bluuebunny/crossref_metadata_2025_split huggingface dataset:
Direct and integrating sampling in terahertz receivers from wafer-scalable InAs nanowires
Authors: Peng Kun , Morgan Nicholas Paul , Wagner Ford M. , Siday Thomas , Xia Chelsea Qiushi , Dede Didem , Boureau Victor , Piazza Valerio , Fontcuberta i Morral Anna , Johnston Michael B. 
Published: January 2024

AbstractTerahertz (THz) radiation will play a pivotal role in wireless communications, sensing, spectroscopy and imaging technologies in the decades to come. THz emitters and receivers should thus be simplified in their design and miniaturized to become a commodity. In this work we demonstrate scalable photoconductive THz receivers based on horizontally-grown InAs nanowires (NWs) embedded in a bow-tie antenna that work at room temperature. The NWs provide a short photoconductivity lifetime while conserving high electron mobility. The large surface-to-volume ratio also ensures low dark current and thus low thermal noise, compared to narrow-bandgap bulk devices. By engineering the NW morphology, the NWs exhibit greatly different photoconductivity lifetimes, enabling the receivers to detect THz photons via both direct and integrating sampling modes. The broadband NW receivers are compatible with gating lasers across the entire range of telecom wavelengths (1.2–1.6 μm) and thus are ideal for inexpensive all-optical fibre-based THz time-domain spectroscopy and imaging systems. The devices are deterministically positioned by lithography and thus scalable to the wafer scale, opening the path for a new generation of commercial THz receivers.
Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells
Authors: Zhu Qiuhong , Liang Panpan , Meng Hao , Li Fangzhen , Miao Wei , Chu Cuiying , Wang Wei , Li Dongxue , Chen Cong , Shi Yu , Yu Xingjiang , Ping Yifang , Niu Chaoshi , Wu Hai-bo , Zhang Aili , Bian Xiu-wu , Zhou Wenchao 
Published: January 2024

AbstractThe peptidyl-prolyl cis-trans isomerase Pin1 is a pivotal therapeutic target in cancers, but the regulation of Pin1 protein stability is largely unknown. High Pin1 expression is associated with SUMO1-modified protein hypersumoylation in glioma stem cells (GSCs), but the underlying mechanisms remain elusive. Here we demonstrate that Pin1 is deubiquitinated and stabilized by USP34, which promotes isomerization of the sole SUMO E2 enzyme Ubc9, leading to SUMO1-modified hypersumoylation to support GSC maintenance. Pin1 interacts with USP34, a deubiquitinase with preferential expression and oncogenic function in GSCs. Such interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Disruption of USP34 or inhibition of Plk1 promotes poly-ubiquitination and degradation of Pin1. Furthermore, Pin1 isomerizes Ubc9 to upregulate Ubc9 thioester formation with SUMO1, which requires CDK1-mediated phosphorylation of Ubc9. Combined inhibition of Pin1 and CDK1 with sulfopin and RO3306 most effectively suppresses orthotopic tumor growth. Our findings provide multiple molecular targets to induce Pin1 degradation and suppress hypersumoylation for cancer treatment.
Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel
Authors: Dalal Vikram , Arcario Mark J. , Petroff John T. , Tan Brandon K. , Dietzen Noah M. , Rau Michael J. , Fitzpatrick James A. J. , Brannigan Grace , Cheng Wayland W. L. 
Published: January 2024

AbstractLipid nanodiscs have become a standard tool for studying membrane proteins, including using single particle cryo-electron microscopy (cryo-EM). We find that reconstituting the pentameric ligand-gated ion channel (pLGIC), Erwinia ligand-gated ion channel (ELIC), in different nanodiscs produces distinct structures by cryo-EM. The effect of the nanodisc on ELIC structure extends to the extracellular domain and agonist binding site. Additionally, molecular dynamic simulations indicate that nanodiscs of different size impact ELIC structure and that the nanodisc scaffold directly interacts with ELIC. These findings suggest that the nanodisc plays a crucial role in determining the structure of pLGICs, and that reconstitution of ion channels in larger nanodiscs may better approximate a lipid membrane environment.
Decoding the gene regulatory network of endosperm differentiation in maize
Authors: Yuan Yue , Huo Qiang , Zhang Ziru , Wang Qun , Wang Juanxia , Chang Shuaikang , Cai Peng , Song Karen M. , Galbraith David W. , Zhang Weixiao , Huang Long , Song Rentao , Ma Zeyang 
Published: January 2024

AbstractThe persistent cereal endosperm constitutes the majority of the grain volume. Dissecting the gene regulatory network underlying cereal endosperm development will facilitate yield and quality improvement of cereal crops. Here, we use single-cell transcriptomics to analyze the developing maize (Zea mays) endosperm during cell differentiation. After obtaining transcriptomic data from 17,022 single cells, we identify 12 cell clusters corresponding to five endosperm cell types and revealing complex transcriptional heterogeneity. We delineate the temporal gene-expression pattern from 6 to 7 days after pollination. We profile the genomic DNA-binding sites of 161 transcription factors differentially expressed between cell clusters and constructed a gene regulatory network by combining the single-cell transcriptomic data with the direct DNA-binding profiles, identifying 181 regulons containing genes encoding transcription factors along with their high-confidence targets, Furthermore, we map the regulons to endosperm cell clusters, identify cell-cluster-specific essential regulators, and experimentally validated three predicted key regulators. This study provides a framework for understanding cereal endosperm development and function at single-cell resolution.
Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Authors: Teuber A. , Schulz T. , Fletcher B. S. , Gontla R. , Mühlenberg T. , Zischinsky M.-L. , Niggenaber J. , Weisner J. , Kleinbölting S. B. , Lategahn J. , Sievers S. , Müller M. P. , Bauer S. , Rauh D. 
Published: January 2024

AbstractAvapritinib is the only potent and selective inhibitor approved for the treatment of D842V-mutant gastrointestinal stromal tumors (GIST), the most common primary mutation of the platelet-derived growth factor receptor α (PDGFRA). The approval was based on the NAVIGATOR trial, which revealed overall response rates of more than 90%. Despite this transformational activity, patients eventually progress, mostly due to acquired resistance mutations or following discontinuation due to neuro-cognitive side effects. These patients have no therapeutic alternative and face a dismal prognosis. Notable, little is known about this drug’s binding mode and its medicinal chemistry development, which is instrumental for the development of the next generation of drugs. Against this background, we solve the crystal structures of avapritinib in complex with wild-type and mutant PDGFRA and stem cell factor receptor (KIT), which provide evidence and understanding of inhibitor binding and lead to the identification of a sub-pocket (Gα-pocket). We utilize this information to design, synthesize and characterize avapritinib derivatives for the determination of key pharmacophoric features to overcome drug resistance and limit potential blood-brain barrier penetration.
Structural heterogeneity of the ion and lipid channel TMEM16F
Authors: Ye Zhongjie , Galvanetto Nicola , Puppulin Leonardo , Pifferi Simone , Flechsig Holger , Arndt Melanie , Triviño Cesar Adolfo Sánchez , Di Palma Michael , Guo Shifeng , Vogel Horst , Menini Anna , Franz Clemens M. , Torre Vincent , Marchesi Arin 
Published: January 2024

AbstractTransmembrane protein 16 F (TMEM16F) is a Ca2+-activated homodimer which functions as an ion channel and a phospholipid scramblase. Despite the availability of several TMEM16F cryogenic electron microscopy (cryo-EM) structures, the mechanism of activation and substrate translocation remains controversial, possibly due to restrictions in the accessible protein conformational space. In this study, we use atomic force microscopy under physiological conditions to reveal a range of structurally and mechanically diverse TMEM16F assemblies, characterized by variable inter-subunit dimerization interfaces and protomer orientations, which have escaped prior cryo-EM studies. Furthermore, we find that Ca2+-induced activation is associated to stepwise changes in the pore region that affect the mechanical properties of transmembrane helices TM3, TM4 and TM6. Our direct observation of membrane remodelling in response to Ca2+ binding along with additional electrophysiological analysis, relate this structural multiplicity of TMEM16F to lipid and ion permeation processes. These results thus demonstrate how conformational heterogeneity of TMEM16F directly contributes to its diverse physiological functions.
Probing the critical nucleus size in tetrahydrofuran clathrate hydrate formation using surface-anchored nanoparticles
Authors: Xue Han , Li Linhai , Wang Yiqun , Lu Youhua , Cui Kai , He Zhiyuan , Bai Guoying , Liu Jie , Zhou Xin , Wang Jianjun 
Published: January 2024

AbstractControlling the formation of clathrate hydrates is crucial for advancing hydrate-based technologies. However, the microscopic mechanism underlying clathrate hydrate formation through nucleation remains poorly elucidated. Specifically, the critical nucleus, theorized as a pivotal step in nucleation, lacks empirical validation. Here, we report uniform nanoparticles, e.g., graphene oxide (GO) nanosheets and gold or silver nanocubes with controlled sizes, as nanoprobes to experimentally measure the size of the critical nucleus of tetrahydrofuran (THF) clathrate hydrate formation. The capability of the nanoparticles in facilitating THF clathrate hydrate nucleation displays generally an abrupt change at a nanoparticle-size-determined specific supercooling. It is revealed that the free-energy barrier shows an abrupt change when the nanoparticles have an approximately the same size as that of the critical nucleus. Thus, it is inferred that THF clathrate hydrate nucleation involves the creation of a critical nucleus with its size being inversely proportional to the supercooling. By proving the existence and determining the supercooling-dependent size of the critical nucleus of the THF clathrate hydrates, this work brings insights in the microscopic pictures of the clathrate hydrate nucleation.
FOXP3+ regulatory T cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity
Authors: Liu Xinnan , Zhang Weiqi , Han Yichao , Cheng Hao , Liu Qi , Ke Shouyu , Zhu Fangming , Lu Ying , Dai Xin , Wang Chuan , Huang Gonghua , Su Bing , Zou Qiang , Li Huabing , Zhao Wenyi , Xiao Lianbo , Lu Linrong , Tong Xuemei , Pan Fan , Li Hecheng , Li Bin 
Published: January 2024

AbstractTargeting tumor-infiltrating regulatory T cells (Tregs) is an efficient way to evoke an anti-tumor immune response. However, how Tregs maintain their fragility and stability remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. On the contrary, the decreased IFITM3 expression in STAT1-deficient Tregs indicates that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of tumor-infiltrating Tregs in the tumor model. Overall, our study demonstrates that the perturbation of tumor-infiltrating Tregs through the IFNγ-IFITM3-STAT1 feedback loop is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.
Atomic-resolution structure analysis inside an adaptable porous framework
Authors: Wada Yuki , Usov Pavel M. , Chan Bun , Mukaida Makoto , Ohmori Ken , Ando Yoshio , Fuwa Haruhiko , Ohtsu Hiroyoshi , Kawano Masaki 
Published: January 2024

AbstractWe introduce a versatile metal-organic framework (MOF) for encapsulation and immobilization of various guests using highly ordered internal water network. The unique water-mediated entrapment mechanism is applied for structural elucidation of 14 bioactive compounds, including 3 natural product intermediates whose 3D structures are clarified. The single-crystal X-ray diffraction analysis reveals that incorporated guests are surrounded by hydrogen-bonded water networks inside the pores, which uniquely adapt to each molecule, providing clearly defined crystallographic sites. The calculations of host-solvent-guest structures show that the guests are primarily interacting with the MOF through weak dispersion forces. In contrast, the coordination and hydrogen bonds contribute less to the total stabilization energy, however, they provide highly directional point interactions, which help align the guests inside the pore.
Modular assembly of an artificially concise biocatalytic cascade for the manufacture of phenethylisoquinoline alkaloids
Authors: Gao Yue , Li Fei , Luo Zhengshan , Deng Zhiwei , Zhang Yan , Yuan Zhenbo , Liu Changmei , Rao Yijian 
Published: January 2024

AbstractPlant-derived alkaloids are an important class of pharmaceuticals. However, they still rely on phytoextraction to meet their diverse market demands. Since multistep biocatalytic cascades have begun to revolutionize the manufacture of natural or unnatural products, to address the synthetic challenges of alkaloids, herein we establish an artificially concise four-enzyme biocatalytic cascade with avoiding plant-derived P450 modification for synthesizing phenethylisoquinoline alkaloids (PEIAs) after enzyme discovery and enzyme engineering. Efficient biosynthesis of diverse natural and unnatural PEIAs is realized from readily available substrates. Most importantly, the scale-up preparation of the colchicine precursor (S)-autumnaline with a high titer is achieved after replacing the rate-limitingO-methylation by the plug-and-play strategy. This study not only streamlines future engineering endeavors for colchicine biosynthesis, but also provides a paradigm for constructing more artificial biocatalytic cascades for the manufacture of diverse alkaloids through synthetic biology.
Experimental determination and mathematical modeling of standard shapes of forming autophagosomes
Authors: Sakai Yuji , Takahashi Satoru , Koyama-Honda Ikuko , Saito Chieko , Mizushima Noboru 
Published: January 2024

AbstractThe formation of autophagosomes involves dynamic morphological changes of a phagophore from a flat membrane cisterna into a cup-shaped intermediate and a spherical autophagosome. However, the physical mechanism behind these morphological changes remains elusive. Here, we determine the average shapes of phagophores by statistically investigating three-dimensional electron micrographs of more than 100 phagophores. The results show that the cup-shaped structures adopt a characteristic morphology; they are longitudinally elongated, and the rim is catenoidal with an outwardly recurved shape. To understand these characteristic shapes, we establish a theoretical model of the shape of entire phagophores. The model quantitatively reproduces the average morphology and reveals that the characteristic shape of phagophores is primarily determined by the relative size of the open rim to the total surface area. These results suggest that the seemingly complex morphological changes during autophagosome formation follow a stable path determined by elastic bending energy minimization.
Primase promotes the competition between transcription and replication on the same template strand resulting in DNA damage
Authors: Zhang Weifeng , Yang Zhuo , Wang Wenjie , Sun Qianwen 
Published: January 2024

AbstractTranscription-replication conflicts (TRCs), especially Head-On TRCs (HO-TRCs) can introduce R-loops and DNA damage, however, the underlying mechanisms are still largely unclear. We previously identified a chloroplast-localized RNase H1 protein AtRNH1C that can remove R-loops and relax HO-TRCs for genome integrity. Through the mutagenesis screen, we identify a mutation in chloroplast-localized primase ATH that weakens the binding affinity of DNA template and reduces the activities of RNA primer synthesis and delivery. This slows down DNA replication, and reduces competition of transcription-replication, thus rescuing the developmental defects of atrnh1c. Strand-specific DNA damage sequencing reveals that HO-TRCs cause DNA damage at the end of the transcription unit in the lagging strand and overexpression of ATH can boost HO-TRCs and exacerbates DNA damage. Furthermore, mutation of plastid DNA polymerase Pol1A can similarly rescue the defects in atrnh1c mutants. Taken together these results illustrate a potentially conserved mechanism among organisms, of which the primase activity can promote the occurrence of transcription-replication conflicts leading to HO-TRCs and genome instability.
High throughput intracellular delivery by viscoelastic mechanoporation
Authors: Sevenler Derin , Toner Mehmet 
Published: January 2024

AbstractBrief pulses of electric field (electroporation) and/or tensile stress (mechanoporation) have been used to reversibly permeabilize the plasma membrane of mammalian cells and deliver materials to the cytosol. However, electroporation can be harmful to cells, while efficient mechanoporation strategies have not been scalable due to the use of narrow constrictions or needles which are susceptible to clogging. Here we report a high throughput approach to mechanoporation in which the plasma membrane is stretched and reversibly permeabilized by viscoelastic fluid forces within a microfluidic chip without surface contact. Biomolecules are delivered directly to the cytosol within seconds at a throughput exceeding 250 million cells per minute. Viscoelastic mechanoporation is compatible with a variety of biomolecules including proteins, RNA, and CRISPR-Cas9 ribonucleoprotein complexes, as well as a range of cell types including HEK293T cells and primary T cells. Altogether, viscoelastic mechanoporation appears feasible for contact-free permeabilization and delivery of biomolecules to mammalian cells ex vivo.
Fractional quantum ferroelectricity
Authors: Ji Junyi , Yu Guoliang , Xu Changsong , Xiang H. J. 
Published: January 2024

AbstractFor an ordinary ferroelectric, the magnitude of the spontaneous electric polarization is at least one order of magnitude smaller than that resulting from the ionic displacement of the lattice vectors, and the direction of the spontaneous electric polarization is determined by the point group of the ferroelectric. Here, we introduce a new class of ferroelectricity termed Fractional Quantum Ferroelectricity. Unlike ordinary ferroelectrics, the polarization of Fractional Quantum Ferroelectricity arises from substantial atomic displacements that are comparable to lattice constants. Applying group theory analysis, we identify 27 potential point groups that can realize Fractional Quantum Ferroelectricity, including both polar and non-polar groups. The direction of polarization in Fractional Quantum Ferroelectricity is found to always contradict with the symmetry of the “polar” phase, which violates Neumann’s principle, challenging conventional symmetry-based knowledge. Through the Fractional Quantum Ferroelectricity theory and density functional calculations, we not only explain the puzzling experimentally observed in-plane polarization of monolayer α-In2Se3, but also predict polarization in a cubic compound of AgBr. Our findings unveil a new realm of ferroelectric behavior, expanding the understanding and application of these materials beyond the limits of traditional ferroelectrics.
Spin polarized Fe1−Ti pairs for highly efficient electroreduction nitrate to ammonia
Authors: Dai Jie , Tong Yawen , Zhao Long , Hu Zhiwei , Chen Chien-Te , Kuo Chang-Yang , Zhan Guangming , Wang Jiaxian , Zou Xingyue , Zheng Qian , Hou Wei , Wang Ruizhao , Wang Kaiyuan , Zhao Rui , Gu Xiang-Kui , Yao Yancai , Zhang Lizhi 
Published: January 2024

AbstractElectrochemical nitrate reduction to ammonia offers an attractive solution to environmental sustainability and clean energy production but suffers from the sluggish *NO hydrogenation with the spin–state transitions. Herein, we report that the manipulation of oxygen vacancies can contrive spin−polarized Fe1−Ti pairs on monolithic titanium electrode that exhibits an attractive NH3 yield rate of 272,000 μg h−1 mgFe−1 and a high NH3 Faradic efficiency of 95.2% at −0.4 V vs. RHE, far superior to the counterpart with spin−depressed Fe1−Ti pairs (51000 μg h–1 mgFe–1) and the mostly reported electrocatalysts. The unpaired spin electrons of Fe and Ti atoms can effectively interact with the key intermediates, facilitating the *NO hydrogenation. Coupling a flow−through electrolyzer with a membrane-based NH3 recovery unit, the simultaneous nitrate reduction and NH3 recovery was realized. This work offers a pioneering strategy for manipulating spin polarization of electrocatalysts within pair sites for nitrate wastewater treatment.
Sequential immunotherapy and targeted therapy for metastatic BRAF V600 mutated melanoma: 4-year survival and biomarkers evaluation from the phase II SECOMBIT trial
Authors: Ascierto Paolo A. , Casula Milena , Bulgarelli Jenny , Pisano Marina , Piccinini Claudia , Piccin Luisa , Cossu Antonio , Mandalà Mario , Ferrucci Pier Francesco , Guidoboni Massimo , Rutkowski Piotr , Ferraresi Virginia , Arance Ana , Guida Michele , Maiello Evaristo , Gogas Helen , Richtig Erika , Fierro Maria Teresa , Lebbe Celeste , Helgadottir Hildur , Queirolo Paola , Spagnolo Francesco , Tucci Marco , Del Vecchio Michele , Cao Maria Gonzales , Minisini Alessandro Marco , De Placido Sabino , Sanmamed Miguel F. , Mallardo Domenico , Paone Miriam , Vitale Maria Grazia , Melero Ignacio , Grimaldi Antonio M. , Giannarelli Diana , Dummer Reinhard , Sileni Vanna Chiarion , Palmieri Giuseppe 
Published: January 2024

AbstractNo prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.