian tumor cells by modulating apoptotic pathways
Authors: Kashimoto Rio , Ohgitani Eriko , Makimura Yutaka , Miyazaki Tatsuya , Kimura Chihiro , Shin-Ya Masaharu , Nishimura Hiroshi , Pezzotti Giuseppe , Watanabe Takashi , Mazda Osam 
Published: January 2024

AbstractLignin, the most abundant renewable aromatic polymer, has been shown to suppress the growth of mammalian tumor cells. Despite being a textbook example, there is little information on the biological activity of lignin in relation to its molecular structure or the molecular mechanisms by which lignin suppresses tumor cells in mammalian species. Here, we prepared Microwave-assisted Acid-catalyzed Solvolysis Lignin (MASL) and assessed its effects on human and mouse tumor cells. Our data showed MASL significantly reduced viability of tumor cells by modulating apoptotic pathways. MASL treatment upregulated TNF-α, Fas, and FasL expression levels, while suppressing anti-apoptotic NF-κB and mTOR pathways in tumor cells. In-vivo experiments were also performed using tumor-bearing mice to confirm the anti-tumor effects of MASL. An administration of MASL significantly suppressed tumor growth in mice in association with elevation of caspase 3 expression. These findings strongly suggest the potential usefulness of low molecular weight lignin as an effective therapeutic against malignancies.
Cause and chondroprotective effects of prostaglandin E2 secretion during mesenchymal stromal cell chondrogenesis
Authors: Schmidt S. , Klampfleuthner F.A.M. , Renkawitz T. , Diederichs S. 
Published: January 2024

AbstractMesenchymal stromal cells (MSCs) that are promising for cartilage tissue engineering secrete high amounts of prostaglandin E2 (PGE2), an immunoactive mediator involved in endochondral bone development. This study aimed to identify drivers of PGE2 and its role in the inadvertent MSC misdifferentiation into hypertrophic chondrocytes. PGE2 release which rose in the first three weeks of MSC chondrogenesis was jointly stimulated by endogenous BMP, WNT, and hedgehog activity that supported the exogenous stimulation by TGF-β1 and insulin, and overcame the PGE2 inhibition by dexamethasone. Experiments with PGE2 treatment or the inhibitor celecoxib or specific receptor antagonists demonstrated that although driven by prohypertrophic signals, PGE2 exerted broad autocrine antihypertrophic effects. This chondroprotective effect makes PGE2 not only a promising option for future combinatorial approaches to direct MSC tissue engineering approaches into chondral instead of endochondral development, but could potentially have implications for the use of COX-2-selective inhibitors in osteoarthritis pain management.
Collagen mineralization decreases NK cell-mediated cytotoxicity of breast cancer cells via increased glycocalyx thickness
Authors: Park Sangwoo , Choi Siyoung , Shimpi Adrian A. , Estroff Lara A. , Fischbach Claudia , Paszek Matthew J. 
Published: January 2024

AbstractSkeletal metastasis is common in patients with advanced breast cancer, and often caused by immune evasion of disseminated tumor cells (DTCs). In the skeleton, tumor cells not only disseminate to the bone marrow, but also to osteogenic niches in which they interact with newly mineralizing bone extracellular matrix (ECM). However, it remains unclear how mineralization of collagen type I, the primary component of bone ECM, regulates tumor-immune cell interactions. Here, we have utilized a combination of synthetic bone matrix models with controlled mineral content, nanoscale optical imaging, and flow cytometry to evaluate how collagen type I mineralization affects the biochemical and biophysical properties of the tumor cell glycocalyx, a dense layer of glycosylated proteins and lipids decorating their cell surface. Our results suggest that collagen mineralization upregulates mucin-type O-glycosylation and sialylation by tumor cells, which increased their glycocalyx thickness while enhancing resistance to attack by Natural Killer (NK) cells. These changes were functionally linked as treatment with a sialylation inhibitor decreased mineralization-dependent glycocalyx thickness and made tumor cells more susceptible to NK cell attack. Together, our results suggest that interference with glycocalyx sialylation may represent a therapeutic strategy to enhance cancer immunotherapies targeting bone-metastatic breast cancer.
A general model for two-locus assortative mating analysis and prediction
Authors: Smith Reginald D. 
Published: January 2024

AbstractThe analytical framework to investigate the effect of assortative mating for phenotypes that are determined by two loci is over a hundred years old and well established by Jennings, Wentworth, Remick, Robbins, and Wright. However, some known aspects of assortative mating have not received a concise analytical analysis or clear expression. Chief among these are linkage disequilibrium and identity disequilibrium but also the change in heterozygosity outside of the simple case ofPA=PB= 1/2. In order to understand the effects of assortative mating in more detail, a general model is proposed that uses recursive difference equations rather than simulation to solve most assortative mating problems. Using this, we will expand the cases for which an exact or approximate expression for population genetic variables can be determined. In particular, the first closed form expressions for linkage disequilibrium and identity disequilibrium for two-locus assortative mating are given. We also show that assortative mating does not generate linkage disequilibrium when the loci are completely linked. Finally, this model will be used to investigate two possible cases of two-locus assortative mating in human populations regarding variants for non-syndromic deafness and the variants that largely determine blue eye color.
Stronger evidence for relaxed selection than adaptive evolution in high-elevation animal mtDNA
Authors: Iverson Erik N. K. , Criswell Abby , Havird Justin C. 
Published: January 2024

AbstractMitochondrial (mt) genes are the subject of many adaptive hypotheses due to the key role of mitochondria in energy production and metabolism. One widespread adaptive hypothesis is that selection imposed by life at high elevation leads to the rapid fixation of beneficial alleles in mtDNA, reflected in the increased rates of mtDNA evolution documented in many high-elevation species. However, the assumption that fast mtDNA evolution is caused by positive, rather than relaxed purifying selection has rarely been tested. Here, we calculated thedN/dSratio, a metric of nonsynonymous substitution bias, and explicitly tested for relaxed selection in the mtDNA of over 700 species of terrestrial vertebrates, freshwater fishes, and arthropods, with information on elevation and latitudinal range limits, range sizes, and body sizes. We confirmed that mitochondrial genomes of high-elevation taxa have slightly higherdN/dSratios compared to low-elevation relatives. High-elevation species tend to have smaller ranges, which predict higherdN/dSratios and more relaxed selection across species and clades, while absolute elevation and latitude do not predict higherdN/dS. We also find a positive relationship between body mass anddN/dS, supporting a role for small effective population size leading to relaxed selection. We conclude that higher mtdN/dSamong high-elevation species is more likely to reflect relaxed selection due to smaller ranges and reduced effective population size than adaptation to the environment. Our results highlight the importance of rigorously testing adaptive stories against non-adaptive alternative hypotheses, especially in mt genomes.
Postmortem MRI of Tissue Frozen at Autopsy
Authors: Nair Govind , Sun Roy , Merkle Hellmut , Hoskin Kyra , Bree Kendyl , Dodd Stephen , Koretsky Alan 
Published: January 2024

AbstractIntroductionPostmortem MRI provides insight into location of pathology within tissue blocks, enabling efficient targeting of histopathological studies. While postmortem imaging of fixed tissue is gaining popularity, imaging tissue frozen at the time of extraction is significantly more challenging.MethodsTissue integrity was examined using RNA integrity number (RIN), in mouse brains placed between -20 °C and 20 °C for up to 24 hours, to determine the highest temperature that could potentially be used for imaging without tissue degeneration. Human tissue frozen at the time of autopsy was sealed in a tissue chamber filled with 2-methylbutane to prevent contamination of the MRI components. The tissue was cooled to a range of temperatures in a 9.4T MRI using a recirculating aqueous ethylene glycol solution. MRI was performed using a magnetization-prepared rapid gradient echo (MPRAGE) sequence with inversion time of 1400 ms to null the signal from 2-methylbutane bath, isotropic resolution between 0.3-0.4 mm, and scan time of about 4 hours was used to study the anatomical details of the tissue block.Results and DiscussionA temperature of -7 °C was chosen for imaging as it was below the highest temperature that did not show significant RIN deterioration for over 12 hours, at the same time gave robust imaging signal and contrast between brain tissue types. Imaging performed on various human tissue blocks revealed good gray-white matter contrast and revealing subpial, subcortical, and deep white matter lesions typical of multiple sclerosis enabling further spatially targeted studies.ConclusionHere, we describe a new method to image cold tissue, while maintaining tissue integrity and biosafety during scanning. In addition to improving efficiency of downstream processes, imaging tissue at sub-zero temperatures may also improve our understanding of compartment specificity of MRI signal.
The unseen invaders: tracking phylogeographic dynamics and genetic diversity of crypticPomacea canaliculata and P. maculata(Golden Apple Snails) across Taiwan
Authors: Banerjee Pritam , Dey Gobinda , Maity Jyoti Prakash , Stewart Kathryn A. , Sharma Raju Kumar , Chan Michael W.Y. , Lee Kuan Hsien , Chen Chien-Yen 
Published: January 2024

AbstractThe cryptic invasion of golden apple snails (Pomacea canaliculata and P. maculata) in Taiwan has caused significant ecological and economical damage over last few decades, however, their management remains difficult due to inadequate taxonomic identification, complex phylogeny and limited population genetic information. We aim to understand the current distribution, putative population of origin, genetic diversity and potential path of cryptic invasion ofPomacea canaliculata and P. maculataacross Taiwan to aid in improved mitigation approaches. The present investigation conducted a nationwide survey with 254 samples collected from 41 locations from 14 counties or cities across Taiwan. We identifiedP. canaliculataandP. maculatabased on mitochondrial COI and compared their genetic diversity across Taiwan, as well as other introduced and native countries (based on publicly available COI data) to understand the possible paths of invasion in Taiwan. Based on mitochondrial COI barcoding, sympatric and heterogeneous distributions of invasiveP. canaliculataandP. maculatawere noted. Our haplotype analysis and mismatch distribution suggested multiple introductions ofP. canaliculatain Taiwan was likely originated directly from Argentina, whereasP. maculatawas probably introduced from a single, or a few, introduction event(s) from Argentina and Brazil. Our population genetic data further demonstrated a higher haplotype and genetic diversity forP. canaliculataandP. maculatain Taiwan compared to other introduced regions. Based on our current understanding, the establishment ofP. canaliculataandP. maculatais alarming and widespread beyond geopolitical borders, requiring a concerted and expedited national and international invasive species mitigation program.
Diurnal rhythmicity in metabolism and salivary effector expression shapes host colonization by aphids
Authors: Han Jinlong , Kunk Daniel , Cui Meihua , Goldstein Yoshiahu , Tzin Vered , Nalam Vamsi J. 
Published: January 2024

AbstractDiurnal rhythms influence insect behavior, physiology, and metabolism, optimizing their performance by adapting to daily changes in the environment. While their impact on agricultural pests has been briefly explored, our understanding of how these rhythms drive adaptative responses in pest biology and influence host colonization remains elusive. Here, we show that a notorious global aphid pest,Rhopalosiphum padi, exhibits distinct diurnal patterns in feeding behavior, with elevated honeydew excretion at night and extended phloem salivation during early nighttime. Temporal aphid transcriptome profiling reveals four diurnally rhythmic clusters, two of which peak at night, exhibiting enrichment in carbohydrate and amino acid metabolism. Beyond the established role in manipulating host responses and allowing sustained feeding, our study reveals the first evidence in any insect species for cyclical fluctuations in salivary effector expression. Silencing key effector genes, peaking in expression during the increased nighttime salivation, results in a more pronounced reduction in aphid feeding activity on host plants during the night compared to the day, a phenomenon not observed on artificial diets. A better understanding of aphid diurnal rhythms and their roles on host colonization provides a promising avenue to refine and optimize pest management, granting a strategic advantage for minimizing crop damage.
Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomes in pulmonary arterial hypertension
Authors: Alotaibi Mona , Harvey Lloyd D. , Nichols William C. , Pauciulo Michael W. , Hemnes Anna , Long Tao , Watrous Jeramie D. , Begzati Arjana , Tuomilehto Jaakko , Havulinna Aki S. , Niiranen Teemu J. , Jousilahti Pekka , Salomaa Veikko , Bertero Thomas , Kim Nick H. , Desai Ankit A. , Malhotra Atul , Yuan Jason X.-J. , Cheng Susan , Chan Stephen Y. , Jain Mohit 
Published: January 2024

AbstractPulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.One-Sentence SummaryThis work identifies pulmonary primary oxysterol and bile acid synthesis as altered in pulmonary arterial hypertension, thus establishing a new prognostic test for this disease.
Bioreversible anionic cloaking enables intracellular protein delivery with ionizable lipid nanoparticles
Authors: Alamgir Azmain , Ghosal Souvik , DeLisa Matthew P. , Alabi Christopher A. 
Published: January 2024

AbstractProtein-based therapeutics comprise a rapidly growing subset of pharmaceuticals, but enabling their delivery into cells for intracellular applications has been a longstanding challenge. To overcome the delivery barrier, we explored a reversible, bioconjugation-based approach to modify the surface charge of protein cargos with an anionic “cloak” to facilitate electrostatic complexation and delivery with lipid nanoparticle (LNP) formulations. We demonstrate that the conjugation of lysine-reactive sulfonated compounds can allow for the delivery of various protein cargos using FDA-approved LNP formulations of the ionizable cationic lipid DLin-MC3-DMA (MC3). We apply this strategy to functionally deliver RNase A for cancer cell killing as well as a full-length antibody to inhibit oncogenic β-catenin signaling. Further, we show that LNPs encapsulating cloaked fluorescent proteins distribute to major organs in mice following systemic administration. Overall, our results point towards a generalizable platform that can be employed for intracellular delivery of a wide range of protein cargos.
Tirzepatide attenuates mammary tumor progression in diet-induced obese mice
Authors: Glenny Elaine M. , Ho Alyssa N. , Kiesel Violet A. , Chen Fangxin , Gates Claire E. , Paules Evan M. , Xu Ruihan , Holt C. Alex , Coleman Michael F. , Hursting Stephen D. 
Published: January 2024

AbstractWe report for the first time an anticancer benefit of tirzepatide—a dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist—in a model of obesity and breast cancer in female mice. Long-term tirzepatide treatment induced weight loss, mitigated obesity-driven changes in circulating metabolic hormone levels, and suppressed orthotopic E0771 mammary tumor growth. Relative to tirzepatide, chronic calorie restriction, an established anticancer intervention in preclinical models, promoted even greater weight loss, systemic hormonal regulation, and tumor suppression. We conclude that tirzepatide represents a promising pharmacologic approach for mitigating the procancer effects of obesity. Moreover, strategies promoting greater weight loss than achieved with tirzepatide alone may augment the anticancer benefits of tirzepatide.
A CANCER PERSISTENT DNA REPAIR CIRCUIT DRIVEN BY MDM2, MDM4 (MDMX), AND MUTANT P53 FOR RECRUITMENT OF MDC1 AND 53BP1 TO CHROMATIN
Authors: Ellison Viola , Polotskaia Alla , Xiao Gu , Leybengrub Pamella , Qiu Weigang , Lee Rusia , Hendrickson Ronald , Hu Wenwei , Bargonetti Jill 
Published: January 2024

AbstractThe influence of the metastasis promoting proteins mutant p53 (mtp53) and MDM2 onCancerPersistentRepair(CPR) to promote cancer cell survival is understudied. Interactions between the DNA repair choice protein 53BP1 and wild type tumor suppressor protein p53 (wtp53) regulates cell cycle control. Cancer cells often express elevated levels of transcriptionally inactive missense mutant p53 (mtp53) that interacts with MDM2 and MDM4/MDMX (herein called MDMX). The ability of mtp53 to maintain a 53BP1 interaction while in the context of interactions with MDM2 and MDMX has not been described. We asked if MDM2 regulates chromatin-based phosphorylation events in the context of mtp53 by comparing the chromatin of T47D breast cancer cells with and without MDM2 in a phospho-peptide stable isotope labeling in cell culture (SILAC) screen. We found reduced phospho-53BP1 chromatin association, which we confirmed by chromatin fractionation and immunofluorescence in multiple breast cancer cell lines. We used the Proximity Ligation Assay (PLA) in breast cancer cell lines and detected 53BP1 in close proximity to mtp53, MDM2, and the DNA repair protein MDC1. Through disruption of the mtp53-MDM2 interaction, by either Nutlin 3a or a mtp53 R273H C-terminal deletion, we uncovered that mtp53 was required for MDM2-53BP1 interaction foci. Our data suggests that mtp53 works with MDM2 and 53BP1 to promote CPR and cell survival.
Nutrient addition on grazing lawns and selection by free-roaming mammalian herbivores in a nutrient poor savanna
Authors: Schroder Bradley , Van Langevelde Frank , Schroder Nicola-Anne Hawkins , Prins Herbert H. T. 
Published: January 2024

AbstractGrazing lawns are important food sources in nutrient poor savannas for free-roaming mammalian herbivores. It has been hypothesized that increased grazing pressure by mammalian herbivores can create and maintain patches of lawn grass. We tested whether the application of specific nutrients, nitrogen (N), phosphorus (P) or in combination with calcitic and dolomitic lime (Ca), in a nutrient poor African savanna, would make the grass sward more nutrient rich, which would attract mammalian herbivores to graze more frequently. We investigated the grazing patterns of six species of mammalian herbivores, namely, blue wildebeest (Connochaetes taurinus), Burchell’s zebra (Equus quagga burchellii), common eland (Taurotragus oryx), impala (Aepyceros melampus), square-lipped rhinoceros (Ceratotherium simum) and warthog (Phacochoerus africanus). We show that the addition of N attracts and increases the grazing pressure for three of the herbivore species, namely, blue wildebeest, Burchell’s zebra and impala. Our findings suggest that these often abundantly present mammalian herbivores with intermediate body mass, attracted to grazing lawns by the addition of N, can maintain grazing lawns.Conservation implicationsArtificial fertilization with nitrogen attracts large free-roaming herbivore species to localized grazing lawns, stimulating the creation and expansion of high nutrient quality lawn grasses in nutrient poor savannas. This results in a nutrient high food source which would normally not be available in nutrient poor savannas.
β-Cells as a Cell Factory for On-Demand Recombinant Protein Dosing: Harnessing the Neuroendocrine Cell Secretory Pathway for Controlled Release
Authors: Thomson Ella A. , Xu Haixia , Lee Sooyeon , Lal Rayhan A. , Annes Justin P. , Poon Ada S. Y. 
Published: January 2024

ABSTRACTThis study explores the potential of utilizingβ-cells, exemplified with R7T1β-cell pseudoislets, as a transplantable cell factory for on-demand recombinant protein therapeutic delivery. While mammalian cell lines are widely used forin vitroprotein production, the commonly utilized constitutive secretion pathway poses challenges toin vivocell therapy, especially for delivering proteins requiring precise exposure kinetics. The proposed approach capitalizes on unique aspects ofβ-cells, including substantial vesicular protein storage capacity and electrochemically-regulated protein release, to facilitate timely and titratablein vivotherapeutic delivery. Examining a variety of strategies to acheiveβ-cell glucagon or glucagon-like peptide 1 (GLP-1) storage and secretion, we devised a flexibleβ-cell-based expression platform for efficient cellular peptide production and on-demand release. This platform utilizes the preproinsulin coding sequence as a template, wherein therapeutic peptides of interest (glucagon or GLP-1) are substituted for C-peptide while the A- and B-peptide insulin chains are mutated to prevent bio-active insulin production. This approach overcomes the challenge of efficient bio-active peptide expression by leveraging the endogenousβ-cell peptide expression, translation, processing, storage and secretion machinery. Furthermore,β-cells provide a mechanism for scalable electyrochemnically-triggered peptide delivery. This transformative strategy, which may be extended to other proteins and peptide expression cassettes, holds significant promise for targeted and temporally controlledin vivoproduction and release of recombinant protein therapeutics. The study suggests potential applications in addressing challenges in metabolic disorders, blood disorders, and oncology. Future refinements may focus on optimizing vector design, peptide production, andin vivoadaptation.