bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes
Authors: Raguseo Federica , Wang Yiran , Li Jessica , Petrić Howe Marija , Balendra Rubika , Huyghebaert Anouk , Vadukul Devkee M. , Tanase Diana A. , Maher Thomas E. , Malouf Layla , Rubio-Sánchez Roger , Aprile Francesco A. , Elani Yuval , Patani Rickie , Di Michele Lorenzo , Di Antonio Marco 
Published: December 2023

AbstractAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.
Particle-associated denitrification is the primary source of N2O in oxic coastal waters
Authors: Wan Xianhui S. , Sheng Hua-Xia , Liu Li , Shen Hui , Tang Weiyi , Zou Wenbin , Xu Min N. , Zheng Zhenzhen , Tan Ehui , Chen Mingming , Zhang Yao , Ward Bess B. , Kao Shuh-Ji 
Published: December 2023

AbstractThe heavily human-perturbed coastal oceans are hotspots of nitrous oxide (N2O) emission to the atmosphere. The processes underpinning the N2O flux, however, remain poorly understood, leading to large uncertainties in assessing global N2O budgets. Using a suite of nitrogen isotope labeling experiments, we show that multiple processes contribute to N2O production throughout the estuarine-coastal gradient, sustaining intensive N2O flux to the atmosphere. Unexpectedly, denitrification, rather than ammonia oxidation as previously assumed, constitutes the major source of N2O in well-oxygenated coastal waters. Size-fractionated manipulation experiments with gene analysis further reveal niche partitioning of ammonia oxidizers and denitrifiers across the particle size spectrum; denitrification dominated on large particles and ammonia oxidizers on small particles. Total N2O production rate increases with substrate and particle concentrations, suggesting a crucial interplay between nutrients and particles in controlling N2O production. The controlling factors identified here may help understand climate feedback mechanisms between human activity and coastal oceans.
Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors
Authors: Habrian Chris , Latorraca Naomi , Fu Zhu , Isacoff Ehud Y. 
Published: December 2023

AbstractMetabotropic glutamate receptors (mGluRs) are dimeric class C G-protein–coupled receptors that operate in glia and neurons. Glutamate affinity and efficacy vary greatly between the eight mGluRs. The molecular basis of this diversity is not understood. We used single-molecule fluorescence energy transfer to monitor the structural rearrangements of activation in the mGluR ligand binding domain (LBD). In saturating glutamate, group II homodimers fully occupy the activated LBD conformation (full efficacy) but homodimers of group III mGluRs do not. Strikingly, the reduced efficacy of Group III homodimers does not arise from differences in the glutamate binding pocket but, instead, from interactions within the extracellular dimerization interface that impede active state occupancy. By contrast, the functionally boosted mGluR II/III heterodimers lack these interface ‘brakes’ to activation and heterodimer asymmetry in the flexibility of a disulfide loop connecting LBDs greatly favors occupancy of the activated conformation. Our results suggest that dimerization interface interactions generate substantial functional diversity by differentially stabilizing the activated conformation. This diversity may optimize mGluR responsiveness for the distinct spatio-temporal profiles of synaptic versus extrasynaptic glutamate.
Accurate integration of single-cell DNA and RNA for analyzing intratumor heterogeneity using MaCroDNA
Authors: Edrisi Mohammadamin , Huang Xiru , Ogilvie Huw A. , Nakhleh Luay 
Published: December 2023

AbstractCancers develop and progress as mutations accumulate, and with the advent of single-cell DNA and RNA sequencing, researchers can observe these mutations and their transcriptomic effects and predict proteomic changes with remarkable temporal and spatial precision. However, to connect genomic mutations with their transcriptomic and proteomic consequences, cells with either only DNA data or only RNA data must be mapped to a common domain. For this purpose, we present MaCroDNA, a method that uses maximum weighted bipartite matching of per-gene read counts from single-cell DNA and RNA-seq data. Using ground truth information from colorectal cancer data, we demonstrate the advantage of MaCroDNA over existing methods in accuracy and speed. Exemplifying the utility of single-cell data integration in cancer research, we suggest, based on results derived using MaCroDNA, that genomic mutations of large effect size increasingly contribute to differential expression between cells as Barrett’s esophagus progresses to esophageal cancer, reaffirming the findings of the previous studies.
Structural variants involved in high-altitude adaptation detected using single-molecule long-read sequencing
Authors: Shi Jinlong , Jia Zhilong , Sun Jinxiu , Wang Xiaoreng , Zhao Xiaojing , Zhao Chenghui , Liang Fan , Song Xinyu , Guan Jiawei , Jia Xue , Yang Jing , Chen Qi , Yu Kang , Jia Qian , Wu Jing , Wang Depeng , Xiao Yuhui , Xu Xiaoman , Liu Yinzhe , Wu Shijing , Zhong Qin , Wu Jue , Cui Saijia , Bo Xiaochen , Wu Zhenzhou , Park Minsung , Kellis Manolis , He Kunlun 
Published: December 2023

AbstractStructural variants (SVs), accounting for a larger fraction of the genome than SNPs/InDels, are an important pool of genetic variation, enabling environmental adaptations. Here, we perform long-read sequencing data of 320 Tibetan and Han samples and show that SVs are highly involved in high-altitude adaptation. We expand the landscape of global SVs, apply robust models of selection and population differentiation combining SVs, SNPs and InDels, and use epigenomic analyses to predict enhancers, target genes and biological functions. We reveal diverse Tibetan-specific SVs affecting the regulatory circuitry of biological functions, including the hypoxia response, energy metabolism and pulmonary function. We find a Tibetan-specific deletion disrupts a super-enhancer and downregulatesEPAS1using enhancer reporter, cellular knock-out and DNA pull-down assays. Our study expands the global SV landscape, reveals the role of gene-regulatory circuitry rewiring in human adaptation, and illustrates the diverse functional roles of SVs in human biology.
Cell geometry regulates tissue fracture
Authors: Bidhendi Amir J. , Lampron Olivier , Gosselin Frédérick P. , Geitmann Anja 
Published: December 2023

AbstractIn vascular plants, the epidermal surfaces of leaves and flower petals often display cells with wavy geometries forming intricate jigsaw puzzle patterns. The prevalence and diversity of these complex epidermal patterns, originating from simple polyhedral progenitor cells, suggest adaptive significance. However, despite multiple efforts to explain the evolutionary drivers behind these geometrical features, compelling validation remains elusive. Employing a multidisciplinary approach that integrates microscopic and macroscopic fracture experiments with computational fracture mechanics, we demonstrate that wavy epidermal cells toughen the plants’ protective skin. Through a multi-scale framework, we demonstrate that this energy-efficient patterning mechanism is universally applicable for toughening biological and synthetic materials. Our findings reveal a tunable structural-mechanical strategy employed in the microscale design of plants to protect them from deleterious surface fissures while facilitating and strategically directing beneficial ones. These findings hold implications for targeted plant breeding aimed at enhancing resilience in fluctuating environmental conditions. From an engineering perspective, our work highlights the sophisticated design principles the plant kingdom offers to inspire metamaterials.
Decadal oscillation provides skillful multiyear predictions of Antarctic sea ice
Authors: Liu Yusen , Sun Cheng , Li Jianping , Kucharski Fred , Di Lorenzo Emanuele , Abid Muhammad Adnan , Li Xichen 
Published: December 2023

AbstractOver the satellite era, Antarctic sea ice exhibited an overall long-term increasing trend, contrary to the Arctic reduction under global warming. However, the drastic decline of Antarctic sea ice in 2014–2018 raises questions about its interannual and decadal-scale variabilities, which are poorly understood and predicted. Here, we identify an Antarctic sea ice decadal oscillation, exhibiting a quasi-period of 8–16 years, that is anticorrelated with the Pacific Quasi-Decadal Oscillation (r = −0.90). By combining observations, Coupled Model Intercomparison Project historical simulations, and pacemaker climate model experiments, we find evidence that the synchrony between the sea ice decadal oscillation and Pacific Quasi-Decadal Oscillation is linked to atmospheric poleward-propagating Rossby wave trains excited by heating in the central tropical Pacific. These waves weaken the Amundsen Sea Low, melting sea ice due to enhanced shortwave radiation and warm advection. A Pacific Quasi-Decadal Oscillation-based regression model shows that this tropical-polar teleconnection carries multi-year predictability.
Evolution of neuronal cell classes and types in the vertebrate retina
Authors: Hahn Joshua , Monavarfeshani Aboozar , Qiao Mu , Kao Allison H. , Kölsch Yvonne , Kumar Ayush , Kunze Vincent P. , Rasys Ashley M. , Richardson Rose , Wekselblatt Joseph B. , Baier Herwig , Lucas Robert J. , Li Wei , Meister Markus , Trachtenberg Joshua T. , Yan Wenjun , Peng Yi-Rong , Sanes Joshua R. , Shekhar Karthik 
Published: December 2023

AbstractThe basic plan of the retina is conserved across vertebrates, yet species differ profoundly in their visual needs1. Retinal cell types may have evolved to accommodate these varied needs, but this has not been systematically studied. Here we generated and integrated single-cell transcriptomic atlases of the retina from 17 species: humans, two non-human primates, four rodents, three ungulates, opossum, ferret, tree shrew, a bird, a reptile, a teleost fish and a lamprey. We found high molecular conservation of the six retinal cell classes (photoreceptors, horizontal cells, bipolar cells, amacrine cells, retinal ganglion cells (RGCs) and Müller glia), with transcriptomic variation across species related to evolutionary distance. Major subclasses were also conserved, whereas variation among cell types within classes or subclasses was more pronounced. However, an integrative analysis revealed that numerous cell types are shared across species, based on conserved gene expression programmes that are likely to trace back to an early ancestral vertebrate. The degree of variation among cell types increased from the outer retina (photoreceptors) to the inner retina (RGCs), suggesting that evolution acts preferentially to shape the retinal output. Finally, we identified rodent orthologues of midget RGCs, which comprise more than 80% of RGCs in the human retina, subserve high-acuity vision, and were previously believed to be restricted to primates2. By contrast, the mouse orthologues have large receptive fields and comprise around 2% of mouse RGCs. Projections of both primate and mouse orthologous types are overrepresented in the thalamus, which supplies the primary visual cortex. We suggest that midget RGCs are not primate innovations, but are descendants of evolutionarily ancient types that decreased in size and increased in number as primates evolved, thereby facilitating high visual acuity and increased cortical processing of visual information.
Brain-wide correspondence of neuronal epigenomics and distant projections
Authors: Zhou Jingtian , Zhang Zhuzhu , Wu May , Liu Hanqing , Pang Yan , Bartlett Anna , Peng Zihao , Ding Wubin , Rivkin Angeline , Lagos Will N. , Williams Elora , Lee Cheng-Ta , Miyazaki Paula Assakura , Aldridge Andrew , Zeng Qiurui , Salinda J. L. Angelo , Claffey Naomi , Liem Michelle , Fitzpatrick Conor , Boggeman Lara , Yao Zizhen , Smith Kimberly A. , Tasic Bosiljka , Altshul Jordan , Kenworthy Mia A. , Valadon Cynthia , Nery Joseph R. , Castanon Rosa G. , Patne Neelakshi S. , Vu Minh , Rashid Mohammad , Jacobs Matthew , Ito Tony , Osteen Julia , Emerson Nora , Lee Jasper , Cho Silvia , Rink Jon , Huang Hsiang-Hsuan , Pinto-Duartec António , Dominguez Bertha , Smith Jared B. , O’Connor Carolyn , Zeng Hongkui , Chen Shengbo , Lee Kuo-Fen , Mukamel Eran A. , Jin Xin , Margarita Behrens M. , Ecker Joseph R. , Callaway Edward M. 
Published: December 2023

AbstractSingle-cell analyses parse the brain’s billions of neurons into thousands of ‘cell-type’ clusters residing in different brain structures1. Many cell types mediate their functions through targeted long-distance projections allowing interactions between specific cell types. Here we used epi-retro-seq2 to link single-cell epigenomes and cell types to long-distance projections for 33,034 neurons dissected from 32 different regions projecting to 24 different targets (225 source-to-target combinations) across the whole mouse brain. We highlight uses of these data for interrogating principles relating projection types to transcriptomics and epigenomics, and for addressing hypotheses about cell types and connections related to genetics. We provide an overall synthesis with 926 statistical comparisons of discriminability of neurons projecting to each target for every source. We integrate this dataset into the larger BRAIN Initiative Cell Census Network atlas, composed of millions of neurons, to link projection cell types to consensus clusters. Integration with spatial transcriptomics further assigns projection-enriched clusters to smaller source regions than the original dissections. We exemplify this by presenting in-depth analyses of projection neurons from the hypothalamus, thalamus, hindbrain, amygdala and midbrain to provide insights into properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription-factor-binding motifs, and neurotransmitter use.
Indigenous Australian genomes show deep structure and rich novel variation
Authors: Silcocks Matthew , Farlow Ashley , Hermes Azure , Tsambos Georgia , Patel Hardip R. , Huebner Sharon , Baynam Gareth , Jenkins Misty R. , Vukcevic Damjan , Easteal Simon , Leslie Stephen ,   The National Centre for Indigenous Genomics, Farlow Ashley , Hermes Azure , Patel Hardip R. , Huebner Sharon , Baynam Gareth , Jenkins Misty R. , Easteal Simon , Leslie Stephen 
Published: December 2023

AbstractThe Indigenous peoples of Australia have a rich linguistic and cultural history. How this relates to genetic diversity remains largely unknown because of their limited engagement with genomic studies. Here we analyse the genomes of 159 individuals from four remote Indigenous communities, including people who speak a language (Tiwi) not from the most widespread family (Pama–Nyungan). This large collection of Indigenous Australian genomes was made possible by careful community engagement and consultation. We observe exceptionally strong population structure across Australia, driven by divergence times between communities of 26,000–35,000 years ago and long-term low but stable effective population sizes. This demographic history, including early divergence from Papua New Guinean (47,000 years ago) and Eurasian groups1, has generated the highest proportion of previously undescribed genetic variation seen outside Africa and the most extended homozygosity compared with global samples. A substantial proportion of this variation is not observed in global reference panels or clinical datasets, and variation with predicted functional consequence is more likely to be homozygous than in other populations, with consequent implications for medical genomics2. Our results show that Indigenous Australians are not a single homogeneous genetic group and their genetic relationship with the peoples of New Guinea is not uniform. These patterns imply that the full breadth of Indigenous Australian genetic diversity remains uncharacterized, potentially limiting genomic medicine and equitable healthcare for Indigenous Australians.
Inhibition of the KCa2 potassium channel in atrial fibrillation: a randomized phase 2 trial
Authors: Holst Anders G. , Tomcsányi János , Vestbjerg Birgitte , Grunnet Morten , Sørensen Ulrik S. , Diness Jonas G. , Bentzen Bo H. , Edvardsson Nils , Hohnloser Stefan H. , Bhatt Deepak L. , Dorian Paul 
Published: December 2023

AbstractExisting antiarrhythmic drugs to treat atrial fibrillation (AF) have incomplete efficacy, contraindications and adverse effects, including proarrhythmia. AP30663, an inhibitor of the KCa2 channel, has demonstrated AF efficacy in animals; however, its efficacy in humans with AF is unknown. Here we conducted a phase 2 trial in which patients with a current episode of AF lasting for 7 days or less were randomized to receive an intravenous infusion of 3 or 5 mg kg−1 AP30663 or placebo. The trial was prematurely discontinued because of slow enrollment during the coronavirus disease 2019 pandemic. The primary endpoint of the trial was cardioversion from AF to sinus rhythm within 90 min from the start of the infusion, analyzed with Bayesian statistics. Among 59 patients randomized and included in the efficacy analyses, the primary endpoint occurred in 42% (5 of 12), 55% (12 of 22) and 0% (0 of 25) of patients treated with 3 mg kg−1 AP30663, 5 mg kg−1 AP30663 or placebo, respectively. Both doses demonstrated more than 99.9% probability of superiority over placebo, surpassing the prespecified 95% threshold. The mean time to cardioversion, a secondary endpoint, was 47 (s.d. = 23) and 41 (s.d. = 24) minutes for 3 mg kg−1 and 5 mg kg−1 AP30663, respectively. AP30663 caused a transient increase in the QTcF interval, with a maximum mean effect of 37.7 ms for the 5 mg kg−1 dose. For both dose groups, no ventricular arrhythmias occurred and adverse event rates were comparable to the placebo group. AP30663 demonstrated AF cardioversion efficacy in patients with recent-onset AF episodes. KCa2 channel inhibition may be an attractive mechanism for rhythm control of AF that should be studied further in randomized trials. ClinicalTrials.gov registration: NCT04571385.
KTt-45, a T-type calcium channel blocker, acts as an anticancer agent by inducing apoptosis on HeLa cervical cancer cell line
Authors: Du Nguyen Huy , Ngoc Truong Thi Bich , Cang Huynh Qui , Luyen Nguyen Thi Thuy , Thuoc Tran Linh , Le Quan Tran , Thao Dang Thi Phuong 
Published: December 2023

AbstractThe abnormal expression in the T-type calcium channels is involved in various cancer types, thus inhibiting T-type calcium channels is one of approaches in cancer treatment. The fact that KTt-45 acted as a T-type calcium channel inhibitor as well as a pain-relief agent prompts us to address if KTt-45 plays any role against cancer cells. The results showed that KTt-45 caused cytotoxic effects towards HeLa cervical, Raji lymphoma, MCF-7 breast cancer, and A549 lung cancer cell lines with IC50 values less than 100 μM, in which highly selective toxicity was against HeLa cells (IC50 = 37.4 μM, SI > 3.2). Strikingly, the KTt-45 induced an accumulation of cytoplasmic vacuoles after 48 h treatment and mitochondrial-dependent apoptosis activation as evidenced by morphological features, chromatin condensation, nuclear fragmentation, and significant activation of caspase-9 as well as caspase-3. In conclusion, KTt-45 could inhibit cell growth and trigger mitochondrial-dependent apoptosis in HeLa cervical cancer cells. The results, taken together, strongly demonstrated that KTt-45 is a potential agent for further study on anticancer drug development which not only targets cancer cells but also helps to relieve neuropathic pain in cancer patients.
Absence of COVID-19 associated mucormycosis in a tertiary intensive care unit in the Netherlands
Authors: Schippers J. R. , Verweij P. E. , Heunks L. M. A. , van Dijk K. ,   the ArtDECO consortium, Nossent Esther J. , Duitman JanWillem , Saris Anno , De Vries Heder , Meijboom Lilian J. , Bos Lieuwe D. J. , Blok Siebe G. , Schuurman Alex R. , Reijnders Tom D. Y. , Vallejo Juan J. Garcia , Bontkes Hetty , Vlaar Alexander P. J. , Wiersinga W. Joost , Lutter René , van der Poll Tom , Bogaard Harm Jan , Heunks Leo , Zhang Shiqi , Kullberg Robert F. J. , de Brabander Justin , Boers Leonoor S. 
Published: December 2023

AbstractMucormycosis is a severe complication in critically ill COVID-19 patients. Throughout the pandemic, a notable prevalence of mucormycosis has been observed in the Indian population, whereas lower occurrences have been reported in Europe. However, limited data exist regarding its prevalence in Europe, which is potentially underestimated due to the low sensitivity of bronchoalveolar lavage (BAL) cultures. We aimed to evaluate the prevalence of mucormycosis in a high-risk critically ill COVID-19 population in the Netherlands, and to evaluate the potential benefit of adding Mucor PCR to BAL as part of routine follow-up. In this study, we included 1035 critically ill COVID-19 patients admitted to either one of the two ICUs at AmsterdamUMC between March 2020 and May 2022; of these, 374 had undergone at least one bronchoscopy. Following the AmsterdamUMC protocols, bronchoscopies were conducted weekly until clinical improvement was achieved. We cultured BAL fluid for fungi and used PCR and galactomannan testing to detect Aspergillus spp. Additionally, we retrospectively performed qPCR targeting Mucorales DNA in the BAL of 89 deceased patients. All cultures were negative for Mucorales, whereas 42 (11%) cultures were positive for Aspergillus. Furthermore, qPCR targeting Mucorales was negative in all 89 deceased patients. This study showed that pulmonary mucormycosis was not present in critically ill COVID-19 patients in two tertiary care ICUs. These results indicate routine Mucorales qPCR screening is not clinically necessary in a high-standard-of-care tertiary ICU in a low-endemic area.