bluuebunny/crossref_metadata_2025 huggingface dataset:
Elastocapillarity-driven 2D nano-switches enable zeptoliter-scale liquid encapsulation
Authors: Ronceray Nathan , Spina Massimo , Chou Vanessa Hui Yin , Lim Chwee Teck , Geim Andre K. , Garaj Slaven
Published: January 2024

Biological nanostructures change their shape and function in response to external stimuli, and significant efforts have been made to design artificial biomimicking devices operating on similar principles. In this work we demonstrate a programmable nanofluidic switch, driven by elastocapillarity, and based on nanochannels built from layered two-dimensional nanomaterials possessing atomically smooth surfaces and exceptional mechanical properties. We explore operational modes of the nanoswitch and develop a theoretical framework to explain the phenomenon. By predicting the switching-reversibility phase diagram—based on material, interfacial and wetting properties, as well as the geometry of the nanofluidic circuit—we rationally design switchable nano-capsules capable of enclosing zeptoliter volumes of liquid, as small as the volumes enclosed in viruses. The nanoswitch will find useful application as an active element in integrated nanofluidic circuitry and could be used to explore nanoconfined chemistry and biochemistry, or be incorporated into shape-programmable materials.
Covalent PARylation of DNA base excision repair proteins regulates DNA demethylation
Authors: Schwarz Simon D. , Xu Jianming , Gunasekera Kapila , Schürmann David , Vågbø Cathrine B. , Ferrari Elena , Slupphaug Geir , Hottiger Michael O. , Schär Primo , Steinacher Roland
Published: January 2024

The intracellular ATP-ribosyltransferases PARP1 and PARP2, contribute to DNA base excision repair (BER) and DNA demethylation and have been implicated in epigenetic programming in early mammalian development. Recently, proteomic analyses identified BER proteins to be covalently poly-ADP-ribosylated by PARPs. The role of this posttranslational modification in the BER process is unknown. Here, we show that PARP1 senses AP-sites and SSBs generated during TET-TDG mediated active DNA demethylation and covalently attaches PAR to each BER protein engaged. Covalent PARylation dissociates BER proteins from DNA, which accelerates the completion of the repair process. Consistently, inhibition of PARylation in mESC resulted both in reduced locus-specific TET-TDG-targeted DNA demethylation, and in reduced general repair of random DNA damage. Our findings establish a critical function of covalent protein PARylation in coordinating molecular processes associated with dynamic DNA methylation.
Unlocking regioselective meta-alkylation with epoxides and oxetanes via dynamic kinetic catalyst control
Authors: Bai Peng-Bo , Durie Alastair , Wang Gang-Wei , Larrosa Igor
Published: January 2024

Regioselective arene C−H bond alkylation is a powerful tool in synthetic chemistry, yet subject to many challenges. Herein, we report the meta-C−H bond alkylation of aromatics bearing N-directing groups using (hetero)aromatic epoxides as alkylating agents. This method results in complete regioselectivity on both the arene as well as the epoxide coupling partners, cleaving exclusively the benzylic C−O bond. Oxetanes, which are normally unreactive, also participate as alkylating reagents under the reaction conditions. Our mechanistic studies reveal an unexpected reversible epoxide ring opening process undergoing catalyst-controlled regioselection, as key for the observed high regioselectivities.
Effects of plant tissue permeability on invasion and population bottlenecks of a phytopathogen
Authors: Jiang Gaofei , Zhang Yuling , Chen Min , Ramoneda Josep , Han Liangliang , Shi Yu , Peyraud Rémi , Wang Yikui , Shi Xiaojun , Chen Xinping , Ding Wei , Jousset Alexandre , Hikichi Yasufumi , Ohnishi Kouhei , Zhao Fang-Jie , Xu Yangchun , Shen Qirong , Dini-Andreote Francisco , Zhang Yong , Wei Zhong
Published: January 2024

Pathogen genetic diversity varies in response to environmental changes. However, it remains unclear whether plant barriers to invasion could be considered a genetic bottleneck for phytopathogen populations. Here, we implement a barcoding approach to generate a pool of 90 isogenic and individually barcoded Ralstonia solanacearum strains. We used 90 of these strains to inoculate tomato plants with different degrees of physical permeability to invasion (intact roots, wounded roots and xylem inoculation) and quantify the phytopathogen population dynamics during invasion. Our results reveal that the permeability of plant roots impacts the degree of population bottleneck, genetic diversity, and composition of Ralstonia populations. We also find that selection is the main driver structuring pathogen populations when barriers to infection are less permeable, i.e., intact roots, the removal of root physical and immune barriers results in the predominance of stochasticity in population assembly. Taken together, our study suggests that plant root permeability constitutes a bottleneck for phytopathogen invasion and genetic diversity.
Mucosal TLR5 activation controls healthspan and longevity
Authors: Lim Jae Sung , Jeon Eun Jae , Go Hye Sun , Kim Hyung-Jin , Kim Kye Young , Nguyen Thi Quynh Trang , Lee Da Young , Kim Kyu Suk , Pietrocola Federico , Hong Seol Hee , Lee Shee Eun , Kim Kyoung-Shim , Park Tae-Shin , Choi Dong-Hee , Jeong Yu-Jin , Park Jong-Hwan , Kim Hyeon Sik , Min Jung-Joon , Kim Yong Sook , Park Joon Tae , Cho Jae-Ho , Lee Gil-Woo , Lee Ji Hyeon , Choy Hyon E. , Park Sang Chul , Lee Chul-Ho , Rhee Joon Haeng , Serrano Manuel , Cho Kyung A
Published: January 2024

Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.
Electronic paddle-wheels in a solid-state electrolyte
Authors: Dhattarwal Harender S. , Somni Rahul , Remsing Richard C.
Published: January 2024

Solid-state superionic conductors (SSICs) are promising alternatives to liquid electrolytes in batteries and other energy storage technologies. The rational design of SSICs and ultimately their deployment in battery technologies is hindered by the lack of a thorough understanding of their ion conduction mechanisms. In SSICs containing molecular ions, rotational dynamics couple with translational diffusion to create a paddle-wheel effect that facilitates conduction. The paddle-wheel mechanism explains many important features of molecular SSICs, but an explanation for ion conduction and anharmonic lattice dynamics in SSICs composed of monatomic ions is still needed. We predict that ion conduction in the classic SSIC AgI involves electronic paddle-wheels, rotational motion of localized electron pairs that couples to and facilitates ion diffusion. The electronic paddle-wheel mechanism creates a universal perspective for understanding ion conductivity in both monatomic and molecular SSICs that will create design principles for engineering solid-state electrolytes from the electronic level up to the macroscale.
The ALT pathway generates telomere fusions that can be detected in the blood of cancer patients
Authors: Muyas Francesc , Rodriguez Manuel José Gómez , Cascão Rita , Afonso Angela , Sauer Carolin M. , Faria Claudia C. , Cortés-Ciriano Isidro , Flores Ignacio
Published: January 2024

Telomere fusions (TFs) can trigger the accumulation of oncogenic alterations leading to malignant transformation and drug resistance. Despite their relevance in tumour evolution, our understanding of the patterns and consequences of TFs in human cancers remains limited. Here, we characterize the rates and spectrum of somatic TFs across >30 cancer types using whole-genome sequencing data. TFs are pervasive in human tumours with rates varying markedly across and within cancer types. In addition to end-to-end fusions, we find patterns of TFs that we mechanistically link to the activity of the alternative lengthening of telomeres (ALT) pathway. We show that TFs can be detected in the blood of cancer patients, which enables cancer detection with high specificity and sensitivity even for early-stage tumours and cancers of high unmet clinical need. Overall, we report a genomic footprint that enables characterization of the telomere maintenance mechanism of tumours and liquid biopsy analysis.
Non-canonical interplay between glutamatergic NMDA and dopamine receptors shapes synaptogenesis
Authors: Bénac Nathan , Ezequiel Saraceno G. , Butler Corey , Kuga Nahoko , Nishimura Yuya , Yokoi Taiki , Su Ping , Sasaki Takuya , Petit-Pedrol Mar , Galland Rémi , Studer Vincent , Liu Fang , Ikegaya Yuji , Sibarita Jean-Baptiste , Groc Laurent
Published: January 2024

Direct interactions between receptors at the neuronal surface have long been proposed to tune signaling cascades and neuronal communication in health and disease. Yet, the lack of direct investigation methods to measure, in live neurons, the interaction between different membrane receptors at the single molecule level has raised unanswered questions on the biophysical properties and biological roles of such receptor interactome. Using a multidimensional spectral single molecule-localization microscopy (MS-SMLM) approach, we monitored the interaction between two membrane receptors, i.e. glutamatergic NMDA (NMDAR) and G protein-coupled dopamine D1 (D1R) receptors. The transient interaction was randomly observed along the dendritic tree of hippocampal neurons. It was higher early in development, promoting the formation of NMDAR-D1R complexes in an mGluR5- and CK1-dependent manner, favoring NMDAR clusters and synaptogenesis in a dopamine receptor signaling-independent manner. Preventing the interaction in the neonate, and not adult, brain alters in vivo spontaneous neuronal network activity pattern in male mice. Thus, a weak and transient interaction between NMDAR and D1R plays a structural and functional role in the developing brain.
Self-assembly of the smallest and tightest molecular trefoil knot
Authors: Li Zhiwen , Zhang Jingjing , Li Gao , Puddephatt Richard J.
Published: January 2024

Molecular knots, whose synthesis presents many challenges, can play important roles in protein structure and function as well as in useful molecular materials, whose properties depend on the size of the knotted structure. Here we report the synthesis by self-assembly of molecular trefoil metallaknot with formula [Au6{1,2-C6H4(OCH2CC)2}3{Ph2P(CH2)4PPh2}3], Au6, from three units of each of the components 1,2-C6H4(OCH2CCAu)2 and Ph2P(CH2)4PPh2. Structure determination by X-ray diffraction revealed that the chiral trefoil knot contains only 54 atoms in the backbone, so that Au6 is the smallest and tightest molecular trefoil knot known to date.
Turnkey photonic flywheel in a microresonator-filtered laser
Authors: Nie Mingming , Musgrave Jonathan , Jia Kunpeng , Bartos Jan , Zhu Shining , Xie Zhenda , Huang Shu-Wei
Published: January 2024

Dissipative Kerr soliton (DKS) microcomb has emerged as an enabling technology that revolutionizes a wide range of applications in both basic science and technological innovation. Reliable turnkey operation with sub-optical-cycle and sub-femtosecond timing jitter is key to the success of many intriguing microcomb applications at the intersection of ultrafast optics and microwave electronics. Here we propose an approach and demonstrate the first turnkey Brillouin-DKS frequency comb to the best of our knowledge. Our microresonator-filtered laser design offers essential benefits, including phase insensitivity, self-healing capability, deterministic selection of the DKS state, and access to the ultralow noise comb state. The demonstrated turnkey Brillouin-DKS frequency comb achieves a fundamental comb linewidth of 100 mHz and DKS timing jitter of 1 femtosecond for averaging times up to 56 μs. The approach is universal and generalizable to various device platforms for user-friendly and field-deployable comb devices.
Chronic oxytocin administration stimulates the oxytocinergic system in children with autism
Authors: Moerkerke Matthijs , Daniels Nicky , Tibermont Laura , Tang Tiffany , Evenepoel Margaux , Van der Donck Stephanie , Debbaut Edward , Prinsen Jellina , Chubar Viktoria , Claes Stephan , Vanaudenaerde Bart , Willems Lynn , Steyaert Jean , Boets Bart , Alaerts Kaat
Published: January 2024

Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR)epigenetics (DNA-methylation), oxytocin-induced reductions inOXTRDNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reducedOXTRDNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.
Microbiome homeostasis on rice leaves is regulated by a precursor molecule of lignin biosynthesis
Authors: Su Pin , Kang Houxiang , Peng Qianze , Wicaksono Wisnu Adi , Berg Gabriele , Liu Zhuoxin , Ma Jiejia , Zhang Deyong , Cernava Tomislav , Liu Yong
Published: January 2024

In terrestrial ecosystems, plant leaves provide the largest biological habitat for highly diverse microbial communities, known as the phyllosphere microbiota. However, the underlying mechanisms of host-driven assembly of these ubiquitous communities remain largely elusive. Here, we conduct a large-scale and in-depth assessment of the rice phyllosphere microbiome aimed at identifying specific host-microbe links. A genome-wide association study reveals a strong association between the plant genotype and members of four bacterial orders, Pseudomonadales, Burkholderiales, Enterobacterales and Xanthomonadales. Some of the associations are specific to a distinct host genomic locus, pathway or even gene. The compound 4-hydroxycinnamic acid (4-HCA) is identified as the main driver for enrichment of bacteria belonging to Pseudomonadales. 4-HCA can be synthesized by the host plant’s OsPAL02 from the phenylpropanoid biosynthesis pathway. A knockout mutant of OsPAL02 results in reduced Pseudomonadales abundance, dysbiosis of the phyllosphere microbiota and consequently higher susceptibility of rice plants to disease. Our study provides a direct link between a specific plant metabolite and rice phyllosphere homeostasis opening possibilities for new breeding strategies.
STYXL1 regulates CCT complex assembly and flagellar tubulin folding in sperm formation
Authors: Chen Yu , Luo Mengjiao , Tu Haixia , Qi Yaling , Guo Yueshuai , Zhang Xiangzheng , Cui Yiqiang , Gao Mengmeng , Zhou Xin , Zhu Tianyu , Zhu Hui , Situ Chenghao , Li Yan , Guo Xuejiang
Published: January 2024

Tubulin-based microtubule is a core component of flagella axoneme and essential for sperm motility and male fertility. Structural components of the axoneme have been well explored. However, how tubulin folding is regulated in sperm flagella formation is still largely unknown. Here, we report a germ cell-specific co-factor of CCT complex, STYXL1. Deletion of Styxl1 results in male infertility and microtubule defects of sperm flagella. Proteomic analysis of Styxl1-/- sperm reveals abnormal downregulation of flagella-related proteins including tubulins. The N-terminal rhodanese-like domain of STYXL1 is important for its interactions with CCT complex subunits, CCT1, CCT6 and CCT7. Styxl1 deletion leads to defects in CCT complex assembly and tubulin polymerization. Collectively, our findings reveal the vital roles of germ cell-specific STYXL1 in CCT-facilitated tubulin folding and sperm flagella development.
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

Terahertz (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

The 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

Lipid 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

The 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

Avapritinib 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

Transmembrane 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

Controlling 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

Targeting 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

We 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

Plant-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

The 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

Transcription-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

Brief 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

For 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

Electrochemical 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

No 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.
Heparin-network-mediated long-lasting coatings on intravascular catheters for adaptive antithrombosis and antibacterial infection
Authors: Liu Lin , Yu Huan , Wang Lei , Zhou Dongfang , Duan Xiaozheng , Zhang Xu , Yin Jinghua , Luan Shifang , Shi Hengchong
Published: January 2024

Bacteria-associated infections and thrombosis, particularly catheter-related bloodstream infections and catheter-related thrombosis, are life-threatening complications. Herein, we utilize a concise assembly of heparin sodium with organosilicon quaternary ammonium surfactant to fabricate a multifunctional coating complex. In contrast to conventional one-time coatings, the complex attaches to medical devices with arbitrary shapes and compositions through a facile dipping process and further forms robust coatings to treat catheter-related bloodstream infections and thrombosis simultaneously. Through their robustness and adaptively dissociation, coatings not only exhibit good stability under extreme conditions but also significantly reduce thrombus adhesion by 60%, and shows broad-spectrum antibacterial activity ( > 97%) in vitro and in vivo. Furthermore, an ex vivo rabbit model verifies that the coated catheter has the potential to prevent catheter-related bacteremia during implantation. This substrate-independent and portable long-lasting multifunctional coating can be employed to meet the increasing clinical demands for combating catheter-related bloodstream infections and thrombosis.
Tensile straining of iridium sites in manganese oxides for proton-exchange membrane water electrolysers
Authors: Su Hui , Yang Chenyu , Liu Meihuan , Zhang Xu , Zhou Wanlin , Zhang Yuhao , Zheng Kun , Lian Shixun , Liu Qinghua
Published: January 2024

Although the acidic oxygen evolution reaction (OER) plays a crucial role in proton-exchange membrane water electrolysis (PEMWE) devices, challenges remain owing to the lack of efficient and acid-stable electrocatalysts. Herein, we present a low-iridium electrocatalyst in which tensile-strained iridium atoms are localized at manganese-oxide surface cation sites (TS-Ir/MnO2) for high and sustainable OER activity. In situ synchrotron characterizations reveal that the TS-Ir/MnO2 can trigger a continuous localized lattice oxygen-mediated (L-LOM) mechanism. In particular, the L-LOM process could substantially boost the adsorption and transformation of H2O molecules over the oxygen vacancies around the tensile-strained Ir sites and prevent further loss of lattice oxygen atoms in the inner MnO2 bulk to optimize the structural integrity of the catalyst. Importantly, the resultant PEMWE device fabricated using TS-Ir/MnO2 delivers a current density of 500 mA cm−2 and operates stably for 200 h.
A distant global control region is essential for normal expression of anterior HOXA genes during mouse and human craniofacial development
Authors: Wilderman Andrea , D’haene Eva , Baetens Machteld , Yankee Tara N. , Winchester Emma Wentworth , Glidden Nicole , Roets Ellen , Van Dorpe Jo , Janssens Sandra , Miller Danny E. , Galey Miranda , Brown Kari M. , Stottmann Rolf W. , Vergult Sarah , Weaver K. Nicole , Brugmann Samantha A. , Cox Timothy C. , Cotney Justin
Published: January 2024

Craniofacial abnormalities account for approximately one third of birth defects. The regulatory programs that build the face require precisely controlled spatiotemporal gene expression, achieved through tissue-specific enhancers. Clusters of coactivated enhancers and their target genes, known as superenhancers, are important in determining cell identity but have been largely unexplored in development. In this study we identified superenhancer regions unique to human embryonic craniofacial tissue. To demonstrate the importance of such regions in craniofacial development and disease, we focused on an ~600 kb noncoding region located between NPVF and NFE2L3. We identified long range interactions with this region in both human and mouse embryonic craniofacial tissue with the anterior portion of the HOXA gene cluster. Mice lacking this superenhancer exhibit perinatal lethality, and present with highly penetrant skull defects and orofacial clefts phenocopying Hoxa2-/- mice. Moreover, we identified two cases of de novo copy number changes of the superenhancer in humans both with severe craniofacial abnormalities. This evidence suggests we have identified a critical noncoding locus control region that specifically regulates anterior HOXA genes and copy number changes are pathogenic in human patients.
Flood exposure and pregnancy loss in 33 developing countries
Authors: He Cheng , Zhu Yixiang , Zhou Lu , Bachwenkizi Jovine , Schneider Alexandra , Chen Renjie , Kan Haidong
Published: January 2024

Floods have affected billions worldwide. Yet, the indirect health impacts of floods on vulnerable groups, particularly women in the developing world, remain underexplored. Here, we evaluated the risk of pregnancy loss for women exposed to floods. We analyzed 90,465 individual pregnancy loss records from 33 developing countries, cross-referencing each with spatial-temporal flood databases. We found that gestational flood exposure is associated with increased pregnancy loss with an odds ratio of 1.08 (95% confidence interval: 1.04 - 1.11). This risk is pronounced for women outside the peak reproductive age range (<21 or >35) or during the mid and late-stage of pregnancy. The risk escalated for women dependent on surface water, with lower income or education levels. We estimated that, over the 2010s, gestational flood events might be responsible for approximately 107,888 (CIs: 53,944 - 148,345) excess pregnancy losses annually across 33 developing countries. Notably, there is a consistent upward trend in annual excess pregnancy losses from 2010 to 2020, and was more prominent over Central America, the Caribbean, South America, and South Asia. Our findings underscore the disparities in maternal and child health aggravated by flood events in an evolving climate.