bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial-nuclear variation for metabolic plasticity with potential consequences for invasion success in New Zealand mud snails
Authors: Matoo Omera B. , Mohammed Humu , Patel Himani , Neiman Maurine , Montooth Kristi L. 
Published: September 2023

ABSTRACTMetabolic rate is an emergent organismal trait that integrates energetic costs of living and influences species distributions and response to climate change. For ectotherms, metabolic rate is likely shaped by interactions between mitochondrial and nuclear genomes and environmental temperature. Variation in reproductive mode (e.g., asexual vs. sexual reproduction) can enhance or interfere with cross-generational transmission of these interactions, with implications for evolutionary responses to selection on standing genetic variation for metabolism-related traits. We leveraged known patterns of mitochondrial-nuclear discordance in a global invader, the snailPotamopyrgus antipodarum, to measure thermal plasticity of metabolic rate in invasive vs. native asexual lineages that combined multiple mitochondrial haplotypes with nuclear genomic variation from distinct lake populations. Native lineages harbored significant mitochondrial-nuclear variation for metabolic plasticity, with some genotypes maintaining low metabolic rates at high temperature. Invasive lineages contained only a small subset of this variation, with non-plastic and lower metabolic rates relative to native lineages at high temperature. Together, these data indicate that mitochondrial-nuclear-environment interactions contribute to variation in the metabolic rate of asexual lineages. Our results also demonstrate that invasive lineages have metabolic phenotypes that could facilitate successful colonization of aquatic habitats via decreased maintenance metabolism under high temperatures.
Engineering TALE-linked deaminases to facilitate precision adenine base editing in mitochondrial DNA
Authors: Cho Sung-Ik , Lim Kayeong , Hong Seongho , Lee Jaesuk , Kim Annie , Lee Ji Min , Mok Young Geun , Chung Eugene , Han Seunghun , Cho Sang-Mi , Kim Jieun , Kim Sanghun , Kim Eun-Kyoung , Nam Ki-Hoan , Oh Yeji , Choi Minkyung , Lee Seonghyun , Lee Hyunji , Kim Jin-Soo 
Published: September 2023

ABSTRACTDddA-derived cytosine base editors (DdCBEs) and transcription activator-like effector (TALE)-linked deaminases (TALEDs) catalyze targeted base editing of mitochondrial DNA (mtDNA) in eukaryotic cells, a method useful for modeling of mitochondrial genetic disorders and developing novel therapeutic modalities. Here, we report that A-to-G editing TALEDs but not C-to-T editing DdCBEs induce tens of thousands of transcriptome-wide off-target edits in human cells. To avoid these unwanted RNA edits, we engineered the substrate-binding site in TadA8e, the deoxy-adenine deaminase in TALEDs, and created TALED variants with fine-tuned deaminase activity. Our engineered TALED variants not only reduced RNA off-target edits by > 99% but also minimized off-target mtDNA mutations and bystander edits at a target site. Unlike wild-type versions, our TALED variants were not cytotoxic and did not cause developmental arrest of mouse embryos. As a result, we obtained mice with pathogenic mtDNA mutations, associated with Leigh disease, which showed reduced heart rates.
Safety and immunogenicity of VLPCOV-02, a SARS-CoV-2 self-amplifying RNA vaccine with a modified base, 5-methylcytosine, in healthy individuals
Authors: Aboshi Masayuki , Matsuda Kenta , Kawakami Daisuke , Kono Kaoru , Kazami Yoko , Sekida Takashi , Komori Mai , Morey Amber L. , Suga Shigeru , Smith Jonathan F. , Fukuhara Takasuke , Iwatani Yasumasa , Yamamoto Takuya , Sato Nobuaki , Akahata Wataru 
Published: September 2023

SUMMARYContinuing emergence of variants of concern resulting in reduced SARS-CoV-2 vaccine efficacy necessitates additional prevention strategies. The structure of VLPCOV-01, a lipid nanoparticle-encapsulated, self-amplifying RNA COVID-19 vaccine with a comparable immune response to BNT162b2, was revised by incorporating a modified base, 5-methylcytosine, to reduce reactogenicity, and an updated receptor-binding domain derived from Brazil (gamma) variant. Interim analyses of a phase 1 dose-escalation booster vaccination study with the resulting construct, VLPCOV-02, in healthy, previously vaccinated Japanese individuals (N=96) are reported (jRCT2051230005). A dose-related increase in solicited local and systemic adverse events was observed, which were generally rated mild or moderate. The most commonly occurring events were tenderness, pain, fatigue, and myalgia. Serum SARS-CoV-2 immunoglobulin titers increased during the 4 weeks post-immunization. VLPCOV-02 demonstrated a favorable safety profile compared with VLPCOV-01, with a lower frequency of adverse events and fewer fever events at an equivalent dose. These findings support further study of VLPCOV-02.
Comparison ofTP53Mutations in Myelodysplasia and Acute Leukemia Suggests Divergent Roles in Initiation and Progression
Authors: Jambhekar Ashwini , Ackerman Emily E. , Alpay Berk A. , Lahav Galit , Lovitch Scott B. 
Published: September 2023

AbstractTP53mutation predicts adverse prognosis in many cancers, including myeloid neoplasms, but the mechanisms by which specific mutations impact disease biology, and whether they differ between disease categories, remain unknown. We analyzedTP53mutations in four myeloid neoplasm subtypes (MDS, AML, AML with myelodysplasia-related changes (AML-MRC), and therapy-related acute myeloid leukemia (tAML)), and identified differences in mutation types, spectrum, and hotspots between disease categories and compared to solid tumors. Missense mutations in the DNA-binding domain were most common across all categories, whereas inactivating mutations and mutations outside the DNA binding domain were more common in AML-MRC compared to MDS.TP53mutations in MDS were more likely to retain transcriptional activity, and co-mutation profiles were distinct between disease categories and mutation types. Our findings suggest that mutatedTP53contributes to initiation and progression of neoplasia via distinct mechanisms, and support the utility of specific identification ofTP53mutations in myeloid malignancies.Statement of SignificanceThe distribution and functional consequences ofTP53mutations differ between hematologic malignancies and solid tumors, and, among myeloid neoplasms, between myelodysplastic syndrome and acute leukemia. These findings suggest distinct biological mechanisms for mutated p53 in hematologic malignancies, specifically in initiation and progression of myeloid neoplasia, that warrant further investigation.
Childhood Bullying as a Risk Factor for Late-Life Psychological Distress and Cognitive Impairment
Authors: Mejía-Guevara Iván , Periyakoil V.S. 
Published: September 2023

ABSTRACTIn the United States, non-Hispanic Black (19%) older adults are more likely to develop dementia than White older adults (10%). As genetics alone cannot account for these differences, the impact of historical social factors is considered. This study examined whether childhood and late-life psychological distress associated with dementia risk could explain part of these disparities. Using longitudinal data from 379 White and 141 Black respondents from the Panel Study of Income Dynamics, we assessed the association between childhood bullying and late-life dementia risk, testing for mediation effects from late-life psychological distress. Mediation analysis was computed via negative binomial regression modeling, stratified by race (White/Black), type of bullying experience (target, bully, and bully-target), and the age range at which the experience occurred (6-12, 13-16). The results indicated that late-life psychological distress fully mediated the association between Black respondents who were bullies and dementia risk. However, no significant association was observed among White respondents. These results suggest that interventions aimed at preventing and treating psychological distress throughout the lifespan could be crucial in mitigating the development and progression of dementia risk.
HOXB13 alters chromatin accessibility in prostate cancer through interactions with the SWI/SNF complex
Authors: Lingadahalli Shreyas , Fazlioglu Betul Ersoy , Altintas Umut Berkay , Cingoz Ahmet , Tekoglu Emirhan , Yu Ivan Pak Lok , Dikbas Ugur Meric , Andomat Hans , Kulac Ibrahim , Morova Tunc , Xiao Kevin , Gleave Martin , Fazli Ladan , Cejas Paloma , Cherkasov Artem , Zwart Wilbert , Long Henry , Collins Colin , Bagci-Onder Tugba , Lack Nathan A. 
Published: September 2023

ABSTRACTHOXB13 is a posterior homeobox protein that is associated with the initiation and growth of prostate cancer (PCa). While most research has focused on the role of HOXB13 on androgen receptor (AR) activity, we demonstrate that HOXB13 is essential to the proliferation of both AR-positive and -negative PCa. Strikingly, HOXB13 is remarkably selective and has almost no effect on non-prostatic tissues. Despite this common essentiality in PCa, HOXB13 activity is markedly different in AR-negative PCa, where interactions with the AP-1 change the HOXB13 cistrome in stem-cell like castration-resistant prostate cancer. We show that HOXB13 activity is commonly mediated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. Despite the distinct transcription factor interactions in AR-positive and -negative PCa the HOXB13/SMARCD2 commonly alters chromatin accessibility at HOXB13 binding sites that causes increased proliferation in PCa. Overall, this work demonstrates a novel mechanism of action for HOXB13 and highlights its critical role in AR-negative castration-resistant prostate cancer.
KAT2paralogs prevent dsRNA accumulation and interferon signaling to maintain intestinal stem cells
Authors: Nguyen Mai-Uyen , Potgieter Sarah , Huang Winston , Pfeffer Julie , Woo Sean , Zhao Caifeng , Lawlor Matthew , Yang Richard , Halstead Angela , Dent Sharon , Sáenz José B. , Zheng Haiyan , Yuan Zuo-Fei , Sidoli Simone , Ellison Christopher E. , Verzi Michael 
Published: September 2023

ABSTRACTHistone acetyltransferasesKAT2AandKAT2Bare paralogs highly expressed in the intestinal epithelium, but their functions are not well understood. In this study, double knockout of murineKat2genes in the intestinal epithelium was lethal, resulting in robust activation of interferon signaling and interferon-associated phenotypes including the loss of intestinal stem cells. Use of pharmacological agents and sterile organoid cultures indicated a cell-intrinsic double-stranded RNA trigger for interferon signaling. Acetyl-proteomics and dsRIP-seq were employed to interrogate the mechanism behind this response, which identified mitochondria-encoded double-stranded RNA as the source of intrinsic interferon signaling.Kat2aandKat2btherefore play an essential role in regulating mitochondrial functions as well as maintaining intestinal health.Highlights of the workKat2aandKat2bdouble knockout in the murine intestinal epithelium triggers activation of the interferon signaling pathwayKat2a/Kat2bknockout leads to intestinal stem cell loss and other mucosal phenotypes consistent with interferon activationHistone PTM mass spec profiling reveals the first in vivo study showing H3K9ac-specific loss withKat2aandKat2bdouble knockout, yet without correlation to interferon signaling pathway genesComprehensive proteomic analysis identifies non-histone acetyl-lysine targets of KAT2 in the mouse intestine in vivo, including mitochondrial proteinsMitochondrial function is compromised uponKat2lossdsRIP-seq identifies double-stranded RNA from the mitochondria as a trigger for the intrinsic immune response uponKat2double knockout
An atypical endomembrane localized CNL-type immune receptor with a conserved deletion in the N-terminal signaling domain functions in cell death and immunity
Authors: Sunil Sruthi , Beeh Simon , Stöbbe Eva , Fischer Kathrin , Wilhelm Franziska , Meral Aron , Paris Celia , Teasdale Luisa , Jiang Zhihao , Zhang Lisha , Parras Emmanuel Aguilar , Nürnberger Thorsten , Weigel Detlef , Lozano-Duran Rosa , Kasmi Farid El 
Published: September 2023

ABSTRACTPlants have evolved intracellular nucleotide-binding leucine rich repeat receptors (NLRs) to induce a superior immune response. Upon activation, coiled-coil (CC) domain containing NLRs (CNLs) oligomerize to form apparent cation channels that promote calcium influx and cell death induction, with the alpha-1 helix of the individual CC domains penetrating membranes. Some members of a monophyletic subclass of CNLs, the ancient and autonomous NLRs (ANLs), are characterized by putative N- myristoylation and S-acylation sites at the N-terminus of their CCG10/GAdomain, potentially mediating permanent membrane association. Whether thesePotentiallyMembraneLocalized NLRs (PMLs) mediate cell death upon activation in a similar way as reported for other CNLs has been unknown. We integrated phylogenetic, cell- biological, and functional studies to uncover the cell death function of an atypical but conserved Arabidopsis PML, PML5, which has a 113 amino acid deletion in its CCG10/GAdomain. Active PML5 oligomers localize in Golgi membranes and the tonoplast, changes vacuolar morphology, and induce cell death, with the short N- terminus being sufficient for cell death. Mutant analysis supports a potential key role of PMLs in plant immunity. Similar deletions as in Arabidopsis PML5 are found in several Brassicales paralogs, pointing to the evolutionary importance of this innovation. PML5 is thus a naturally occurring CNL variant with a minimal signaling ‘domain’ and its further study should help in understanding the functional importance of this minimal domain for NLR signaling.
Comparisons of newborn birthweights with maternal factors at Phalombe District Hospital, Malawi: a retrospective record review
Authors: Mfipa Dumisani , Hajison Precious L. , Mpachika-Mfipa Felistas 
Published: September 2023

AbstractBackgroundBirthweight is an important indicator of the newborn’s future health. Maternal factors, including age, HIV status, parity and obstetric complications ([pre]-eclampsia, antepartum hemorrhage [APH] and sepsis), however, have been shown as risk factors of low birthweight (LBW). For data-guided interventions, we compared newborn birthweights with these factors at Phalombe District Hospital, Malawi.MethodsUsing a retrospective record review study design, we extracted data of 1,308 women and their newborns from maternity registers (October, 2022-March, 2023). Data were skewed. Its distribution in each group had different variabilities/shapes. We used Mann-Whitney U/Kruskal- Wallis H tests to compare mean rank of birthweights.ResultsPrevalence of LBW was 17.4% and median birthweight was 2,900.00g (interquartile range [IQR] 2,600.00g-3,200.00g). We observed significant difference in newborn birthweights among adolescent girls (≤19 years), young women (20-24 years), older women (25-34 years) and women of advanced maternal age (≥35 years), (mean ranks: 600.32, 650.85, 690.62 and 735.34, respectively, H[3] = 20.30, p<.001, η2= 0.01). Pairwise comparisons showed significant differences in newborn birthweights of adolescent girls and older women (p = .006), adolescent girls and women of advanced maternal age (p<.001). We observed no significant differences in newborn birthweights between HIV+ and HIV- women (mean ranks: 608.86 and 659.28, respectively, U = 67,748.50, Z = -1.417, p = .157, r = 0.04). We found significant differences in newborn birthweights between primiparous and multiparous women (mean ranks: 600.95 and 697.16, respectively, U = 180,062.00, Z = -4.584, p<.001, r = 0.13), women with and women with no (pre)-eclampsia, APH and sepsis (mean ranks: 340.09 and 662.64, respectively, U = 10,662.00, Z = -4.852, p<.001, r=0.13).ConclusionSignificant differences reported notwithstanding, small effect sizes and a high prevalence of LBW were observed. Thus, all pregnant women should be prioritized to improve birthweight outcomes. Those with complications, however, require special care.
Characterizing Tissue Structures from Spatial Omics with Spatial Cellular Graph Partition
Authors: Wu Zhenqin , Kondo Ayano , McGrady Monee , Baker Ethan A. G. , Wu Eric , Rahim Maha K. , Bracey Nathan A. , Charu Vivek , Cho Raymond J. , Cheng Jeffrey B. , Afkarian Maryam , Zou James , Mayer Aaron T. , Trevino Alexandro E. 
Published: September 2023

AbstractSpatial transcriptomic and proteomic measurements enable high-dimensional characterization of tissues. However, understanding organizations of cells at different spatial scales and extracting tissue structures of interest remain challenging tasks that require extensive human annotations. To address this need for consistent identification of tissue structures, in this work, we present a novel annotation method Spatial Cellular Graph Partitioning (SCGP) that allows unsupervised identification of tissue structures that reflect the anatomical and functional units of human tissues. We further present a reference-query extension pipeline SCGP-Extension that enables the generalization of existing reference tissue structures to previously unseen samples. Our experiments demonstrate reliable and robust partitionings of both spatial transcriptomics and proteomics datasets encompassing different tissue types and profiling techniques. Downstream analysis on SCGP-identified tissue structures reveals disease-relevant insights regarding diabetic kidney disease and skin disorder, underscoring its potential in facilitating spatial analysis and driving new discoveries.
A hybrid receptor binding protein enables phage F341 infection ofCampylobacterby binding to flagella and lipooligosaccharides
Authors: Ostenfeld Line Jensen , Sørensen Anders Nørgaard , Neve Horst , Vitt Amira , Klumpp Jochen , Holst Sørensen Martine C. 
Published: September 2023

AbstractFlagellotropic bacteriophages are interesting candidates as therapeutics against pathogenic bacteria dependent on flagellar motility for colonization and causing disease. Yet, phage resistance other than loss of motility has been scarcely studied. Here we developed a soft agar assay to study flagellotropic phage F341 resistance in motileCampylobacter jejuni. We found that phage adsorption was prevented by diverse genetic mutations in the lipooligosaccharides forming the secondary receptor of phage F341. Genome sequencing showed phage F341 belongs to theFletchervirusgenus otherwise comprising capsular-dependentC. jejuniphages. Interestingly, phage F341 encodes a hybrid receptor binding protein (RBP) predicted as a short tail fiber showing partial similarity to RBP1 encoded by capsular-dependentFletchervirus,but with a receptor binding domain similar to tail fiber protein H ofC. jejuniCJIE1 prophages. Thus,C. jejuniprophages may represent a genetic pool from where lyticFletchervirusphages can acquire new traits like recognition of new receptors.
Engineered human myogenic cells in hydrogels generate functional myofibers within dystrophic mouse muscle
Authors: Kowala Anna , Meng Jinhong , Pourquié Olivier , Connelly John , Morgan Jennifer E , Lin Yung-Yao 
Published: September 2023

AbstractTransplantation of human myogenic progenitor cells (MPCs) is a promising therapeutic strategy for treating muscle-wasting diseases, e.g., Duchenne muscular dystrophy (DMD). To increase engraftment efficiency of donor stem cells, modulation of host muscles is required, significantly limiting their clinical translation. Here we develop a clinically relevant transplantation strategy synergising hydrogel-mediated delivery and engineered human MPCs generated from CRISPR-corrected DMD patient-derived pluripotent stem cells (PSCs). We demonstrate that donor-derived human myofibers produce full-length dystrophin at 4 weeks and 5 – 6 months (long-term) post transplantation in the unmodulated muscles of the dystrophin-deficient mouse model of DMD. Remarkably, human myofibers are innervated by mouse motor neurons forming neuromuscular junctions and supported by vascularisation after long-term engraftment in dystrophic mice. PAX7+ cells of human origin replenish the satellite cell niche. There was no evidence of tumorigenesis in mice engrafted with hydrogel-encapsulated human MPCs. Our results provide a proof-of-concept in developing hydrogel-based cell therapy for muscle-wasting diseases.
Light-induced Trpin/Metout switching during BLUF domain activation in ATP-bound photoactivatable adenylate cyclase OaPAC
Authors: Chretien Anaïs , Nagel Marius F. , Botha Sabine , de Wijn Raphaël , Brings Lea , Dörner Katerina , Han Huijong , Koliyadu Jayanath C. P. , Letrun Romain , Round Adam , Sato Tokushi , Schmidt Christina , Secareanu Radu-Costin , von Stetten David , Vakili Mohammad , Wrona Agnieszka , Bean Richard , Mancuso Adrian , Schulz Joachim , Pearson Arwen R. , Kottke Tilman , Lorenzen Kristina , Schubert Robin 
Published: September 2023

AbstractThe understanding of signal transduction mechanisms in photoreceptor proteins is essential for elucidating how living organisms respond to light as environmental stimuli. In this study, we investigated the ATP binding, photoactivation and signal transduction process in the photoactivatable adenylate cyclase fromOscillatoria acuminata(OaPAC) upon blue light excitation. Structural models with ATP bound in the active site of native OaPAC at cryogenic as well as room temperature are presented. ATP is found in one conformation at cryogenic- and in two conformations at ambient-temperature, and is bound in a non-productive conformation. However, FTIR spectroscopic experiments confirm that the non-productive conformation is the native binding mode in dark state OaPAC and that transition to a productive conformation for ATP turnover only occurs after light activation. A combination of time-resolved crystallography experiments at synchrotron and X-ray Free Electron Lasers sheds light on the initial events around the Flavin Adenine Dinucleotide (FAD) chromophore in the light-sensitive BLUF domain of OaPAC. Initial changes involve the highly conserved amino acids Tyr6, Gln48 and Met92. Crucially, the Gln48 side chain performs a 180° rotation during activation, leading to the stabilization of the FAD chromophore. Cryo-trapping experiments allowed us to investigate a late light-activated state of the reaction and revealed significant conformational changes in the BLUF domain around the FAD chromophore. In particular, a Trpin/Metouttransition upon illumination is observed for the first time in the BLUF domain and its role in signal transmission via α-helix 3 and 4 in the linker region between sensor and effector domain is discussed.