bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Freeze‐Thaw Deformation Responses to the 2018 and 2019 Fires Near Batagaika Megaslump, Northeast Siberia
Authors: Yanagiya K. , Furuya M. , Danilov P. , Iwahana G.
Published: February 2023

Wildfires in Arctic regions impact landforms via permafrost degradation and subsequent deformation that can last for many years. However, it remains uncertain on if and how much deformations occur, and what controls their magnitude, particularly during the first couple of years. Here, we examine the transient post‐fire deformation responses near the Batagaika megaslump, which is the world's largest retrogressive thaw slump at Batagay, Sakha Republic. There were wildfires in the summers of 2018 and 2019 on the same slope, which could trigger the formation of another megaslump; many fires occurred nearby in 2019. We use interferometric synthetic aperture radar (InSAR) to measure surface displacements, including both post‐fire and span‐fire images. We also perform onsite measurements of temperature and thaw depth around the two scars near Batagaika megaslump in 2019, 2020, and 2021 and around the 2014 scar in 2019. At the three fire scars formed in 2018 and 2019, we demonstrate year‐to‐year and location‐specific changes in the amplitude of subsidence, heave, and duration. The 2018 scar shows cumulative subsidences of up to 10 cm by March 2021, more clearly than the nearby 2019 scar. On the other hand, another 2019 scar adjacent to the 2014 scar shows up to 13 cm net subsidence during the first span‐fire year, although the subsiding area is limited. These diverse transient post‐fire responses demonstrate that under the yedoma area the spatial heterogeneities of the active layer depth and the timing of fires will control subsequent thermokarst processes.
Self‐Regulation Mechanisms in Porous Media: The Origin of the Diversity of Fluid Displacement Patterns
Authors: Guo Xiaokang , Liu Runcong , Wang Xiaodong
Published: February 2023

During two‐phase fluid displacement in a porous medium, self‐regulation mechanisms provide negative feedback to approach a state of minimum operating power. The versatility of these self‐regulation mechanisms results in a large diversity of fluid displacement patterns. For example, the introduction of a highly tortuous displacement channel, the appearance of the retention and development regions of the displaced phase, and the expansion of the displacement path area of the invading phase are the macroscopic responses of the two‐phase flow system to the self‐regulation mechanisms under different constraints. These new findings provide compelling physical explanations for the underlying mechanisms governing fluid displacement pattern transitions and the influence of inertial effects on the displacement patterns.
Solute Trapping and the Mechanisms of Non‐Fickian Transport in Partially Saturated Porous Media
Authors: Ben‐Noah Ilan , Hidalgo Juan J. , Jimenez‐Martinez Joaquin , Dentz Marco
Published: February 2023

We study the upscaling of pore‐scale solute transport in partially saturated porous media at different saturation degrees. The interaction between structural heterogeneity, phases distribution and small‐scale flow dynamics induces complex flow patterns and broad probability distributions of flow, which control key aspects of transport, such as residence and arrival times, dispersion, and spatial solute distributions, as well as chemical reactions. A continuous‐time random walk (CTRW) framework that integrates the processes of advection, diffusion, and trapping in immobile zones is used to upscale and evaluate the transport of diluted solutes. Results of this model were compared to direct numerical simulations solving the advection‐diffusion equation in experimental saturation patterns. The comparison between simulations results, with different Péclet numbers (Pe), and the physics‐based upscaled CTRW approach allows for a quantitative analysis of the governing factors of transport in partially saturated porous media. This analysis shows that the fluid phase saturation decreases the advective tortuosity, the media's characteristic length, the fraction of the immobile region, and the mean trapping time. At the same time, for a given saturation degree, the normalized mean trapping time is proportional to the Pe. This suggests that the characteristic trapping length is proportional to the media's characteristic (correlation) length. Moreover, the trapping frequency decreases with increasing Pe.
Centuries-Old Archive Reveals Far-Flung Impacts of Major Eruptions
Authors: Banks Shannon
Published: February 2023

Weather records preserved by staff and students at Williams College reveal cool spells in New England after volcanic blasts in Indonesia and South Asia.
Activation of GABAB receptors in central amygdala attenuates activity of PKCδ + neurons and suppresses punishment-resistant alcohol self-administration in rats
Authors: Domi Esi , Xu Li , Toivainen Sanne , Wiskerke Joost , Coppola Andrea , Holm Lovisa , Augier Eric , Petrella Michele , Heilig Markus
Published: February 2023

Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKCδ + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABABreceptors in CeA can attenuate the activity of PKCδ + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABABagonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 µl/side) reduced the activity of PKCδ + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKCδ + neurons express the GABABreceptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABABreceptors, and that lack these limitations, such as e.g., GABABpositive allosteric modulators (PAM:s).
Transgenic IDH2R172K and IDH2R140Q zebrafish models recapitulated features of human acute myeloid leukemia
Authors: Wang Dandan , Zheng Lichuan , Cheng Bowie Yik Ling , Sin Chun-Fung , Li Runsheng , Tsui Sze Pui , Yi Xinyu , Ma Alvin Chun Hang , He Bai Liang , Leung Anskar Yu Hung , Sun Xuan
Published: February 2023

Isocitrate dehydrogenase 2 (IDH2) mutations occur in more than 15% of cytogenetically normal acute myeloid leukemia (CN-AML) but comparative studies of their roles in leukemogenesis have been scarce. We generated zebrafish models ofIDH2R172KandIDH2R140QAML and reported their pathologic, functional and transcriptomic features and therapeutic responses to target therapies. Transgenic embryos co-expressingFLT3ITDandIDH2mutations showed accentuation of myelopoiesis. As these embryos were raised to adulthood, full-blown leukemia ensued with multi-lineage dysplasia, increase in myeloblasts and marrow cellularity and splenomegaly. The leukemia cells were transplantable into primary and secondary recipients and resulted in more aggressive disease. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in T-cell development at embryonic and adult stages. Single-cell transcriptomic analysis revealed increased myeloid skewing, differentiation blockade and enrichment of leukemia-associated gene signatures in both zebrafish models. Tg(Runx1:FLT3ITDIDH2R172K) but not Tg(Runx1:FLT3ITDIDH2R140Q) zebrafish showed an increase in interferon signals at the adult stage. Leukemic phenotypes in both zebrafish could be ameliorated by quizartinib and enasidenib. In conclusion, the zebrafish models ofIDH2mutated AML recapitulated the morphologic, clinical, functional and transcriptomic characteristics of human diseases, and provided the prototype for developing zebrafish leukemia models of other genotypes that would become a platform for high throughput drug screening.
The anti-cancer agent APR-246 can activate several programmed cell death processes to kill malignant cells
Authors: Wang Zilu , Hu Huimin , Heitink Luuk , Rogers Kelly , You Yue , Tan Tao , Suen Connie Li Wai , Garnham Alex , Chen Hao , Lieschke Elizabeth , Diepstraten Sarah T. , Chang Catherine , Chen Tianwei , Moujalled Diane , Sutherland Kate , Lessene Guillaume , Sieber Oliver M. , Visvader Jane , Kelly Gemma L. , Strasser Andreas
Published: February 2023

Mutant TP53 proteins are thought to drive the development and sustained expansion of cancers at least in part through the loss of the wild-type (wt) TP53 tumour suppressive functions. Therefore, compounds that can restore wt TP53 functions in mutant TP53 proteins are expected to inhibit the expansion of tumours expressing mutant TP53. APR-246 has been reported to exert such effects in malignant cells and is currently undergoing clinical trials in several cancer types. However, there is evidence that APR-246 may also kill malignant cells that do not express mutant TP53. To support the clinical development of APR-246 it is important to understand its mechanism(s) of action. By establishing isogenic background tumour cell lines with different TP53/TRP53 states, we found that APR-246 can kill malignant cells irrespective of their TP53/TRP53 status. Accordingly, RNAseq analysis revealed that treatment with APR-246 induces expression of the same gene set in Eμ-Myc mouse lymphoma cells of all four possible TRP53 states, wt, wt alongside mutant, knockout and knockout alongside mutant. We found that depending on the type of cancer cell and the concentration of APR-246 used, this compound can kill malignant cells through induction of various programmed cell death pathways, including apoptosis, necroptosis and ferroptosis. The sensitivity of non-transformed cells to APR-246 also depended on the cell type. These findings reveal that the clinical testing of APR-246 should not be limited to cancers expressing mutant TP53 but expanded to cancers that express wt TP53 or are TP53-deficient.
VHL-HIF-2α axis-induced SEMA6A upregulation stabilized β-catenin to drive clear cell renal cell carcinoma progression
Authors: Ji Jing , Xu Yuxin , Xie Mengru , He Xingbei , Ren Dexu , Qiu Teng , Liu Wenwen , Chen Zefeng , Shi Wen , Zhang Zhen , Wang Xiujun , Wang Weiling , Ma Jinming , Qian Qilan , Jing Aixin , Ma Xinhui , Qin Jingting , Ding Yuanyuan , Geng Ting , Yang Jiayan , Sun Zhichao , Liu Wei , Liu Shunfang , Liu Bin
Published: February 2023

SEMA6Ais a multifunctional transmembrane semaphorin protein that participates in various cellular processes, including axon guidance, cell migration, and cancer progression. However, the role ofSEMA6Ain clear cell renal cell carcinoma (ccRCC) is unclear. Based on high-throughput sequencing data, here we report thatSEMA6Ais a novel target gene of theVHL-HIF-2αaxis and overexpressed in ccRCC. Chromatin immunoprecipitation and reporter assays revealed thatHIF-2αdirectly activatedSEMA6Atranscription in hypoxic ccRCC cells.Wnt/β-catenin pathway activation is correlated with the expression ofSEMA6Ain ccRCC; the latter physically interacted withSEC62and promoted ccRCC progression throughSEC62-dependent β-catenin stabilization and activation. Depletion ofSEMA6AimpairedHIF-2α-inducedWnt/β-catenin pathway activation and led to defective ccRCC cell proliferation both in vitro and in vivo.SEMA6Aoverexpression promoted the malignant phenotypes of ccRCC, which was reversed bySEC62depletion. Collectively, this study revealed a potential role forVHL-HIF-2α-SEMA6A-SEC62axis in the activation ofWnt/β-catenin pathway. Thus,SEMA6Amay act as a potential therapeutic target, especially inVHL-deficient ccRCC.
NSUN2 alleviates doxorubicin-induced myocardial injury through Nrf2-mediated antioxidant stress
Authors: Wang Yi , Zan Yuxin , Huang Yingying , Peng Xiaoyun , Ma Shinan , Ren Ji , Li Xiao , Wei Lin , Wang Xiaoli , Yuan Yahong , Tang Junming , Zhan Zhongqun , Wang Zhixiao , Ding Yan
Published: February 2023

Doxorubicin (DOX) is a commonly used antitumor drug, but its application has been limited because of its strong cardiac damage. This study aims to explore the role of NSUN2 in DOX-induced heart injury. C57BL/6J mice were intraperitoneally injected with 20 mg/Kg DOX to induce heart injury. After 3 days, the cardiac function, cardiac histopathology, myocardial apoptosis, and the expression level of NSUN2 were detected. In vitro, H9C2 cells were transfected with NSUN2 siRNA or overexpressed lentivirus and then treated with 500 ng/ml DOX. After 24 h, the changes in reactive oxygen species (ROS), apoptosis, and NSUN2 expression were detected. After DOX treatment, both in vitro and in vivo experiments showed that the cardiac function decreased, the number of apoptotic cells increased, and the expression level of NSUN2 increased. Interfering the expression of NSUN2 by siRNA promoted DOX-induced heart injury, while overexpression of NSUN2 could inhibit DOX-induced heart injury. Further study showed that NSUN2 promoted antioxidative stress by upregulating the Nrf2 protein level. In addition, NSUN2 overexpression could increase the half-life of Nrf2 mRNA. m5C RNA methylation immunoprecipitation (MeRIP) also showed that the level of Nrf2 m5C mRNA was significantly increased in NSUN2 overexpressed group when compared to the GFP group. NSUN2 enhances the expression of Nrf2 by promoting Nrf2 mRNA m5C modification and enhances its antioxidative stress effect to alleviate DOX-induced myocardial injury.
The GSK3β/Mcl-1 axis is regulated by both FLT3-ITD and Axl and determines the apoptosis induction abilities of FLT3-ITD inhibitors
Authors: Qiu Yang , Li Ying , Chai Meng , Hua Huiming , Wang Rui , Waxman Samuel , Jing Yongkui
Published: February 2023

Acute myeloid leukemia (AML) patients with FLT3-ITD mutations are associated with poor prognosis. FLT3-ITD inhibitors are developed and result in transient disease remission, but generally resistance develops. We propose that resistance occurs due to apoptosis evasion. We compared the abilities of five clinically used FLT3-ITD inhibitors, namely, midostaurin, crenolanib, gilteritinib, quizartinib, and sorafenib, to induce apoptosis. These drugs inhibit FLT3-ITD and induce apoptosis. Apoptosis induction is associated with GSK3β activation, Mcl-1 downregulation, and Bim upregulation. Sorafenib-resistant MOLM-13/sor cells have the secondary D835Y mutation and increased Axl signaling pathway with cross-resistance to quizartinib. Gilteritinib and crenolanib inhibit both FLT3-ITD and Axl and induce apoptosis in MOLM-13/sor cells, in which they activate GSK3β and downregulate Mcl-1. Inactivation of GSK3β through phosphorylation and inhibitors blocks apoptosis and Mcl-1 reduction. The Axl/GSK3β/Mcl-1 axis works as a feedback mechanism to attenuate apoptosis of FLT3-ITD inhibition. Homoharringtonine decreases the protein levels of Mcl-1, FLT3-ITD, and Axl. Moreover, it synergistically induces apoptosis with gilteritinib in vitro and prolongs survival of MOLM-13/sor xenografts. The GSK3β/Mcl-1 axis works as the hub of FLT3-ITD inhibitors and plays a critical role in resistance against FLT3-ITD AML-targeted therapy.
MiR-7-5p/KLF4 signaling inhibits stemness and radioresistance in colorectal cancer
Authors: Shang Yuanyuan , Zhu Zhe , Zhang Yuanyuan , Ji Fang , Zhu Lian , Liu Mengcheng , Deng Yewei , Lv Guifen , Li Dan , Zhou Zhuqing , Lu Bing , Fu Chuan-gang
Published: February 2023

Resistance to radiotherapy remains a major unmet clinical obstacle in the treatment of locally advanced rectal cancer. Cancer stem cells (CSCs) are considered to mediate tumor development and radioresistance. However, the role of CSCs in regulating resistance to radiotherapy in colorectal cancer (CRC) remains largely unknown. We established two radioresistant CRC cell lines, HCT116-R and RKO-R, using fractionated irradiation. Analysis using miRNA sequencing and quantitative real-time PCR confirmed lower levels of miR-7-5p in both of the radioresistant cells compared to their parental cells. Subsequently, we validated that miR-7-5p expression was decreased in cancerous tissues from radiotherapy-resistant rectal cancer patients. The Cancer Genome Atlas (TCGA) database analyses revealed that low miR-7-5p expression was significantly correlated with poor prognosis in CRC patients. Overexpression of miR-7-5p led to a rescue of radioresistance and an increase in radiation-induced apoptosis, and attenuated the stem cell-like properties in HCT116-R and RKO-R cells. Conversely, knocking down miR-7-5p in parental HCT116 and RKO cells suppressed the sensitivity to radiation treatment and enhance cancer cell stemness. Stemness-associated transcription factor KLF4 was demonstrated as a target of miR-7-5p. Rescue experiments revealed that miR-7-5p/KLF4 axis could induce radiosensitivity by regulating CSCs in colorectal cancer cells. Furthermore, we used CRC tumor tissues which exhibited resistance to neoadjuvant radiotherapy to establish a patient-derived xenograft (PDX) mouse model. Tail vein injection of magnetic nanoparticles carrying miR-7-5p mimics into the PDX mice significantly inhibited tumor growth with or without irradiation treatment in vivo. Our current studies not only demonstrate an anti-cancer function of miR-7-5p in regulating CSC properties and radiosensitivity in colorectal cancer, but also provide a novel potential strategy for delaying or reverse radiation resistance in preoperative radiotherapy of CRC patients.
Chiral excitonic order from twofold van Hove singularities in kagome metals
Authors: Scammell Harley D. , Ingham Julian , Li Tommy , Sushkov Oleg P.
Published: February 2023

Recent experiments on kagome metals AV3Sb5 (A=K,Rb,Cs) identify twofold van Hove singularities (TvHS) with opposite concavity near the Fermi energy, generating two approximately hexagonal Fermi surfaces – one electron-like and the other hole-like. Here we propose that a TvHS generates a novel time-reversal symmetry breaking excitonic order – arising due to bound pairs of electrons and holes located at opposite concavity van Hove singularities. We introduce a minimal model for the TvHS and investigate interaction induced many-body instabilities via the perturbative renormalisation group technique and a free energy analysis. Specialising to parameters appropriate for the kagome metals AV3Sb5, we construct a phase diagram comprising chiral excitons, charge density wave and a region of coexistence. We propose this as an explanation of a diverse range of experimental observations in AV3Sb5. Notably, the chiral excitonic state gives rise to a quantum anomalous Hall conductance, providing an appealing interpretation of the observed anomalous Hall effect in kagome metals. Possible alternative realisations of the TvHS mechanism in bilayer materials are also discussed. We suggest that TvHS open up interesting possibilities for correlated phases, enriching the set of competing ground states to include excitonic order.
Direct observation of accelerating hydrogen spillover via surface-lattice-confinement effect
Authors: Liu Yijing , Zhang Rankun , Lin Le , Wang Yichao , Liu Changping , Mu Rentao , Fu Qiang
Published: February 2023

Uncovering how hydrogen transfers and what factors control hydrogen conductivity on solid surface is essential for enhancing catalytic performance of H-involving reactions, which is however hampered due to the structural complexity of powder catalysts, in particular, for oxide catalysts. Here, we construct stripe-like MnO(001) and grid-like Mn3O4(001) monolayers on Pt(111) substrate and investigate hydrogen spillover atop. Atomic-scale visualization demonstrates that hydrogen species from Pt diffuse unidirectionally along the stripes on MnO(001), whereas it exhibits an isotropic pathway on Mn3O4(001). Dynamic surface imaging in H2 atmosphere reveals that hydrogen diffuses 4 times more rapidly on MnO than the case on Mn3O4, which is promoted by one-dimension surface-lattice-confinement effect. Theoretical calculations indicate that a uniform and medium O-O distance favors hydrogen diffusion while low-coordinate surface O atom inhibits it. Our work illustrates the surface-lattice-confinement effect of oxide catalysts on hydrogen spillover and provides a promising route to improve the hydrogen spillover efficiency.
Ambient temperature CO2 fixation to pyruvate and subsequently to citramalate over iron and nickel nanoparticles
Authors: Beyazay Tuğçe , Belthle Kendra S. , Farès Christophe , Preiner Martina , Moran Joseph , Martin William F. , Tüysüz Harun
Published: February 2023

The chemical reactions that formed the building blocks of life at origins required catalysts, whereby the nature of those catalysts influenced the type of products that accumulated. Recent investigations have shown that at 100 °C awaruite, a Ni3Fe alloy that naturally occurs in serpentinizing systems, is an efficient catalyst for CO2 conversion to formate, acetate, and pyruvate. These products are identical with the intermediates and products of the acetyl-CoA pathway, the most ancient CO2 fixation pathway and the backbone of carbon metabolism in H2-dependent autotrophic microbes. Here, we show that Ni3Fe nanoparticles prepared via the hard-templating method catalyze the conversion of H2 and CO2 to formate, acetate and pyruvate at 25 °C under 25 bar. Furthermore, the 13C-labeled pyruvate can be further converted to acetate, parapyruvate, and citramalate over Ni, Fe, and Ni3Fe nanoparticles at room temperature within one hour. These findings strongly suggest that awaruite can catalyze both the formation of citramalate, the C5 product of pyruvate condensation with acetyl-CoA in microbial carbon metabolism, from pyruvate and the formation of pyruvate from CO2 at very moderate reaction conditions without organic catalysts. These results align well with theories for an autotrophic origin of microbial metabolism under hydrothermal vent conditions.
ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling
Authors: Gentili Matteo , Liu Bingxu , Papanastasiou Malvina , Dele-Oni Deborah , Schwartz Marc A. , Carlson Rebecca J. , Al’Khafaji Aziz M. , Krug Karsten , Brown Adam , Doench John G. , Carr Steven A. , Hacohen Nir
Published: February 2023

Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling.
Insights into azalomycin F assembly-line contribute to evolution-guided polyketide synthase engineering and identification of intermodular recognition
Authors: Zhai Guifa , Zhu Yan , Sun Guo , Zhou Fan , Sun Yangning , Hong Zhou , Dong Chuan , Leadlay Peter F. , Hong Kui , Deng Zixin , Zhou Fuling , Sun Yuhui
Published: February 2023

Modular polyketide synthase (PKS) is an ingenious core machine that catalyzes abundant polyketides in nature. Exploring interactions among modules in PKS is very important for understanding the overall biosynthetic process and for engineering PKS assembly-lines. Here, we show that intermodular recognition between the enoylreductase domain ER1/2 inside module 1/2 and the ketosynthase domain KS3 inside module 3 is required for the cross-module enoylreduction in azalomycin F (AZL) biosynthesis. We also show that KS4 of module 4 acts as a gatekeeper facilitating cross-module enoylreduction. Additionally, evidence is provided that module 3 and module 6 in the AZL PKS are evolutionarily homologous, which makes evolution-oriented PKS engineering possible. These results reveal intermodular recognition, furthering understanding of the mechanism of the PKS assembly-line, thus providing different insights into PKS engineering. This also reveals that gene duplication/conversion and subsequent combinations may be a neofunctionalization process in modular PKS assembly-lines, hence providing a different case for supporting the investigation of modular PKS evolution.
Conductive and elastic bottlebrush elastomers for ultrasoft electronics
Authors: Xu Pengfei , Wang Shaojia , Lin Angela , Min Hyun-Kee , Zhou Zhanfeng , Dou Wenkun , Sun Yu , Huang Xi , Tran Helen , Liu Xinyu
Published: February 2023

Understanding biological systems and mimicking their functions require electronic tools that can interact with biological tissues with matched softness. These tools involve biointerfacing materials that should concurrently match the softness of biological tissue and exhibit suitable electrical conductivities for recording and reading bioelectronic signals. However, commonly employed intrinsically soft and stretchable materials usually contain solvents that limit stability for long-term use or possess low electronic conductivity. To date, an ultrasoft (i.e., Young’s modulus <30 kPa), conductive, and solvent-free elastomer does not exist. Additionally, integrating such ultrasoft and conductive materials into electronic devices is poorly explored. This article reports a solvent-free, ultrasoft and conductive PDMS bottlebrush elastomer (BBE) composite with single-wall carbon nanotubes (SWCNTs) as conductive fillers. The conductive SWCNT/BBE with a filler concentration of 0.4 − 0.6 wt% reveals an ultralow Young’s modulus (<11 kPa) and satisfactory conductivity (>2 S/m) as well as adhesion property. Furthermore, we fabricate ultrasoft electronics based on laser cutting and 3D printing of conductive and non-conductive BBEs and demonstrate their potential applications in wearable sensing, soft robotics, and electrophysiological recording.
Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis
Authors: Okuda Kosaku , Nakahara Kengo , Ito Akihiro , Iijima Yuta , Nomura Ryosuke , Kumar Ashutosh , Fujikawa Kana , Adachi Kazuya , Shimada Yuki , Fujio Satoshi , Yamamoto Reina , Takasugi Nobumasa , Onuma Kunishige , Osaki Mitsuhiko , Okada Futoshi , Ukegawa Taichi , Takeuchi Yasuo , Yasui Norihisa , Yamashita Atsuko , Marusawa Hiroyuki , Matsushita Yosuke , Katagiri Toyomasa , Shibata Takahiro , Uchida Koji , Niu Sheng-Yong , Lang Nhi B. , Nakamura Tomohiro , Zhang Kam Y. J. , Lipton Stuart A. , Uehara Takashi
Published: February 2023

DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine withS-adenosyl-l-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affectsCcnd2expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibitS-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibitsS-nitrosylation of DNMT3B at low concentrations (IC50 ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrantS-nitrosylation of DNMT3B.
Universal exploration dynamics of random walks
Authors: Régnier Léo , Dolgushev Maxim , Redner S. , Bénichou Olivier
Published: February 2023

The territory explored by a random walk is a key property that may be quantified by the number of distinct sites that the random walk visits up to a given time. We introduce a more fundamental quantity, the timeτnrequired by a random walk to find a site that it never visited previously when the walk has already visitedndistinct sites, which encompasses the full dynamics about the visitation statistics. To study it, we develop a theoretical approach that relies on a mapping with a trapping problem, in which the spatial distribution of traps is continuously updated by the random walk itself. Despite the geometrical complexity of the territory explored by a random walk, the distribution of theτncan be accounted for by simple analytical expressions. Processes as varied as regular diffusion, anomalous diffusion, and diffusion in disordered media and fractals, fall into the same universality classes.
Self-spinning filaments for autonomously linked microfibers
Authors: Barber Dylan M. , Emrick Todd , Grason Gregory M. , Crosby Alfred J.
Published: February 2023

Filamentous bundles are ubiquitous in Nature, achieving highly adaptive functions and structural integrity from assembly of diverse mesoscale supramolecular elements. Engineering routes to synthetic, topologically integrated analogs demands precisely coordinated control of multiple filaments’ shapes and positions, a major challenge when performed without complex machinery or labor-intensive processing. Here, we demonstrate a photocreasing design that encodes local curvature and twist into mesoscale polymer filaments, enabling their programmed transformation into target 3-dimensional geometries. Importantly, patterned photocreasing of filament arrays drives autonomous spinning to form linked filament bundles that are highly entangled and structurally robust. In individual filaments, photocreases unlock paths to arbitrary, 3-dimensional curves in space. Collectively, photocrease-mediated bundling establishes a transformative paradigm enabling smart, self-assembled mesostructures that mimic performance-differentiating structures in Nature (e.g., tendon and muscle fiber) and the macro-engineered world (e.g., rope).
An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration
Authors: Rahman M. Tanvir , Koski M. Kristian , Panecka-Hofman Joanna , Schmitz Werner , Kastaniotis Alexander J. , Wade Rebecca C. , Wierenga Rik K. , Hiltunen J. Kalervo , Autio Kaija J.
Published: February 2023

Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E-enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δetr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.
Type of adjuvant endocrine therapy and disease-free survival in patients with early HR-positive/HER2-positive BC: analysis from the phase III randomized ShortHER trial
Authors: Dieci Maria Vittoria , Bisagni Giancarlo , Bartolini Stefania , Frassoldati Antonio , Vicini Roberto , Balduzzi Sara , D’amico Roberto , Conte Pierfranco , Guarneri Valentina
Published: February 2023

The optimal adjuvant endocrine therapy for HR-positive/HER2-positive breast cancer patients is unknown. We included in this analysis 784 patients with HR-positive/HER2-positive BC from the randomized ShortHER trial of adjuvant trastuzumab (1 year vs 9 weeks) + chemotherapy. At a median follow-up of 8.7 years, patients who received AI had a significantly better DFS vs patients who received TAM or TAM-AI: 8-yr DFS 86.4 vs 79.7%, log-rank P = 0.013 (HR 1.52, 95% CI 1.09–2.11). In multivariate analysis, the type of endocrine therapy maintained a significant association with DFS (HR 1.64, 95% CI 1.07–2.52, p = 0.025 for TAM/TAM-AI vs AI). Among premenopausal patients aged ≤45 years, the use of GnRHa was associated with longer DFS: 8-yr DFS rate 85.2 vs 62.6% (log-rank p = 0.019, HR 0.41, 95% CI 0.19–0.88). In this post-hoc analysis of the ShortHER trial adjuvant treatment with AI was independently associated with improved DFS. Subgroup analysis in premenopausal patients suggests benefits with ovarian suppression.

Trial registration: NCI ClinicalTrials.gov number: NCT00629278.
nNPipe: a neural network pipeline for automated analysis of morphologically diverse catalyst systems
Authors: Treder Kevin P. , Huang Chen , Bell Cameron G. , Slater Thomas J. A. , Schuster Manfred E. , Özkaya Doğan , Kim Judy S. , Kirkland Angus I.
Published: February 2023

We describe nNPipe for the automated analysis of morphologically diverse catalyst materials. Automated imaging routines and direct-electron detectors have enabled the collection of large data stacks over a wide range of sample positions at high temporal resolution. Simultaneously, traditional image analysis approaches are slow and hence unsuitable for large data stacks and consequently, researchers have progressively turned towards machine learning and deep learning approaches. Previous studies often detail work on morphologically uniform material systems with clearly discernible features, limited workable image sizes and training data that may be biased due to manual labelling. The nNPipe data-processing method consists of two standalone convolutional neural networks that were exclusively trained on multislice image simulations and enables fast analysis of 2048 × 2048 pixel images. Inference performance compared between idealised and real industrial catalytic samples and insights derived from subsequent data analysis are placed into the context of an automated imaging scenario.
Optical observations of thunderstorms from the International Space Station: recent results and perspectives
Authors: Neubert Torsten , Gordillo-Vázquez Francisco J. , Huntrieser Heidi
Published: February 2023

The International Space Station (ISS) is in the lowest available orbit at ~400 km altitude, bringing instruments as close to the atmosphere as possible from the vantage point of space. The orbit inclination is 51.6°, which brings the ISS over all the low- and mid-latitude regions of the Earth and at all local times. It is an ideal platform to observe deep convection and electrification of thunderstorms, taken advantage of by the Lightning Imaging Sensor (LIS) and the Atmosphere Space Interaction Monitor (ASIM) experiments. In the coming years, meteorological satellites in geostationary orbit (~36,000 km altitude) will provide sophisticated cloud and lightning observations with almost complete coverage of the Earth’s thunderstorm regions. In addition, Earth-observing satellite instruments in geostationary- and low-Earth orbit (LEO) will measure more atmospheric parameters at a higher resolution than we know today. The new infrastructure in space offers an opportunity to advance our understanding of the role of thunderstorms in atmospheric dynamics and climate change. Here, we discuss how observations from the ISS or other LEO platforms with instruments that view the atmosphere at slanted angles can complement the measurements from primarily nadir-oriented instruments of present and planned missions. We suggest that the slanted viewing geometry from LEO may resolve the altitude of electrical activity and the cloud structure where they occur, with implications for modelling thunderstorms’ effects on the atmosphere’s radiative properties and climate balance.
Streptococcus pyogenes vaccine candidates do not induce autoimmune responses in a rheumatic heart disease model
Authors: Reynolds Simone , Rafeek Rukshan Ahamed Mohamed , Hamlin Adam , Lepletier Ailin , Pandey Manisha , Ketheesan Natkunam , Good Michael F.
Published: February 2023

We have developed a candidate vaccine to protect against multiple strains of Streptococcus pyogenes infections. The candidate vaccine contains two synthetic peptides derived from S. pyogenes proteins: the M-protein epitope, p*17 and the IL-8 degrading S. pyogenes Cell-Envelope Proteinase (SpyCEP) epitope, K4S2. In this study we utilise a rat autoimmune valvulitis model that displays both the cardiac and neurobehavioural pathology associated with post-streptococcal sequelae, to assess if the vaccine candidate antigens induce autoimmune complications and inflammatory pathology. Each antigen was conjugated to carrier protein diphtheria toxoid (DT) and independently assessed for potential to induce autoimmune pathology in female Lewis rats. Rats were administered three subcutaneous doses, and one intranasal dose over a four-week study with a two-week recovery period. A positive control group received recombinant S. pyogenes M5 (rM5) protein, and the negative control group received PBS. Rats that received rM5 developed significant cardiac and neurological pathologies. There was no evidence of these pathologies in the PBS control group, or the rats administered either P*17-DT or K4S2-DT. This study provides further preclinical evidence of the safety of the vaccine candidates p*17 and K4S2 and their appropriateness as candidates in human clinical trials.
Annotated Datasets of Oil Palm Fruit Bunch Piles for Ripeness Grading Using Deep Learning
Authors: Suharjito  , Junior Franz Adeta , Koeswandy Yosua Putra , Debi  , Nurhayati Pratiwi Wahyu , Asrol Muhammad , Marimin
Published: February 2023

The quality of palm oil is strongly influenced by the maturity level of the fruit to be processed into palm oil. Many studies have been carried out for detecting and classifying the maturity level of oil palm fruit to improve the quality with the use of computer vision. However, most of these studies use datasets in the form of images of oil palm fresh fruit bunches (FFB) with incomplete categorization according to real conditions in palm oil mills. Therefore, this study introduces a new complete dataset obtained directly from palm oil mills in the form of videos and images with different categories in accordance with the real conditions faced by the grading section of the palm oil mill. The video dataset consists of 45 videos with a single category of FFB videos and 56 videos with a collection of FFB with multiple categories for each video. Videos are collected using a smart phone with a size of 1280 × 720 pixels with .mp4 format. In addition, this dataset has also been annotated and labelled based on the maturity level of oil palm fruit with 6 categories, which are unripe, under-ripe, ripe, overripe, empty bunches and abnormal fruit.
Measurements and computational fluid dynamics investigation of the indoor radon distribution in a typical naturally ventilated room
Authors: Adelikhah Mohammademad , Imani Morteza , Kovács Tibor
Published: February 2023

Based on the European Union Basic Safety Standards to protect people against exposure to ionizing radiation, establishing and addressing the reference levels for indoor radon concentrations is necessary. Therefore, the indoor radon concentration should be monitored and control in dwelling and workplaces. However, proper ventilation and sustainability are the major factors that influence how healthy the environment in a building is for its occupants. In this paper, the indoor radon distribution in a typical naturally ventilated room under two scenarios (when the door is closed and open) using the computational fluid dynamics (CFD) technique was studied. The CFD code ANSYS Fluent 2020 R1 based on the finite volume method was employed before the simulation results were compared with analytical calculations as well as passive and active measurements. The average radon concentration from the CFD simulation was found to be between 70.21 and 66.25 Bq m−3 under closed and open-door conditions, respectively, at the desired ventilation rate of 1 ACH (Air Changes per Hour). Moreover, the highest concentrations of radon were measured close to the floor and the lowest values were recorded near to the inlet, resulting in the airflow velocity profile. The simulation results were in good agreement with the maxima of 19% and 7% compared to analytical calculations at different indoor air velocities in the open- and closed-door scenarios, respectively. The measured radon concentrations obtained by the active measurements also fitted well with the CFD results, for example, with a relative standard deviation of around 7% and 2% when measured by AlphaGUARD and RAD7 monitors at a height of 1.0 m above the ground in the open-door scenario. From the simulation results, the effective dose received by an individual from the indoor air of the workplace was also calculated.
Efficacy of ZnO nanoparticles in Zn fortification and partitioning of wheat and rice grains under salt stress
Authors: Mazhar Zuhra , Akhtar Javaid , Alhodaib Aiyeshah , Naz Tayyaba , Zafar Mazhar Iqbal , Iqbal Muhammad Mazhar , Fatima Humaria , Naz Iffat
Published: February 2023

Zinc (Zn) deficiency is a major health concern in developing countries due to dependency on cereal based diet. Cereals are inherently low in Zn and inevitable use of stressed land has further elevated the problem. The aim of current research was to improve wheat and rice grains grain Zn concentration grown in saline soils through zinc oxide nanoparticles (ZnO-NPs) due to their perspective high availability. The ZnO-NPs were prepared by co-precipitation method and characterized through X-ray diffraction (XRD) and Scanning Electron Microscope (SEM). Two separate pot experiments for wheat and rice were conducted to check the relative effectiveness of ZnO-NPs compared to other bulk Zn sources i.e., zinc sulphate heptahydrate (ZnSO4·7H2O) and ZnO. Results showed that salt stress negatively impacted the tested parameters. There was a significant (p ≤ 0.05) improvement in growth, salt tolerance, plant Zn uptake and grain Zn concentrations by Zn application through Zn sources. The ZnO-NPs showed maximum improvement in crops parameters as compared to other sources due to their higher uptake and translocation in plants under both normal and stressed soil conditions. Thus, ZnO nanoparticles proved to be more effective for grain Zn fortification in both tested wheat and rice crops under normal and saline conditions.
Association of hemoglobin variability with the risk of cardiovascular disease: a nationally representative retrospective cohort study from South Korea
Authors: Lee Won Jung , Choi Seulggie , Park Sang Min , Lee Gyeongsil , Chang Jooyoung , Oh Yun Hwan , Son Joung Sik , Kim Kyae Hyung , Choi Soo Jung
Published: February 2023

Hemoglobin variability is known to increase cardiovascular mortality in chronic kidney disease, but the association of hemoglobin variability with the risk of cardiovascular disease (CVD) in the general population is yet unclear. This retrospective cohort study based on ‘the South Korean National Health Insurance Service database’ consisted of 198,347 adults who went through all three health examinations. Hemoglobin variability is defined as the average successive variability of three separate hemoglobin values from each health screening period. Participants were followed up for 6 years to determine the risk of coronary heart disease and stroke. We used multivariate Cox proportional hazards regression to examine the adjusted hazard ratios for CVD according to hemoglobin variability. Per 1 unit increase of hemoglobin variability, the risk for CVD (aHR 1.06, 95% CI 1.02–1.09) and stroke (aHR 1.08, 95% CI 1.03–1.13) increased significantly. The risk-increasing trend was preserved in the low-to-moderate risk group of CVDs (aHR 1.07, 95% CI 1.02–1.11). This result suggests that subjects with high hemoglobin variability who would otherwise be categorized as having low-to-moderate CVD risk may have higher risk of CVD than those with low hemoglobin variability.
Absolute dosimetry for FLASH proton pencil beam scanning radiotherapy
Authors: Lourenço Ana , Subiel Anna , Lee Nigel , Flynn Sam , Cotterill John , Shipley David , Romano Francesco , Speth Joe , Lee Eunsin , Zhang Yongbin , Xiao Zhiyan , Mascia Anthony , Amos Richard A. , Palmans Hugo , Thomas Russell
Published: February 2023

A paradigm shift is occurring in clinical oncology exploiting the recent discovery that short pulses of ultra-high dose rate (UHDR) radiation—FLASH radiotherapy—can significantly spare healthy tissues whilst still being at least as effective in curing cancer as radiotherapy at conventional dose rates. These properties promise reduced post-treatment complications, whilst improving patient access to proton beam radiotherapy and reducing costs. However, accurate dosimetry at UHDR is extremely complicated. This work presents measurements performed with a primary-standard proton calorimeter and derivation of the required correction factors needed to determine absolute dose for FLASH proton beam radiotherapy with an uncertainty of 0.9% (1$$\sigma$$
σ
), in line with that of conventional treatments. The establishment of a primary standard for FLASH proton radiotherapy improves accuracy and consistency of the dose delivered and is crucial for the safe implementation of clinical trials, and beyond, for this new treatment modality.