bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of declining ataxia-telangiectasia-mutated (ATM) function in oocyte aging
Authors: Suzuki Reiko , Tan Xiujuan , Szymanska Katarzyna J. , Kubikova Nada , Perez Columba Avila , Wells Dagan , Oktay Kutluk H. 
Published: June 2024

AbstractDespite the advances in the understanding of reproductive physiology, the mechanisms underlying ovarian aging are still not deciphered. Recent research found an association between impaired ATM-mediated DNA double-strand break (DSB) repair mechanisms and oocyte aging. However, direct evidence connecting ATM-mediated pathway function decline and impaired oocyte quality is lacking. The objective of this study was to determine the role of ATM-mediated DNA DSB repair in the maintenance of oocyte quality in a mouse oocyte knockdown model. Gene interference, in vitro culture, parthenogenesis coupled with genotoxicity assay approaches, as well as molecular cytogenetic analyses based upon next-generation sequencing, were used to test the hypothesis that intact ATM function is critical in the maintenance of oocyte quality. We found that ATM knockdown impaired oocyte quality, resulting in poor embryo development. ATM knockdown significantly lowered or blocked the progression of meiosis in vitro, as well as retarding and reducing embryo cleavage after parthenogenesis. After ATM knockdown, all embryos were of poor quality, and none reached the blastocyst stage. ATM knockdown was also associated with an increased aneuploidy rate compared to controls. Finally, ATM knockdown increased the sensitivity of the oocytes to a genotoxic active metabolite of cyclophosphamide, with increased formation of DNA DSBs, reduced survival, and earlier apoptotic death compared to controls. These findings suggest a key role for ATM in maintaining oocyte quality and resistance to genotoxic stress, and that the previously observed age-induced decline in oocyte ATM function may be a prime factor contributing to oocyte aging.
Comparison of erectile and ejaculatory functional outcomes between unilateral and bilateral cavernosal rupture in penile fractures
Authors: Keskin Emin Taha , Can Osman , Filtekin Yiğit Can , Özdemir Harun , Şahin Mehmet , Çeker Gökhan , Topal Cemal , Canat Halil Lütfi 
Published: June 2024

AbstractThis study aimed to compare the erectile and ejaculatory functional outcomes of unilateral and bilateral ruptures of the corpus cavernosum in penile fractures. Sixty patients’ data were analyzed retrospectively between June 2020 and January 2023. The patients were divided into two groups based on the affected corpus cavernosum (unilateral and bilateral). Preoperative and postoperative 3rd-, 6th-, and 12th-month self-estimated intravaginal-ejaculation-latency-time (IELT), and international index of erectile function-erectile function (IIEF-EF) scores as well as the presence of urethral injury were compared. Bilateral corpus cavernosum fractures were detected in 18.3% of the patients. The IIEF-EF scores of both groups at 3rd-, 6th-, and 12th-month were found to be significantly lower than the preoperative scores (unilateral group:24.1 ± 2.7 vs 23.2 ± 3.5 and 23.3 ± 3.4, respectively, p = 0.011 and 0.014, respectively; bilateral group: 24 ± 1.9 vs 23 ± 1.8 and 23.2 ± 1.5, respectively, p = 0.027 and 0.047, respectively). No significant difference was found between the preoperative and the postoperative 12th month IIEF-EF scores in either group (unilateral group: 24.1 ± 2.7 vs 23.4 ± 3.6, p = 0.207;bilateral group:24 ± 1.9 vs 23.2 ± 1.5, p = 0.057). The self-estimated IELTs of both groups at the postoperative 3rd, 6th, and 12th months demonstrated a significant increase from the preoperative values (unilateral group: 221.6 ± 81.8 vs 252 ± 94.6, 256.5 ± 97.6, and 250.5 ± 104.8, respectively, p < 0.001; bilateral group:241.8 ± 61.6 vs 278.1 ± 55.4, 281.8 ± 56.1, and 283.6 ± 54.2, respectively, p = 0.041, 0.030, and 0.047, respectively). The changes in self-estimated IELTs and IIEF-EF scores between the preoperative period and the postoperative 3rd, 6th, and 12th-months were compared, and no statistical difference was found between patients with unilateral and bilateral corpus cavernosum fractures (p > 0.05). In conclusion, no significant difference in erectile function was found in either group at the 12-month follow-up, and the self-estimated IELTs were found to be prolonged in both groups. Furthermore, no difference was noted between the groups at any follow-up. To explain the effects of unilateral and bilateral injuries on erectile and ejaculatory functions, further studies with a larger-number of patients are necessary.
Personalized and muscle-specific OXPHOS measurement with integrated CrCEST MRI and proton MR spectroscopy
Authors: Armbruster Ryan R. , Kumar Dushyant , Benyard Blake , Jacobs Paul , Khandavilli Aditi , Liu Fang , Nanga Ravi Prakash Reddy , McCormack Shana , Cappola Anne R. , Wilson Neil , Reddy Ravinder 
Published: June 2024

AbstractCreatine chemical exchange saturation transfer (CrCEST) MRI is an emerging high resolution and noninvasive method for measuring muscle specific oxidative phosphorylation (OXPHOS). However, CrCEST measurements are sensitive to changes in muscle pH, which might confound the measurement and interpretation of creatine recovery time (τCr). Even with the same prescribed exercise stimulus, the extent of acidification and hence its impact on τCr is expected to vary between individuals. To address this issue, a method to measure pH pre- and post-exercise and its impact on CrCEST MRI with high temporal resolution is needed. In this work, we integrate carnosine 1H- magnetic resonance spectroscopy (MRS) and 3D CrCEST to establish “mild” and “moderate/intense” exercise stimuli. We then test the dependence of CrCEST recovery time on pH using different exercise stimuli. This comprehensive metabolic imaging protocol will enable personalized, muscle specific OXPHOS measurements in both healthy aging and myriad other disease states impacting muscle mitochondria.
Raman micro-spectroscopy reveals the spatial distribution of fumarate in cells and tissues
Authors: Kamp Marlous , Surmacki Jakub , Segarra Mondejar Marc , Young Tim , Chrabaszcz Karolina , Joud Fadwa , Zecchini Vincent , Speed Alyson , Frezza Christian , Bohndiek Sarah E. 
Published: June 2024

AbstractAberrantly accumulated metabolites elicit intra- and inter-cellular pro-oncogenic cascades, yet current measurement methods require sample perturbation/disruption and lack spatio-temporal resolution, limiting our ability to fully characterize their function and distribution. Here, we show that Raman spectroscopy (RS) can directly detect fumarate in living cells in vivo and animal tissues ex vivo, and that RS can distinguish between Fumarate hydratase (Fh1)-deficient and Fh1-proficient cells based on fumarate concentration. Moreover, RS reveals the spatial compartmentalization of fumarate within cellular organelles in Fh1-deficient cells: consistent with disruptive methods, we observe the highest fumarate concentration (37 ± 19 mM) in mitochondria, where the TCA cycle operates, followed by the cytoplasm (24 ± 13 mM) and then the nucleus (9 ± 6 mM). Finally, we apply RS to tissues from an inducible mouse model of FH loss in the kidney, demonstrating RS can classify FH status. These results suggest RS could be adopted as a valuable tool for small molecule metabolic imaging, enabling in situ non-destructive evaluation of fumarate compartmentalization.
SNM1A is crucial for efficient repair of complex DNA breaks in human cells
Authors: Swift Lonnie P. , Lagerholm B. Christoffer , Henderson Lucy R. , Ratnaweera Malitha , Baddock Hannah T. , Sengerova Blanka , Lee Sook , Cruz-Migoni Abimael , Waithe Dominic , Renz Christian , Ulrich Helle D. , Newman Joseph A. , Schofield Christopher J. , McHugh Peter J. 
Published: June 2024

AbstractDNA double-strand breaks (DSBs), such as those produced by radiation and radiomimetics, are amongst the most toxic forms of cellular damage, in part because they involve extensive oxidative modifications at the break termini. Prior to completion of DSB repair, the chemically modified termini must be removed. Various DNA processing enzymes have been implicated in the processing of these dirty ends, but molecular knowledge of this process is limited. Here, we demonstrate a role for the metallo-β-lactamase fold 5′−3′ exonuclease SNM1A in this vital process. Cells disrupted for SNM1A manifest increased sensitivity to radiation and radiomimetic agents and show defects in DSB damage repair. SNM1A is recruited and is retained at the sites of DSB damage via the concerted action of its three highly conserved PBZ, PIP box and UBZ interaction domains, which mediate interactions with poly-ADP-ribose chains, PCNA and the ubiquitinated form of PCNA, respectively. SNM1A can resect DNA containing oxidative lesions induced by radiation damage at break termini. The combined results reveal a crucial role for SNM1A to digest chemically modified DNA during the repair of DSBs and imply that the catalytic domain of SNM1A is an attractive target for potentiation of radiotherapy.
Structural and mechanistic insights into a lysosomal membrane enzyme HGSNAT involved in Sanfilippo syndrome
Authors: Zhao Boyang , Cao Zhongzheng , Zheng Yi , Nguyen Phuong , Bowen Alisa , Edwards Robert H. , Stroud Robert M. , Zhou Yi , Van Lookeren Campagne Menno , Li Fei 
Published: June 2024

AbstractHeparan sulfate (HS) is degraded in lysosome by a series of glycosidases. Before the glycosidases can act, the terminal glucosamine of HS must be acetylated by the integral lysosomal membrane enzyme heparan-α-glucosaminide N-acetyltransferase (HGSNAT). Mutations of HGSNAT cause HS accumulation and consequently mucopolysaccharidosis IIIC, a devastating lysosomal storage disease characterized by progressive neurological deterioration and early death where no treatment is available. HGSNAT catalyzes a unique transmembrane acetylation reaction where the acetyl group of cytosolic acetyl-CoA is transported across the lysosomal membrane and attached to HS in one reaction. However, the reaction mechanism remains elusive. Here we report six cryo-EM structures of HGSNAT along the reaction pathway. These structures reveal a dimer arrangement and a unique structural fold, which enables the elucidation of the reaction mechanism. We find that a central pore within each monomer traverses the membrane and controls access of cytosolic acetyl-CoA to the active site at its luminal mouth where glucosamine binds. A histidine-aspartic acid catalytic dyad catalyzes the transfer reaction via a ternary complex mechanism. Furthermore, the structures allow the mapping of disease-causing variants and reveal their potential impact on the function, thus creating a framework to guide structure-based drug discovery efforts.
Myeloid-derived miR-6236 potentiates adipocyte insulin signaling and prevents hyperglycemia during obesity
Authors: Paneru Bam D. , Chini Julia , McCright Sam J. , DeMarco Nicole , Miller Jessica , Joannas Leonel D. , Henao-Mejia Jorge , Titchenell Paul M. , Merrick David M. , Lim Hee-Woong , Lazar Mitchell A. , Hill David A. 
Published: June 2024

AbstractAdipose tissue macrophages (ATMs) influence obesity-associated metabolic dysfunction, but the mechanisms by which they do so are not well understood. We show that miR-6236 is a bona fide miRNA that is secreted by ATMs during obesity. Global or myeloid cell-specific deletion of miR-6236 aggravates obesity-associated adipose tissue insulin resistance, hyperglycemia, hyperinsulinemia, and hyperlipidemia. miR-6236 augments adipocyte insulin sensitivity by inhibiting translation of negative regulators of insulin signaling, including PTEN. The human genome harbors a miR-6236 homolog that is highly expressed in the serum and adipose tissue of obese people. hsa-MIR-6236 expression negatively correlates with hyperglycemia and glucose intolerance, and positively correlates with insulin sensitivity. Together, our findings establish miR-6236 as an ATM-secreted miRNA that potentiates adipocyte insulin signaling and protects against metabolic dysfunction during obesity.
Impact of whole-genome duplications on structural variant evolution in Cochlearia
Authors: Hämälä Tuomas , Moore Christopher , Cowan Laura , Carlile Matthew , Gopaulchan David , Brandrud Marie K. , Birkeland Siri , Loose Matthew , Kolář Filip , Koch Marcus A. , Yant Levi 
Published: June 2024

AbstractPolyploidy, the result of whole-genome duplication (WGD), is a major driver of eukaryote evolution. Yet WGDs are hugely disruptive mutations, and we still lack a clear understanding of their fitness consequences. Here, we study whether WGDs result in greater diversity of genomic structural variants (SVs) and how they influence evolutionary dynamics in a plant genus, Cochlearia (Brassicaceae). By using long-read sequencing and a graph-based pangenome, we find both negative and positive interactions between WGDs and SVs. Masking of recessive mutations due to WGDs leads to a progressive accumulation of deleterious SVs across four ploidal levels (from diploids to octoploids), likely reducing the adaptive potential of polyploid populations. However, we also discover putative benefits arising from SV accumulation, as more ploidy-specific SVs harbor signals of local adaptation in polyploids than in diploids. Together, our results suggest that SVs play diverse and contrasting roles in the evolutionary trajectories of young polyploids.
Room temperature, cascadable, all-optical polariton universal gates
Authors: Sannikov Denis A. , Baranikov Anton V. , Putintsev Anton D. , Misko Mikhail , Zasedatelev Anton V. , Scherf Ullrich , Lagoudakis Pavlos G. 
Published: June 2024

AbstractToday, almost all information processing is performed using electronic logic circuits operating at several gigahertz frequency. All-optical logic holds the promise to allow for up to three orders of magnitude higher speed. Whereas essential all-optical transistor functionalities were demonstrated across a range of platforms, utilising them to implement a complete Boolean logic gate set and in particular negation, i.e. switching off an optical signal with another, weaker, optical signal, poses a major challenge. Here, we realize a cascadable NOT gate by introducing the concept of non-ground-state polariton amplification in organic semiconductor microcavities under non-resonant optical excitation. We unravel the importance of vibron-mediated stimulated scattering in room temperature operation of the inverter. Moreover, we extend the concept to a multi-input universal NOR logic gate, where in the presence of any of the input signals non-ground-state amplification supersedes spontaneous ground-state condensation, resulting in a NOR gate with ~1 ps switching time. The realisation of an ultrafast universal logic gate constitutes an essential step for more complex optical circuitry that could boost information processing applications.
The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein
Authors: Mohanty Suchitra , Suklabaidya Sujit , Lavorgna Alfonso , Ueno Takaharu , Fujisawa Jun-ichi , Ngouth Nyater , Jacobson Steven , Harhaj Edward W. 
Published: June 2024

AbstractHuman T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.
Shape of the first mitotic spindles impacts multinucleation in human embryos
Authors: Ono Yuki , Shirasawa Hiromitsu , Takahashi Kazumasa , Goto Mayumi , Ono Takahiro , Sakaguchi Taichi , Okabe Motonari , Hirakawa Takeo , Iwasawa Takuya , Fujishima Akiko , Sugawara Tae , Makino Kenichi , Miura Hiroshi , Fukunaga Noritaka , Asada Yoshimasa , Kumazawa Yukiyo , Terada Yukihiro 
Published: June 2024

AbstractDuring human embryonic development, early cleavage-stage embryos are more susceptible to errors. Studies have shown that many problems occur during the first mitosis, such as direct cleavage, chromosome segregation errors, and multinucleation. However, the mechanisms whereby these errors occur during the first mitosis in human embryos remain unknown. To clarify this aspect, in the present study, we image discarded living human two-pronuclear stage zygotes using fluorescent labeling and confocal microscopy without microinjection of DNA or mRNA and investigate the association between spindle shape and nuclear abnormality during the first mitosis. We observe that the first mitotic spindles vary, and low-aspect-ratio-shaped spindles tend to lead to the formation of multiple nuclei at the 2-cell stage. Moreover, we observe defocusing poles in many of the first mitotic spindles, which are strongly associated with multinucleation. Additionally, we show that differences in the positions of the centrosomes cause spindle abnormality in the first mitosis. Furthermore, many multinuclei are modified to form mononuclei after the second mitosis because the occurrence of pole defocusing is firmly reduced. Our study will contribute markedly to research on the occurrence of mitotic errors during the early cleavage of human embryos.
Dietary fibre directs microbial tryptophan metabolism via metabolic interactions in the gut microbiota
Authors: Sinha Anurag K. , Laursen Martin F. , Brinck Julius E. , Rybtke Morten L. , Hjørne Anna Pii , Procházková Nicola , Pedersen Mikael , Roager Henrik M. , Licht Tine R. 
Published: June 2024

AbstractTryptophan is catabolized by gut microorganisms resulting in a wide range of metabolites implicated in both beneficial and adverse host effects. How gut microbial tryptophan metabolism is directed towards indole, associated with chronic kidney disease, or towards protective indolelactic acid (ILA) and indolepropionic acid (IPA) is unclear. Here we used in vitro culturing and animal experiments to assess gut microbial competition for tryptophan and the resulting metabolites in a controlled three-species defined community and in complex undefined human faecal communities. The generation of specific tryptophan-derived metabolites was not predominantly determined by the abundance of tryptophan-metabolizing bacteria, but rather by substrate-dependent regulation of specific metabolic pathways. Indole-producing Escherichia coli and ILA- and IPA-producing Clostridium sporogenes competed for tryptophan within the three-species community in vitro and in vivo. Importantly, fibre-degrading Bacteroides thetaiotaomicron affected this competition by cross-feeding monosaccharides to E. coli. This inhibited indole production through catabolite repression, thus making more tryptophan available to C. sporogenes, resulting in increased ILA and IPA production. The fibre-dependent reduction in indole was confirmed using human faecal cultures and faecal-microbiota-transplanted gnotobiotic mice. Our findings explain why consumption of fermentable fibres suppresses indole production but promotes the generation of other tryptophan metabolites associated with health benefits.
Control of mitophagy initiation and progression by the TBK1 adaptors NAP1 and SINTBAD
Authors: Adriaenssens Elias , Nguyen Thanh Ngoc , Sawa-Makarska Justyna , Khuu Grace , Schuschnig Martina , Shoebridge Stephen , Skulsuppaisarn Marvin , Watts Emily Maria , Csalyi Kitti Dora , Padman Benjamin Scott , Lazarou Michael , Martens Sascha 
Published: June 2024

AbstractMitophagy preserves overall mitochondrial fitness by selectively targeting damaged mitochondria for degradation. The regulatory mechanisms that prevent PTEN-induced putative kinase 1 (PINK1) and E3 ubiquitin ligase Parkin (PINK1/Parkin)-dependent mitophagy and other selective autophagy pathways from overreacting while ensuring swift progression once initiated are largely elusive. Here, we demonstrate how the TBK1 (TANK-binding kinase 1) adaptors NAP1 (NAK-associated protein 1) and SINTBAD (similar to NAP1 TBK1 adaptor) restrict the initiation of OPTN (optineurin)-driven mitophagy by competing with OPTN for TBK1. Conversely, they promote the progression of nuclear dot protein 52 (NDP52)-driven mitophagy by recruiting TBK1 to NDP52 and stabilizing its interaction with FIP200. Notably, OPTN emerges as the primary recruiter of TBK1 during mitophagy initiation, which in return boosts NDP52-mediated mitophagy. Our results thus define NAP1 and SINTBAD as cargo receptor rheostats, elevating the threshold for mitophagy initiation by OPTN while promoting the progression of the pathway once set in motion by supporting NDP52. These findings shed light on the cellular strategy to prevent pathway hyperactivity while still ensuring efficient progression.
Multistage time-to-event models improve survival inference by partitioning mortality processes of tracked organisms
Authors: Sethi Suresh A. , Koeberle Alex L. , Poulton Anna J. , Linden Daniel W. , Diefenbach Duane , Buderman Frances E. , Casalena Mary Jo , Duren Kenneth 
Published: June 2024

AbstractAdvances in tagging technologies are expanding opportunities to estimate survival of fish and wildlife populations. Yet, capture and handling effects could impact survival outcomes and bias inference about natural mortality processes. We developed a multistage time-to-event model that can partition the survival process into sequential phases that reflect the tagged animal experience, including handling and release mortality, post-release recovery mortality, and subsequently, natural mortality. We demonstrate performance of multistage survival models through simulation testing and through fish and bird telemetry case studies. Models are implemented in a Bayesian framework and can accommodate left, right, and interval censorship events. Our results indicate that accurate survival estimates can be achieved with reasonable sample sizes ($$n\approx 100+)$$

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and that multimodel inference can inform hypotheses about the configuration and length of survival stages needed to adequately describe mortality processes for tracked specimens. While we focus on survival estimation for tagged fish and wildlife populations, multistage time-to-event models could be used to understand other phenomena of interest such as migration, reproduction, or disease events across a range of taxa including plants and insects.