bluuebunny/crossref_metadata_2025 huggingface dataset:
Advancement in piezoelectric nanogenerators for acoustic energy harvesting
Authors: Jean Fandi , Khan Muhammad Umair , Alazzam Anas , Mohammad Baker
Published: December 2024

The demand for sustainable energy sources to power small electronics like IoT devices has led to exploring innovative solutions like acoustic energy harvesting using piezoelectric nanogenerators (PENGs). Acoustic energy harvesting leverages ambient noise, converting it into electrical energy through the piezoelectric effect, where certain materials generate an electric charge in response to mechanical stress or vibrations. This review paper provides a comprehensive analysis of the advancements in PENG technology, emphasizing their role in acoustic energy harvesting. We begin by discussing the essential principles of piezoelectricity and the design considerations for nanogenerators to optimize energy capture from sound waves. The discussion includes a detailed examination of various piezoelectric materials, such as polyvinylidene fluoride (PVDF), lead zirconate titanate (PZT), and zinc oxide (ZnO) nanowires, which are known for their superior piezoelectric properties. A critical aspect of this review is the exploration of innovative structural designs and resonance devices that enhance the efficiency of PENGs. We delve into the mechanisms and benefits of using Helmholtz resonators, quarter-wavelength tubes, and cantilever beams, which are instrumental in amplifying acoustic signals and improving energy conversion rates. Each device’s design parameters and operational principles are scrutinized to highlight their contributions to the field. The review addresses practical applications of PENGs in various domains. Environmental monitoring systems, wearable electronics, and medical devices stand to benefit significantly from the continuous and sustainable power supplied by PENGs. These applications can reduce reliance on batteries and minimize maintenance by harnessing ambient acoustic energy, leading to more efficient and longer-lasting operations. Despite the promising potential of PENGs, several challenges remain, including material degradation, efficiency limitations, and integrating these devices into existing technological frameworks. This paper discusses these obstacles in detail and proposes potential solutions to enhance the longevity and performance of PENG systems. Innovations in material science and engineering are crucial to overcoming these hurdles and realizing the full potential of acoustic energy harvesting.
PRMT5-regulated splicing of DNA repair genes drives chemoresistance in breast cancer stem cells
Authors: Gillespie Matthew S. , Chiang Kelly , Regan-Mochrie Gemma L. , Choi Soo-Youn , Ward Ciara M. , Sahay Debashish , Garcia Paloma , Arnold Roland , Davies Clare C.
Published: December 2024

Breast cancer stem cells (BCSCs) are a rare cell population that is responsible for tumour initiation, metastasis and chemoresistance. Despite this, the mechanism by which BCSCs withstand genotoxic stress is largely unknown. Here, we uncover a pivotal role for the arginine methyltransferase PRMT5 in mediating BCSC chemoresistance by modulating DNA repair efficiency. Mechanistically, we identify PRMT5 as a major regulator of DNA damage response (DDR) gene splicing in BCSCs, particularly those integral to the Fanconi Anaemia and homologous recombination pathways, with PRMT5 inhibition synergising with chemotherapy to promote BCSC apoptosis. A comparison of BCSCs and their bulk cell progeny identified some shared (ATM, DDX11, EXO1, FAN1, SLX4) but many unique (ATR, RAD17, RAD51D, RUVBL1) PRMT5-dependent alternative DDR splicing events. Surprisingly, these skipped exons and retained intron events rarely lead to substantial gene expression repression, suggesting that PRMT5 inhibition predominantly results in nuclear detention of intron-containing transcripts and the production of non-canonical isoforms with compromised protein function. Since many genes within the same DDR pathway undergo deregulated splicing, this study thus reveals additional points of vulnerability and alternative combination drug strategies that could improve the therapeutic efficacy of PRMT5 inhibitors to promote BCSC eradication.
Mitochondria-targeted oligomeric α-synuclein induces TOM40 degradation and mitochondrial dysfunction in Parkinson’s disease and parkinsonism-dementia of Guam
Authors: Vasquez Velmarini , Kodavati Manohar , Mitra Joy , Vedula Indira , Hamilton Dale J. , Garruto Ralph M. , Rao K. S. , Hegde Muralidhar L.
Published: December 2024

Mitochondrial dysfunction is a central aspect of Parkinson’s disease (PD) pathology, yet the underlying mechanisms are not fully understood. This study investigates the link between α-Synuclein (α-Syn) pathology and the loss of translocase of the outer mitochondrial membrane 40 (TOM40), unraveling its implications for mitochondrial dysfunctions in neurons. We discovered that TOM40 protein depletion occurs in the brains of patients with Guam Parkinsonism-Dementia (Guam PD) and cultured neurons expressing α-Syn proteinopathy, notably, without corresponding changes in TOM40 mRNA levels. Cultured neurons expressing α-Syn mutants, with or without a mitochondria-targeting signal (MTS) underscores the role of α-Syn’s mitochondrial localization in inducing TOM40 degradation. PDe-related etiological factors, such as 6-hydroxydopamine or ROS/metal ions stress, which promotes α-Syn oligomerization, exacerbate TOM40 depletion in PD patient-derived cells with SNCA gene triplication. Although α-Syn interacts with both TOM40 and TOM20 in the outer mitochondrial membrane, degradation is selective for TOM40, which occurs via the ubiquitin-proteasome system (UPS) pathway. Our comprehensive analyses using Seahorse technology, mitochondrial DNA sequencing, and damage assessments, demonstrate that mutant α-Syn-induced TOM40 loss results in mitochondrial dysfunction, characterized by reduced membrane potential, accumulation of mtDNA damage, deletion/insertion mutations, and altered oxygen consumption rates. Notably, ectopic supplementation of TOM40 or reducing pathological forms of α-Syn using ADP-ribosylation inhibitors ameliorate these mitochondrial defects, suggesting potential therapeutic avenues. In conclusion, our findings provide crucial mechanistic insights into how α-Syn accumulation leads to TOM40 degradation and mitochondrial dysfunction, offering insights for targeted interventions to alleviate mitochondrial defects in PD.
LINC02257 regulates malignant phenotypes of colorectal cancer via interacting with miR-1273g-3p and YB1
Authors: Park Mi-So , Jeong Seong Dong , Shin Chang Hoon , Cha Soojin , Yu Ahran , Kim Eun Ju , Gorospe Myriam , Cho Yong Beom , Won Hong-Hee , Kim Hyeon Ho
Published: December 2024

Colorectal cancer (CRC) is the third most common cancer diagnosed and the second leading cause of cancer-related deaths. Emerging evidence has indicated that long non-coding RNAs (lncRNAs) are involved in the progression of various types of cancer. In this study, we aimed to identify potential causal lncRNAs in CRC through comprehensive multilevel bioinformatics analyses, coupled with functional validation. Our bioinformatics analyses identified LINC02257 as being highly expressed in CRC, and associated with poor survival and advanced tumor stages among patients with CRC. Genome-wide association analysis revealed significant associations between variants near LINC02257 and CRC, suggesting a causal role for LINC02257 in CRC. Network analysis identified LINC02257 as playing a key role in the epithelial-mesenchymal transition pathway. Single-cell RNA sequencing showed that elevated expression of LINC02257 was associated with a reduced proportion of epithelial cells. In vitro experiments showed that LINC02257 positively regulated the metastatic and proliferative potential of CRC cells. Mechanistically, LINC02257 affected CRC malignancy by functioning as a competitive endogenous RNA of microRNAs and RNA-binding proteins. LINC02257 upregulated SERPINE1 by sequestering tumor suppressive miR-1273g-3p, thereby increasing metastatic and proliferative abilities of CRC cells. Additionally, LINC02257 directly interacted with YB1 and induced its phosphorylation, thereby facilitating YB1 nuclear translocation. The transcriptional activation of YB1 target genes was associated with the oncogenic functions of LINC02257. Taken together, our results demonstrate LINC02257 as a promising therapeutic target for CRC treatment.
NIR-715 photodynamic therapy induces immunogenic cancer cell death by enhancing the endoplasmic reticulum stress response
Authors: Zheng Zhen-Yuan , Lin Wan , Su Jia-Wan , Huang Qing-Feng , Zhang Cong , Pan Wen-Xing , Li En-Min , Zhang He-Feng , Xu Li-Yan
Published: December 2024

Effectively interfering with endoplasmic reticulum (ER) function in tumor cells and simultaneously activating an anti-tumor immune microenvironment to attack the tumor cells are promising strategies for cancer treatment. However, precise ER-stress induction is still a huge challenge. In this study, we synthesized a near-infrared (NIR) probe, NIR-715, which induces tumor cell death and inhibits tumor growth without causing apparent side effects. NIR-715 triggers severe ER stress and immunogenic cell death (ICD) after visible light exposure. NIR-715 induced ICD-associated HMGB1 release in vitro and anti-tumor immune responses, including increased cytotoxic T lymphocyte (GZMB+ CD8+ T cell) infiltration and decreased numbers of exhausted T lymphocytes (PD-L1+ CD8+ T cell). These findings suggest that NIR-715 may be a novel agent for “cold” tumor photodynamic therapy (PDT).
Epoxy metabolites of linoleic acid promote the development of breast cancer via orchestrating PLEC/NFκB1/CXCL9-mediated tumor growth and metastasis
Authors: Ni Kai-Di , Fu Xian , Luo Ying , He Xin , Yin Hou-Hua , Mo Dong-Ping , Wu Jing-Xian , Wu Ming-Jun , Zheng Xiao , Liu Ya-Nan , Jiang Qing , Zhang Ling-Tong , Lin Ai-Zhi , Huang Ling , Pan Qing-Jin , Yin Xue-Dong , Zhang Huan-Yu , Meng Yi-Wen , Zhou Xue , Pan Jianbo , Guo Zufeng , Liu Jun-Yan
Published: December 2024

Breast cancer (BC) is a common malignant tumor in women and requires a comprehensive understanding of its pathogenesis for the development of new therapeutic strategies. Polyunsaturated fatty acids (PUFAs) metabolism-driven inflammation is a causative factor in cancer development. However, the function of PUFAs′ metabolism in BC remains largely unknown. Here we report the role and underlying mechanism of epoxyoctadecenoic acids (EpOMEs), the metabolites of linoleic acid mediated by cytochrome P450 (CYP) monooxygenases, in promoting the development of BC, particularly triple-negative BC (TNBC). A metabolomics study identified that EpOMEs were significantly increased in the plasma of BC patients and MMTV-PyMT mice, which accounted for the upregulation of CYP2J2 in BC tumor tissues and tumor cells. Decreased EpOMEs by treatment of CYP monooxygenase inhibitors significantly alleviated tumor development in MMTV-PyMT mice. Treatment with EpOMEs and overexpression of CYP2J2 to increase EpOMEs in TNBC cells significantly promoted cellular proliferation, migration, tumor growth, and metastasis. Whereas knockdown of CYP2J2 to decrease EpOMEs inhibited tumorigenesis and lung metastasis of TNBC, which was reversed by EpOME administration. Transcriptomics and proteomics analyses revealed CXCL9 and PLEC were critical for EpOME-mediated promotion of TNBC. Knockdown of CXCL9 and PLEC inhibited TNBC progression and EpOME-mediated promotion of TNBC. Both overexpression of CYP2J2 and EpOME treatment upregulate PLEC, while PLEC upregulates NFκB1, which is a transcription regulator of CXCL9. This study extends the understanding of the function of PUFAs metabolism in BC development, providing potential therapeutic targets and dietary guidelines for patients with TNBC and other BCs.
TFAP2A drives non-small cell lung cancer (NSCLC) progression and resistance to targeted therapy by facilitating the ESR2-mediated MAPK pathway
Authors: Wang Ding-Guo , Gao Jian , Wang Jing , Li Kun-Chao , Wu Zhi-Bo , Liao Zhong-Min , Wu Yong-Bing
Published: December 2024

Cancer is among the leading causes of death related diseases worldwide, and lung cancer has the highest mortality rate in the world. Transcription factors (TFs) constitute a class of structurally and functionally intricate proteins. Aberrant expression or functional deficiencies of transcription factors may give rise to abnormal gene expression, contributing to various diseases, including tumours. In this study, we propose to elucidate the potential role and mechanism of TFAP2A in NSCLC. We found that TFAP2A levels were significantly greater in tumour tissues than para-tumour tissues, and high expression of TFAP2A was associated with poor prognosis in NSCLC patients. Additionally, TFAP2A overexpression promoted NSCLC progression both in vivo and in vitro. Mechanistically, ESR2 is a potential target regulated by TFAP2A and that TFAP2A can bind to the promoter region of ESR2. Furthermore, the overexpression of both TFAP2A and ESR2 in NSCLC cells was associated with the overactivation of MAPK signalling, and the combination of PHTPP and osimertinib had a synergistic effect on suppressing tumour growth.
MACC1 ablation suppresses the dedifferentiation process of non-CSCs in lung cancer through stabilizing KLF4
Authors: Li Zhuoshi , Wang Shiqing , Guo Tao , Yan Xinyi , Chen Chaoqun , Zhang Wenjing , Zhao Jinyao , Zhang Jinrui , Zhao Shilei , Wang Yang , Qi Yangfan , Gu Chundong
Published: December 2024

Metastasis-associated in colon cancer-1 (MACC1) was identified as a new player in lung cancer development, and some stemness-related genes can be novel transcriptional targets of MACC1. Cancer stem cells (CSCs) are responsible for sustaining tumorigenesis and plasticity. Both CSCs and non-CSCs are plastic and capable of undergoing phenotypic transition, especially the dedifferentiation of non-CSCs switch to CSC-like cells. However, the precise role of MACC1 during this process is largely unknown. Here, we showed that MACC1 promoted the transition from non-CSC to CSC in lung cancer. We found MACC1 was overexpressed in stemness enriched cells, enhancing the transition from no-CSCs to CSCs, while short-hairpin RNA-mediated Knockdown of MACC1 impaired this process. High-throughput sequencing and tumor specimen analysis revealed that MACC1 was negative correlated with Krüppel-like factor 4 (KLF4) expression level, which acts as a negative stemness regulator in lung cancer. Mechanistically, MACC1 delays the degradation of KLF4 mRNA by repressing the expression of microRNA-25, thereby promoting the KLF4 mRNA stabilization at the post-transcriptional level. Collectively, our findings may facilitate efforts to promote the development of precision targeted therapy for cancer stem cells in lung cancer.
Trans-differentiation of Jdp2-depleted Gaba-receptor-positive cerebellar granule cells to Purkinje cells
Authors: Ku Chia-Chen , Pan Jia-Bin , Wuputra Kenly , Hsu Wen-Li , Kato Kohsuke , Noguchi Michiya , Nakamura Yukio , Saito Shigeo , Tsai Cheng-Yu , Lin Ying-Chu , Wu Deng-Chyang , Lin Chang-Shen , Yokoyama Kazunari K.
Published: December 2024

The Jun dimerization protein (Jdp2) gene is active in mouse cerebellar granule cells and its protein product plays a crucial role in the formation of the cerebellum lobes through programmed cell death. However, the role of Jdp2 in cellular differentiation and pluripotency in the cerebellum, and the effect of the antioxidation reaction on cell plasticity, remain unknown. N-acetyl-l-cysteine (NAC) induced the early commitment of the differentiation of granule cell precursors (GCPs) to neurons, especially Purkinje cells, via the γ-aminobutyric acid type A receptor α6 subunit (Gabra6) axis; moreover, Jdp2 depletion enhanced this differentiation program of GCPs. The antioxidative effect of NAC was the main driving force of this decision toward the neural differentiation of the GCP population in the presence of Gabra6 in vitro. This implies that antioxidative drugs are effective agents for rescuing oxidative-stress-induced GCP damages in the cerebellum and commit this Gabra6-positive cell population toward differentiation into Purkinje cells.
USP39 regulates pyruvate handling in non-small cell lung cancer
Authors: Becirovic Tina , Zhang Boxi , Vakifahmetoglu-Norberg Helin , Kaminskyy Vitaliy O. , Kochetkova Elena , Norberg Erik
Published: December 2024

The ubiquitin-specific peptidase 39 (USP39) belongs to the USP family of cysteine proteases representing the largest group of human deubiquitinases (DUBs). While the oncogenic function of USP39 has been investigated in various cancer types, its roles in non-small cell lung cancer (NSCLC) remain largely unknown. Here, by applying a gene set enrichment analysis (GSEA) on lung adenocarcinoma tissues and metabolite set enrichment analysis (MSEA) on NSCLC cells depleted of USP39, we identified a previously unknown link between USP39 and the metabolism in NSCLC cells. Mechanistically, we uncovered a component of the pyruvate dehydrogenase (PDH) complex, pyruvate dehydrogenase E1 subunit alpha (PDHA), as a target of USP39. We further present that USP39 silencing caused an elevation in Lys63 ubiquitination on PDHA and a reduction in the PDH complex activity, the levels of TCA cycle intermediates, mitochondrial respiration, cell proliferation in vitro, and of tumor growth in vivo. Consistently, citrate supplementation restored mitochondrial respiration and cell growth in USP39-depleted cells. Our study elucidates and describes how USP39 regulates pyruvate metabolism through a deubiquitylation process that affects NSCLC tumor growth.
RRM1 promotes homologous recombination and radio/chemo-sensitivity via enhancing USP11 and E2F1-mediated RAD51AP1 transcription
Authors: Yang Shuai , Wang Ruru , Liu Lingling , Xu Feng , Zhao Xipeng , Yao Zhicheng , Zhang Jie , Cheng Xu , Xu An , Wu Lijun , Zhao Guoping
Published: December 2024

Ribonucleotide reductase M1 (RRM1), the catalytic subunit of ribonucleotide reductase, plays a pivotal role in converting ribonucleotides (NTP) into deoxyribonucleotides (dNTP), essential for DNA replication and repair. Elevated RRM1 expression is associated with various human cancers, correlating with poorer prognosis and reduced overall survival rates. Our previous study found that RRM1 will enter the nucleus to promote DNA damage repair. However, the underlying mechanism remains elusive. Here, we unveil a novel role of RRM1 in promoting homologous recombination (HR) by upregulating the expression of RAD51AP1, a critical HR factor, in an E2F1-dependent manner. We demonstrate that RRM1 interacts with USP11 in the cytoplasm, and the recruitment of RRM1 to LaminB1 induced by ionizing radiation (IR) facilitates the binding of USP11 to the nuclear pore complex (NPC), promoting USP11 entry into the nucleus. Upon nuclear translocation, USP11 binds to E2F1 and inhibits the ubiquitin-mediated degradation of E2F1, thereby enhancing the transcriptional expression of RAD51AP1. Moreover, a specific RRM1 mutant lacking amino acids 731–793, crucial for its interaction with USP11 and recruitment to LaminB1, exhibits a dominant-negative effect on RAD51AP1 expression and HR. Truncations of RRM1 fail to inhibit the ubiquitin-mediated degradation of E2F1 and cannot promote the E2F1-mediated transactivation of RAD51AP1. Lastly, the full length of RRM1, not truncations, enhances tumor cells’ sensitivity to IR, underscoring its importance in radiotherapy resistance. Collectively, our results suggest a novel function of RRM1 in promoting HR-mediated DSB repair through positive regulation of RAD51AP1 transcription by direct interaction with USP11 and promoting subsequent USP11-mediated deubiquitination of E2F1. Our findings elucidate a previously unknown mechanism whereby RRM1 promotes HR-mediated DNA repair, presenting a potential therapeutic target for cancer treatment.
An HuR mutant, HuR-V225I, identified in adult T-cell Leukemia/Lymphoma, alters the pro-apoptotic function of HuR
Authors: Colalillo Bianca , Sali Sujitha , Aldouhki Ali H. , Aubry Isabelle , Di Marco Sergio , Tremblay Michel L. , Gallouzi Imed E.
Published: December 2024

The RNA-binding protein HuR regulates various cellular processes, such as proliferation, differentiation, and cell fate. Moreover, recent studies have shown that HuR modulates the expression of factors important for tumor growth and progression. Despite its prominent role in tumorigenesis, until recently, there have been no reported mutations in HuR that have been associated to cancer. Here, we show that a HuR mutation, HuR-V225I, previously identified in a patient with Adult T-cell Leukemia/Lymphoma, interferes with the pro-apoptotic function of HuR. In response to apoptosis, HuR translocates to the cytoplasm and is cleaved in a caspase-dependent manner. In cervical cancer cells, neuroblastoma cells, and T-lymphocytes, we observed a decrease in cleavage of the HuR-V225I mutant under apoptotic conditions. This effect was shown to be mediated by the nuclear retention of HuR-V225I. Finally, expression of the HuR-V225I mutant decreases the cell’s response to apoptotic stimuli through the increased expression of mRNAs encoding anti-apoptotic factors, such as XIAP and BCL-2. Therefore, our data establishes that the absence of HuR cytoplasmic translocation and cleavage promotes cell viability, and that acquiring this mutation during tumorigenesis may thus reduce the efficacy of cancer therapy.
The impact of self-report inaccuracy in the UK Biobank and its interplay with selective participation
Authors: Schoeler Tabea , Pingault Jean-Baptiste , Kutalik Zoltán
Published: December 2024

Although the use of short self-report measures is common practice in biobank initiatives, such a phenotyping strategy is inherently prone to reporting errors. To explore challenges related to self-report errors, we first derived a reporting error score in the UK Biobank (UKBB; n = 73,127), capturing inconsistent self-reporting in time-invariant phenotypes across multiple measurement occasions. We then performed genome-wide scans on the reporting error score, applied downstream analyses (linkage disequilibrium score regression and Mendelian randomization) and compared its properties to the UKBB participation propensity. Finally, we improved phenotype resolution for 24 measures and inspected the changes in genomic findings. We found that reporting error was present across all 33 assessed self-report measures, with repeatability levels as low as 47% (childhood body size). Reporting error was not independent from UKBB participation, evidenced by the negative genetic correlation between the two outcomes (rg = −0.77), their shared causes (for example, education) and the loss in self-report accuracy following participation bias correction. Across all analyses, the impact of reporting error ranged from reduced power (for example, for gene discovery) to biased estimates (for example, if present in the exposure variable) and attenuation of genome-wide quantities (for example, 21% relative attenuation in SNP heritability for childhood height). Our findings highlight that both self-report accuracy and selective participation are competing biases and sources of poor reproducibility for biobank-scale research.
Determining structures of RNA conformers using AFM and deep neural networks
Authors: Degenhardt Maximilia F. S. , Degenhardt Hermann F. , Bhandari Yuba R. , Lee Yun-Tzai , Ding Jienyu , Yu Ping , Heinz William F. , Stagno Jason R. , Schwieters Charles D. , Watts Norman R. , Wingfield Paul T. , Rein Alan , Zhang Jinwei , Wang Yun-Xing
Published: December 2024

Much of the human genome is transcribed into RNAs1, many of which contain structural elements that are important for their function. Such RNA molecules—including those that are structured and well-folded2—are conformationally heterogeneous and flexible, which is a prerequisite for function3,4, but this limits the applicability of methods such as NMR, crystallography and cryo-electron microscopy for structure elucidation. Moreover, owing to the lack of a large RNA structure database, and no clear correlation between sequence and structure, approaches such as AlphaFold5 for protein structure prediction do not apply to RNA. Therefore, determining the structures of heterogeneous RNAs remains an unmet challenge. Here we report holistic RNA structure determination method using atomic force microscopy, unsupervised machine learning and deep neural networks (HORNET), a novel method for determining three-dimensional topological structures of RNA using atomic force microscopy images of individual molecules in solution. Owing to the high signal-to-noise ratio of atomic force microscopy, this method is ideal for capturing structures of large RNA molecules in distinct conformations. In addition to six benchmark cases, we demonstrate the utility of HORNET by determining multiple heterogeneous structures of RNase P RNA and the HIV-1 Rev response element (RRE) RNA. Thus, our method addresses one of the major challenges in determining heterogeneous structures of large and flexible RNA molecules, and contributes to the fundamental understanding of RNA structural biology.
A dormant overmassive black hole in the early Universe
Authors: Juodžbalis Ignas , Maiolino Roberto , Baker William M. , Tacchella Sandro , Scholtz Jan , D’Eugenio Francesco , Witstok Joris , Schneider Raffaella , Trinca Alessandro , Valiante Rosa , DeCoursey Christa , Curti Mirko , Carniani Stefano , Chevallard Jacopo , de Graaff Anna , Arribas Santiago , Bennett Jake S. , Bourne Martin A. , Bunker Andrew J. , Charlot Stéphane , Jiang Brian , Koudmani Sophie , Perna Michele , Robertson Brant , Sijacki Debora , Übler Hannah , Williams Christina C. , Willott Chris
Published: December 2024

Recent observations have found a large number of supermassive black holes already in place in the first few hundred million years after the Big Bang, many of which seem to be overmassive relative to their host galaxy stellar mass when compared with local relation1–9. Several different models have been proposed to explain these findings, ranging from heavy seeds to light seeds experiencing bursts of high accretion rate10–16. Yet, current datasets are unable to differentiate between these various scenarios. Here we report the detection, from the JADES survey, of broad Hα emission in a galaxy at z = 6.68, which traces a black hole with a mass of about 4 × 108M⊙ and accreting at a rate of only 0.02 times the Eddington limit. The black hole to host galaxy stellar mass ratio is about 0.4—that is, about 1,000 times above the local relation—whereas the system is closer to the local relations in terms of dynamical mass and velocity dispersion of the host galaxy. This object is most likely an indication of a much larger population of dormant black holes around the epoch of reionization. Its properties are consistent with scenarios in which short bursts of super-Eddington accretion have resulted in black hole overgrowth and massive gas expulsion from the accretion disk; in between bursts, black holes spend most of their life in a dormant state.
Timely TGFβ signalling inhibition induces notochord
Authors: Rito Tiago , Libby Ashley R. G. , Demuth Madeleine , Domart Marie-Charlotte , Cornwall-Scoones Jake , Briscoe James
Published: December 2024

The formation of the vertebrate body involves the coordinated production of trunk tissues from progenitors located in the posterior of the embryo. Although in vitro models using pluripotent stem cells replicate aspects of this process1–10, they lack crucial components, most notably the notochord—a defining feature of chordates that patterns surrounding tissues11. Consequently, cell types dependent on notochord signals are absent from current models of human trunk formation. Here we performed single-cell transcriptomic analysis of chick embryos to map molecularly distinct progenitor populations and their spatial organization. Guided by this map, we investigated how differentiating human pluripotent stem cells develop a stereotypical spatial organization of trunk cell types. We found that YAP inactivation in conjunction with FGF-mediated MAPK signalling facilitated WNT pathway activation and induced expression of TBXT (also known as BRA). In addition, timely inhibition of WNT-induced NODAL and BMP signalling regulated the proportions of different tissue types, including notochordal cells. This enabled us to create a three-dimensional model of human trunk development that undergoes morphogenetic movements, producing elongated structures with a notochord and ventral neural and mesodermal tissues. Our findings provide insights into the mechanisms underlying vertebrate notochord formation and establish a more comprehensive in vitro model of human trunk development. This paves the way for future studies of tissue patterning in a physiologically relevant environment.
The conformational space of RNase P RNA in solution
Authors: Lee Yun-Tzai , Degenhardt Maximilia F. S. , Skeparnias Ilias , Degenhardt Hermann F. , Bhandari Yuba R. , Yu Ping , Stagno Jason R. , Fan Lixin , Zhang Jinwei , Wang Yun-Xing
Published: December 2024

RNA conformational diversity has fundamental biological roles1–5, but direct visualization of its full conformational space in solution has not been possible using traditional biophysical techniques. Using solution atomic force microscopy, a deep neural network and statistical analyses, we show that the ribonuclease P (RNase P) RNA adopts heterogeneous conformations consisting of a conformationally invariant core and highly flexible peripheral structural elements that sample a broad conformational space, with amplitudes as large as 20–60 Å in a multitude of directions, with very low net energy cost. Increasing Mg2+ drives compaction and enhances enzymatic activity, probably by narrowing the conformational space. Moreover, analyses of the correlations and anticorrelations between spatial flexibility and sequence conservation suggest that the functional roles of both the structure and dynamics of key regions are embedded in the primary sequence. These findings reveal the structure–dynamics basis for the embodiment of both enzymatic precision and substrate promiscuity in the RNA component of the RNase P. Mapping the conformational space of the RNase P RNA demonstrates a new general approach to studying RNA structure and dynamics.
Hierarchical design of pseudosymmetric protein nanocages
Authors: Dowling Quinton M. , Park Young-Jun , Fries Chelsea N. , Gerstenmaier Neil C. , Ols Sebastian , Yang Erin C. , Wargacki Adam J. , Dosey Annie , Hsia Yang , Ravichandran Rashmi , Walkey Carl D. , Burrell Anika L. , Veesler David , Baker David , King Neil P.
Published: December 2024

Discrete protein assemblies ranging from hundreds of kilodaltons to hundreds of megadaltons in size are a ubiquitous feature of biological systems and perform highly specialized functions1,2. Despite remarkable recent progress in accurately designing new self-assembling proteins, the size and complexity of these assemblies has been limited by a reliance on strict symmetry3. Here, inspired by the pseudosymmetry observed in bacterial microcompartments and viral capsids, we developed a hierarchical computational method for designing large pseudosymmetric self-assembling protein nanomaterials. We computationally designed pseudosymmetric heterooligomeric components and used them to create discrete, cage-like protein assemblies with icosahedral symmetry containing 240, 540 and 960 subunits. At 49, 71 and 96 nm diameter, these nanocages are the largest bounded computationally designed protein assemblies generated to date. More broadly, by moving beyond strict symmetry, our work substantially broadens the variety of self-assembling protein architectures that are accessible through design.
A nearly telomere-to-telomere diploid genome assembly of Firmiana kwangsiensis, a threatened species in China
Authors: Wang Boqiang , Zhang Rengang , Sun Weibang , Yang Jing
Published: December 2024

Firmiana kwangsiensis is a tree species of high ornamental value. The species is critically endangered in the wild, and is listed as a first-class national protected wild plant in China, and a Plant Species with Extremely Small Populations in need of urgent protection. We have assembled a chromosome-scale, haplotype-resolved genome for F. kwangsiensis using a combination of PacBio HiFi sequencing, ONT sequencing, and Hi-C sequencing. The final assembled genome is 2.3 G in size and comprises 2n = 40 chromosomes. All chromosomal ends contain telomeric characteristic motifs (TTTAGGG), and there are only 2 gaps within the rDNA regions, both close to a T2T genome assembly. Two complete sets of haplotypes are present, Haplotype A (1169.19 Mb) and Haplotype B (1157.87 Mb), with contig N50 lengths of 58.37 Mb and 57.27 Mb, respectively. The genome contains a total of 67,527 coding genes, with 62,351 genes functionally annotated here. This is the first report of the genome of F. kwangsiensis, and lays the foundation for future conservation genomics research into this species.
A biomathematical model of SARS-CoV-2 in Syrian hamsters
Authors: Schirm Sibylle , Nouailles Geraldine , Kirsten Holger , Trimpert Jakob , Wyler Emanuel , Teixeira Alves Luiz Gustavo , Landthaler Markus , Ahnert Peter , Suttorp Norbert , Witzenrath Martin , Scholz Markus
Published: December 2024

When infected with SARS-CoV-2, Syrian hamsters (Mesocricetus auratus) develop moderate disease severity presenting key features of human COVID-19. We here develop a biomathematical model of the disease course by translating known biological mechanisms of virus-host interactions and immune responses into ordinary differential equations. We explicitly describe the dynamics of virus population, affected alveolar epithelial cells, and involved relevant immune cells comprising for example CD4+ T cells, CD8+ T cells, macrophages, natural killer cells and B cells. We also describe the humoral response dynamics of neutralising antibodies and major regulatory cytokines including CCL8 and CXCL10. The model is developed and parametrized based on experimental data collected at days 2, 3, 5, and 14 post infection. Pulmonary cell composition and their transcriptional profiles were obtained by lung single-cell RNA (scRNA) sequencing analysis. Parametrization of the model resulted in a good agreement of model and data. The model can be used to predict, for example, the time course of the virus population, immune cell dynamics, antibody production and regeneration of alveolar cells for different therapy scenarios or after multiple-infection events. We aim to translate this model to the human situation in the future.
Estimation of minimal data sets sizes for machine learning predictions in digital mental health interventions
Authors: Zantvoort Kirsten , Nacke Barbara , Görlich Dennis , Hornstein Silvan , Jacobi Corinna , Funk Burkhardt
Published: December 2024

Artificial intelligence promises to revolutionize mental health care, but small dataset sizes and lack of robust methods raise concerns about result generalizability. To provide insights on minimal necessary data set sizes, we explore domain-specific learning curves for digital intervention dropout predictions based on 3654 users from a single study (ISRCTN13716228, 26/02/2016). Prediction performance is analyzed based on dataset size (N = 100–3654), feature groups (F = 2–129), and algorithm choice (from Naive Bayes to Neural Networks). The results substantiate the concern that small datasets (N ≤ 300) overestimate predictive power. For uninformative feature groups, in-sample prediction performance was negatively correlated with dataset size. Sophisticated models overfitted in small datasets but maximized holdout test results in larger datasets. While N = 500 mitigated overfitting, performance did not converge until N = 750–1500. Consequently, we propose minimum dataset sizes of N = 500–1000. As such, this study offers an empirical reference for researchers designing or interpreting AI studies on Digital Mental Health Intervention data.
SurgeryLLM: a retrieval-augmented generation large language model framework for surgical decision support and workflow enhancement
Authors: Ong Chin Siang , Obey Nicholas T. , Zheng Yanan , Cohan Arman , Schneider Eric B.
Published: December 2024

SurgeryLLM, a large language model framework using Retrieval Augmented Generation demonstrably incorporated domain-specific knowledge from current evidence-based surgical guidelines when presented with patient-specific data. The successful incorporation of guideline-based information represents a substantial step toward enabling greater surgeon efficiency, improving patient safety, and optimizing surgical outcomes.
Machine-learning-enhanced automatic spectral characterization of x-ray pulses from a free-electron laser
Authors: Ferreira de Lima Danilo Enoque , Davtyan Arman , Laksman Joakim , Gerasimova Natalia , Maltezopoulos Theophilos , Liu Jia , Schmidt Philipp , Michelat Thomas , Mazza Tommaso , Meyer Michael , Grünert Jan , Gelisio Luca
Published: December 2024

A reliable characterization of x-ray pulses is critical to optimally exploit advanced photon sources, such as free-electron lasers. In this paper, we present a method based on machine learning, the virtual spectrometer, that improves the resolution of non-invasive spectral diagnostics at the European XFEL by up to 40%, and significantly increases its signal-to-noise ratio. This improves the reliability of quasi-real-time monitoring, which is critical to steer the experiment, as well as the interpretation of experimental outcomes. Furthermore, the virtual spectrometer streamlines and automates the calibration of the spectral diagnostic device, which is otherwise a complex and time-consuming task, by virtue of its underlying detection principles. Additionally, the provision of robust quality metrics and uncertainties enable a transparent and reliable validation of the tool during its operation. A complete characterization of the virtual spectrometer under a diverse set of experimental and simulated conditions is provided in the manuscript, detailing advantages and limits, as well as its robustness with respect to the different test cases.
Climate change exacerbates compound flooding from recent tropical cyclones
Authors: Grimley L. E. , Hollinger Beatty K. E. , Sebastian A. , Bunya S. , Lackmann G. M.
Published: December 2024

Tropical cyclones (TCs) generate substantial damage raising concerns about how climate change may amplify their impacts. However, linking changes in TC characteristics (wind, precipitation) to shifts in flood hazards and exposure, particularly due to the interaction of multiple drivers, is challenging. In this study, we use highly resolved physics-based models to investigate how flooding from three recent TCs in North and South Carolina would change under 4 degrees Celsius of warming. Runoff processes are the largest contributor to the total flood extent in both the present and future. However, the relative contribution of compound processes increases in the future, expanding upriver and beyond the floodplain where runoff processes previously occurred in isolation. The total area exposed to compound flooding increases by 65% and flood depths in these areas increase by 0.8 m highlighting the importance of simulating compound processes in TC flood exposure assessment.
Salmonella Typhimurium effector SseI regulates host peroxisomal dynamics to acquire lysosomal cholesterol
Authors: Raj Desh , Nair Abhilash Vijay , Singh Anmol , Basu Swarnali , Sarkar Kabita , Sharma Jyotsna , Sharma Shiva , Sharma Sanmi , Rathore Manisha , Singh Shriya , Prakash Shakti , Simran  , Sahu Shikha , Kaushik Aman Chandra , Siddiqi Mohammad Imran , Ghoshal Uday C , Chandra Tulika , Bhosale Vivek , Dasgupta Arunava , Gupta Shashi Kumar , Verma Sonia , Guha Rajdeep , Chakravortty Dipshikha , Ammanathan Veena , Lahiri Amit
Published: December 2024

Salmonella enterica serotype Typhimurium (Salmonella) resides and multiplies intracellularly in cholesterol-rich compartments called Salmonella-containing vacuoles (SCVs) with actin-rich tubular extensions known as Salmonella-induced filaments (SIFs). SCV maturation depends on host-derived cholesterol, but the transport mechanism of low-density lipoprotein (LDL)-derived cholesterol to SCVs remains unclear. Here we find that peroxisomes are recruited to SCVs and function as pro-bacterial organelle. The Salmonella effector protein SseI is required for the interaction between peroxisomes and the SCV. SseI contains a variant of the PTS1 peroxisome-targeting sequence, GKM, localizes to the peroxisomes and activates the host Ras GTPase, ADP-ribosylation factor-1 (ARF-1). Activation of ARF-1 leads to the recruitment of phosphatidylinsolitol-5-phosphate-4 kinase and the generation of phosphatidylinsolitol-4-5-bisphosphate on peroxisomes. This enhances the interaction of peroxisomes with lysosomes and allows for the transfer of lysosomal cholesterol to SCVs using peroxisomes as a bridge. Salmonella infection of peroxisome-depleted cells leads to the depletion of cholesterol on the SCVs, resulting in reduced SIF formation and bacterial proliferation. Taken together, our work identified peroxisomes as a target of Salmonella secretory effectors, and as conveyance of host cholesterol to enhance SCV stability, SIF integrity, and intracellular bacterial growth.
Polymer-based Nanovesicles
Authors: Ceylan S. Ercelen , Bulkurcuoğlu B. , Zaichenko O. , Mitina N. , Harhay Kh. , Finiuk N. , Garamus V.M.
Published: December 2024

Polymer-based nanovesicles are nanosized structures loaded with active pharmaceutical compounds entrapped within, or surface-adsorbed onto, the polymeric core for diagnostic and/or therapeutic purposes. The physicochemical properties of polymeric nanovesicles greatly impact their bioavailability, biocompatibility, biodistribution, and biosafety. In this chapter recent advances in characterization methods of polymeric nanovesicles are discussed.
Metal-based Nanocarriers
Authors: Efthimiadou Eleni K. , Prokopiou Danai , Stavropoulou Anastasia , Papadopoulou Athina , Nikolopoulou Sofia , Tsitsou Evangelia , Theodosiou Maria
Published: December 2024

Metal-based nanocarriers offer a vast spectrum of properties that have revolutionized and extended conventional biomedical therapeutic and imaging approaches. This chapter aims at outlining the framework of metallic nanocarrier systems from synthetic conceptualization and property evaluation to medical implementation. Metal nanocarriers are classified by composition and discussed in groups based on their distinctive properties: localized surface plasmon resonance, superparamagnetism, fluorescence, and photocatalysis. The formation mechanism of metallic nanoparticles and quantum dots is thoroughly discussed, focusing on the wet-chemical approach, followed by the main synthetic strategies to produce and functionalize different types of metal nanocarriers. The characterization methods for each type of metallic nanocarrier are reviewed based on their physicochemical and structural profile. The chapter concludes with their present and prospective therapeutic biomedical applications in cancer, infections, and autoimmune diseases.
Targeted Nanocarriers
Authors: Yalcinkaya D. B. , Dogan S. , Ozalp V. C. , Guvenc Tuna B.
Published: December 2024

This chapter provides an overview of targeted nanocarriers in medicine, discussing their significant advancement in drug delivery and focusing on the general characterization methods. Nanocarriers significantly enhance drug delivery efficacy and specificity, addressing the limitations of traditional methods. These carriers are designed to transport therapeutic agents efficiently to targeted sites, with modifications allowing for ligand attachment and the incorporation of various molecules. A key challenge in drug delivery, the rapid fluctuation of drug concentration in the bloodstream, is addressed by advanced drug delivery systems that maintain therapeutic levels over extended periods. Techniques like surface plasmon resonance, nanoparticle tracking analysis, and various assays for encapsulation efficiency and release of loaded materials are covered. These methods are crucial for optimizing nanocarrier design and assessing their efficacy and safety in drug delivery and diagnostic applications. In vitro and in vivo approaches for the assessment of nanocarriers are detailed. In vitro methods include cellular uptake and viability studies, while in vivo techniques involve imaging and biochemical analysis to understand the behavior, efficacy, and safety of nanocarriers in living organisms. This chapter highlights the diverse applications of nanocarriers in medical research and their potential in future markets while outlining the various methods used to characterize and evaluate these systems.
Computational photochemistry: advances in 2022–2023
Authors: Navarrete-Miguel M. , Cuéllar-Zuquin J. , Carmona-García J. , Abdelgawwad A. M. A. , Soriano-Díaz I. , Roldao J. C. , Halder D. , Borrego-Sánchez A. , Francés-Monerris A. , Giussani A. , Segarra-Martí J. , Roca-Sanjuán D.
Published: December 2024

Computational photochemistry provides a description of light-induced chemical phenomena reaching the molecular size-scale and femtosecond time-scale resolutions. In the period 2022–2023, we can find a significant increase in the use of tools of computational photochemistry in materials science, as compared to previous years, maintaining the relative number of works in the areas of biology, medicine, nanotechnology and atmospheric chemistry. To illustrate such advances in this field, we have chosen here representative applied studies focused on the non-radiative decay paths of DNA nucleobases, the photoreductive repair of thymine dimers, photosensitisers generating singlet oxygen and oxygen-independent photoactivated therapies, conjugated organic oligomers of interest in optoelectronic devices, ionic transition metal complexes for light emitting electrochemical cells, and sulphur chemistry in planetary atmospheres. On this occasion, we also describe the new features implemented in one of the quantum-chemistry packages of software specialised in photochemistry, the OpenMolcas program.
Organic aspects: photochemistry of alkenes, dienes and polyenes (2022–2023)
Authors: Tsuno Takashi
Published: December 2024

This chapter deals with the photochemistry of the title compounds including photocatalytic modification of alkenes, dienes and polyenes through a selection of the literature published during the period January 2022–December 2023. This chapter also covers nanotechnology and supramolecular chemistry utilizing isomerization/electrocyclization/cycloaddition reactions.
An Introduction to Solid-state NMR and Potential Applications for MOFs and COFs
Authors: Wang Zhi-Peng , Wei Cao , Lucier Bryan E. G. , Xue Jia-Peng , Chen Shoushun , Wang Wei
Published: December 2024

Metal–organic frameworks (MOFs) and covalent-organic frameworks (COFs) are materials typically featuring ordered long-range structures and permanent porosities, which have many promising potential applications. Solid state nuclear magnetic resonance (SSNMR) provides rich molecular-level information that is exceptionally useful for the structural characterization of MOFs and COFs. In this chapter, we summarize the history of MOFs and COFs, provide a general background of NMR concepts and describe some typical SSNMR experimental approaches. The three primary types of structural information obtainable from MOFs and COFs using SSNMR spectroscopy are then detailed, and the chapter concludes with an outline of key points presented in the remainder of this book.
Infrared imaging with visible light in microfluidic devices: the water absorption barrier
Authors: Suryana Mona , Produit Thomas , Yang Hongzhi , Birarda Giovanni , Shanmugar Jegan Vishnuwardhana , Krivitsky Leonid , Paterova Anna , Grenci Gianluca
Published: December 2024

We assess the ability of a novel quantum IR-imaging method to see through thick layers of water in microfluidic devices.
Light-activated nanocomposite thin sheet for high throughput contactless biomolecular delivery into hard-to-transfect cells
Authors: Padma Hima Harshan , Dominic Donia , Illath Kavitha , Kar Srabani , Santra Tuhin Subhra
Published: December 2024

Light-activated, contactless, high throughput photoporation platform for highly efficient intracellular biomolecule delivery.