bluuebunny/crossref_metadata_2025 huggingface dataset:
KLF6 alleviates hepatic ischemia-reperfusion injury by inhibiting autophagy
Authors: Li Jiye , Yu Dongsheng , He Chenhui , Yu Qiwen , Huo Zhongkun , Zhang Yi , Zhang Shuijun
Published: July 2023

Hepatic ischemia-reperfusion (I/R) injury, a common clinical complication of liver transplantation, gravely affects patient prognosis. Krüppel-like factors (KLFs) constitute a family of C2/H2 zinc finger DNA-binding proteins. KLF6, a member of the KLF protein family, plays crucial roles in proliferation, metabolism, inflammation, and injury responses; however, its role in HIR is largely remains unknown. After I/R injury, we found that KLF6 expression in mice and hepatocytes was significantly upregulated. Mice were then subjected to I/R following injection of shKLF6- and KLF6-overexpressing adenovirus through the tail vein. KLF6 deficiency markedly exacerbated liver damage, cell apoptosis, and activation of hepatic inflammatory responses, whereas hepatic overexpression of KLF6 in mice produced the opposite results. In addition, we knocked out or overexpressed KLF6 in AML12 cells before exposing them to a hypoxia-reoxygenation challenge. KLF6 knockout decreased cell viability and increased hepatocyte inflammation, apoptosis, and ROS, whereas KLF6 overexpression had the opposite effects. Mechanistically, KLF6 inhibited the overactivation of autophagy at the initial stage, and the regulatory effect of KLF6 on I/R injury was autophagy-dependent. CHIP-qPCR and luciferase reporter gene assays confirmed that KLF6 bound to the promoter region of Beclin1 and inhibited its transcription. Additionally, KLF6 activated the mTOR/ULK1 pathway. Finally, we performed a retrospective analysis of the clinical data of liver transplantation patients and identified significant associations between KLF6 expression and liver function following liver transplantation. In conclusion, KLF6 inhibited the overactivation of autophagy via transcriptional regulation of Beclin1 and activation of the mTOR/ULK1 pathway, thereby protecting the liver from I/R injury. KLF6 is expected to serve as a biomarker for estimating the severity of I/R injury following liver transplantation.
Nrh L11R single nucleotide polymorphism, a new prediction biomarker in breast cancer, impacts endoplasmic reticulum-dependent Ca2+ traffic and response to neoadjuvant chemotherapy
Authors: Duong Minh Quang , Gadet Rudy , Treilleux Isabelle , Borel Stéphane , Nougarède Adrien , Marcillat Olivier , Gonzalo Philippe , Mikaelian Ivan , Popgeorgiev Nikolay , Rimokh Ruth , Gillet Germain
Published: July 2023

Overexpression of Bcl-2 proteins such as Bcl2L10, also referred to as Nrh, is associated with resistance to therapy and poor survival in various cancers, including breast cancer, lung cancer, and leukemia. The single nucleotide polymorphism (SNP) of BCL2L10 in its BH4 domain at position 11 (BCL2L10 Leu11Arg, rs2231292), corresponding to position 11 in the Nrh open reading frame, is reported to lower resistance towards chemotherapy, with patients showing better survival in the context of acute leukemia and colorectal cancer. Using cellular models and clinical data, we aimed to extend this knowledge to breast cancer. We report that the homozygous status of the Nrh Leu11Arg isoform (Nrh-R) is found in 9.7–11% percent of the clinical datasets studied. Furthermore, Nrh-R confers higher sensitivity towards Thapsigargin-induced cell death compared to the Nrh-L isoform, due to altered interactions with IP3R1 Ca2+ channels in the former case. Collectively, our data show that cells expressing the Nrh-R isoform are more prone to death triggered by Ca2+ stress inducers, compared to Nrh-L expressing cells. Analysis of breast cancer cohorts revealed that patients genotyped as Nrh-R/Nrh-R may have a better outcome. Overall, this study supports the notion that the rs2231292 Nrh SNP could be used as a predictive tool regarding chemoresistance, improving therapeutic decision-making processes. Moreover, it sheds new light on the contribution of the BH4 domain to the anti-apoptotic function of Nrh and identifies the IP3R1/Nrh complex as a potential therapeutic target in the context of breast cancer.
Pectolinarigenin inhibits bladder urothelial carcinoma cell proliferation by regulating DNA damage/autophagy pathways
Authors: Deng Zhao , Shen Dexin , Yu Mengxue , Zhou Fenfang , Shan Danni , Fang Yayun , Jin Wan , Qian Kaiyu , Li Shenjuan , Wang Gang , Zhang Yi , Ju Lingao , Xiao Yu , Wang Xinghuan
Published: July 2023

Pectolinarigenin (PEC), an active compound isolated from traditional herbal medicine, has shown potential anti-tumor properties against various types of cancer cells. However, its mechanism of action in bladder cancer (BLCA), which is one of the fatal human carcinomas, remains unexplored. In this study, we first revealed that PEC, as a potential DNA topoisomerase II alpha (TOP2A) poison, can target TOP2A and cause significant DNA damage. PEC induced G2/M phase cell cycle arrest via p53 pathway. Simultaneously, PEC can perform its unique function by inhibiting the late autophagic flux. The blocking of autophagy caused proliferation inhibition of BLCA and further enhanced the DNA damage effect of PEC. In addition, we proved that PEC could intensify the cytotoxic effect of gemcitabine (GEM) on BLCA cells in vivo and in vitro. Summarily, we first systematically revealed that PEC had great potential as a novel TOP2A poison and an inhibitor of late autophagic flux in treating BLCA.
The lncRNA RMST is drastically downregulated in anaplastic thyroid carcinomas where exerts a tumor suppressor activity impairing epithelial-mesenchymal transition and stemness
Authors: De Martino Marco , Pellecchia Simona , Esposito Francesco , Liotti Federica , Credendino Sara Carmela , Prevete Nella , Decaussin-Petrucci Myriam , Chieffi Paolo , De Vita Gabriella , Melillo Rosa Marina , Fusco Alfredo , Pallante Pierlorenzo
Published: July 2023

Thyroid cancer is the most prevalent endocrine malignancy and comprises a wide range of lesions subdivided into differentiated (DTC) and undifferentiated thyroid cancer (UTC), mainly represented by the anaplastic thyroid carcinoma (ATC). This is one of the most lethal malignancies in humankind leading invariably to patient death in few months. Then, a better comprehension of the mechanisms underlying the development of ATC is required to set up new therapeutic approaches. Long non-coding RNAs (lncRNAs) are transcripts over 200 nucleotides in length that do not code for proteins. They show a strong regulatory function at both transcriptional and post-transcriptional level and are emerging as key players in regulating developmental processes. Their aberrant expression has been linked to several biological processes, including cancer, making them potential diagnostic and prognostic markers. We have recently analyzed the lncRNA expression profile in ATC through a microarray technique and have identified rhabdomyosarcoma 2-associated transcript (RMST) as one of the most downregulated lncRNA in ATC. RMST has been reported to be deregulated in a series of human cancers, to play an anti-oncogenic role in triple-negative breast cancer, and to modulate neurogenesis by interacting with SOX2. Therefore, these findings prompted us to investigate the role of RMST in ATC development. In this study we show that RMST levels are strongly decreased in ATC, but only slightly in DTC, indicating that the loss of this lncRNA could be related to the loss of the differentiation and high aggressiveness. We also report a concomitant increase of SOX2 levels in the same subset of ATC, that inversely correlated with RMST levels, further supporting the RMST/SOX2 relationship. Finally, functional studies demonstrate that the restoration of RMST in ATC cells reduces cell growth, migration and the stemness properties of ATC stem cells. In conclusion, these findings support a critical role of RMST downregulation in ATC development.
NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer
Authors: Zhang Guizhen , Liu Liwen , Li Jianhao , Chen Yu , Wang Yun , Zhang Yize , Dong Zihui , Xue Wenhua , Sun Ranran , Cui Guangying
Published: July 2023

NSUN2 is a nuclear RNA methyltransferase which catalyzes 5-methylcytosine (m5C), a posttranscriptional RNA modification. Aberrant m5C modification has been implicated in the development of multiple malignancies. However, its function in pancreatic cancer (PC) needs to be elucidated. Herein, we determined that NSUN2 was overexpressed in PC tissues and related to aggressive clinical features. Silence of NSUN2 by lentivirus weakened the capability of proliferation, migration and invasion of PC cells in vitro and inhibited the growth and metastasis of xenograft tumors in vivo. Contrarily, overexpression of NSUN2 stimulated PC growth and metastasis. Mechanistically, m5C-sequencing (m5C-seq) and RNA-sequencing (RNA-seq) were carried out to identify downstream targets of NSUN2 and results showed that loss of NSUN2 led to decreased m5C modification level concomitant with reduced TIAM2 mRNA expression. Further validation experiments proved that NSUN2 silence accelerated the decay of TIAM2 mRNA in a YBX1-dependent manner. Additionally, NSUN2 exerted its oncogenic function partially through enhancing TIAM2 transcription. More importantly, disruption of the NSUN2/TIAM2 axis repressed the malignant phenotype of PC cells through blocking epithelial-mesenchymal transition (EMT). Collectively, our study highlighted the critical function of NSUN2 in PC and provided novel mechanistic insights into NSUN2/TIAM2 axis as promising therapeutic targets against PC.
Transient receptor potential ankyrin 1 (TRPA1) mediates reactive oxygen species-induced Ca2+ entry, mitochondrial dysfunction, and caspase-3/7 activation in primary cultures of metastatic colorectal carcinoma cells
Authors: Faris Pawan , Rumolo Agnese , Pellavio Giorgia , Tanzi Matteo , Vismara Mauro , Berra-Romani Roberto , Gerbino Andrea , Corallo Salvatore , Pedrazzoli Paolo , Laforenza Umberto , Montagna Daniela , Moccia Francesco
Published: July 2023

Colorectal carcinoma (CRC) represents the fourth most common cancer worldwide and is the third most common cause of malignancy-associated mortality. Distant metastases to the liver and lungs are the main drivers of CRC-dependent death. Pro-oxidant therapies, which halt disease progression by exacerbating oxidative stress, represent an antitumour strategy that is currently exploited by chemotherapy and ionizing radiation. A more selective strategy to therapeutically exploit reactive oxygen species (ROS) signaling would consist in targeting a redox sensor that is up-regulated in metastatic cells and is tightly coupled to the stimulation of cancer cell death programs. The non-selective cation channel, Transient Receptor Potential Ankyrin 1 (TRPA1), serves as a sensor of the cellular redox state, being activated to promote extracellular Ca2+ entry by an increase in oxidative stress. Recent work demonstrated that TRPA1 channel protein is up-regulated in several cancer types and that TRPA1-mediated Ca2+ signals can either engage an antiapoptotic pro-survival signaling pathway or to promote mitochondrial Ca2+ dysfunction and apoptosis. Herein, we sought to assess for the first time the outcome of TRPA1 activation by ROS on primary cultures of metastatic colorectal carcinoma (mCRC cells). We found that TRPA1 channel protein is up-regulated and mediates enhanced hydrogen peroxide (H2O2)-induced Ca2+ entry in mCRC cells as compared to non-neoplastic control cells. The lipid peroxidation product 4-hydroxynonenal (4-HNE) is the main ROS responsible for TRPA1 activation upon mCRC cell exposure to oxidative stress. TRPA1-mediated Ca2+ entry in response to H2O2 and 4-HNE results in mitochondrial Ca2+ overload, followed by mitochondrial depolarization and caspase-3/7 activation. Therefore, targeting TRPA1 could represent an alternative strategy to eradicate metastatic CRC by enhancing its sensitivity to oxidative stress.
Quantum simulation of thermodynamics in an integrated quantum photonic processor
Authors: Somhorst F. H. B. , van der Meer R. , Correa Anguita M. , Schadow R. , Snijders H. J. , de Goede M. , Kassenberg B. , Venderbosch P. , Taballione C. , Epping J. P. , van den Vlekkert H. H. , Timmerhuis J. , Bulmer J. F. F. , Lugani J. , Walmsley I. A. , Pinkse P. W. H. , Eisert J. , Walk N. , Renema J. J.
Published: July 2023

One of the core questions of quantum physics is how to reconcile the unitary evolution of quantum states, which is information-preserving and time-reversible, with evolution following the second law of thermodynamics, which, in general, is neither. The resolution to this paradox is to recognize that global unitary evolution of a multi-partite quantum state causes the state of local subsystems to evolve towards maximum-entropy states. In this work, we experimentally demonstrate this effect in linear quantum optics by simultaneously showing the convergence of local quantum states to a generalized Gibbs ensemble constituting a maximum-entropy state under precisely controlled conditions, while introducing an efficient certification method to demonstrate that the state retains global purity. Our quantum states are manipulated by a programmable integrated quantum photonic processor, which simulates arbitrary non-interacting Hamiltonians, demonstrating the universality of this phenomenon. Our results show the potential of photonic devices for quantum simulations involving non-Gaussian states.
Achieving near-perfect light absorption in atomically thin transition metal dichalcogenides through band nesting
Authors: Lee Seungjun , Seo Dongjea , Park Sang Hyun , Izquierdo Nezhueytl , Lee Eng Hock , Younas Rehan , Zhou Guanyu , Palei Milan , Hoffman Anthony J. , Jang Min Seok , Hinkle Christopher L. , Koester Steven J. , Low Tony
Published: July 2023

Near-perfect light absorbers (NPLAs), with absorbance, $${{{{{{{\mathcal{A}}}}}}}}$$
A
, of at least 99%, have a wide range of applications ranging from energy and sensing devices to stealth technologies and secure communications. Previous work on NPLAs has mainly relied upon plasmonic structures or patterned metasurfaces, which require complex nanolithography, limiting their practical applications, particularly for large-area platforms. Here, we use the exceptional band nesting effect in TMDs, combined with a Salisbury screen geometry, to demonstrate NPLAs using only two or three uniform atomic layers of transition metal dichalcogenides (TMDs). The key innovation in our design, verified using theoretical calculations, is to stack monolayer TMDs in such a way as to minimize their interlayer coupling, thus preserving their strong band nesting properties. We experimentally demonstrate two feasible routes to controlling the interlayer coupling: twisted TMD bi-layers and TMD/buffer layer/TMD tri-layer heterostructures. Using these approaches, we demonstrate room-temperature values of $${{{{{{{\mathcal{A}}}}}}}}$$
A
=95% at λ=2.8 eV with theoretically predicted values as high as 99%. Moreover, the chemical variety of TMDs allows us to design NPLAs covering the entire visible range, paving the way for efficient atomically-thin optoelectronics.
Regulation of the macrolide resistance ABC-F translation factor MsrD
Authors: Fostier Corentin R. , Ousalem Farès , Leroy Elodie C. , Ngo Saravuth , Soufari Heddy , Innis C. Axel , Hashem Yaser , Boël Grégory
Published: July 2023

Antibiotic resistance ABC-Fs (ARE ABC-Fs) are translation factors that provide resistance against clinically important ribosome-targeting antibiotics which are proliferating among pathogens. Here, we combine genetic and structural approaches to determine the regulation of streptococcal ARE ABC-F gene msrD in response to macrolide exposure. We show that binding of cladinose-containing macrolides to the ribosome prompts insertion of the leader peptide MsrDL into a crevice of the ribosomal exit tunnel, which is conserved throughout bacteria and eukaryotes. This leads to a local rearrangement of the 23 S rRNA that prevents peptide bond formation and accommodation of release factors. The stalled ribosome obstructs the formation of a Rho-independent terminator structure that prevents msrD transcriptional attenuation. Erythromycin induction of msrD expression via MsrDL, is suppressed by ectopic expression of mrsD, but not by mutants which do not provide antibiotic resistance, showing correlation between MsrD function in antibiotic resistance and its action on this stalled complex.
ASH1L-MRG15 methyltransferase deposits H3K4me3 and FACT for damage verification in nucleotide excision repair
Authors: Maritz Corina , Khaleghi Reihaneh , Yancoskie Michelle N. , Diethelm Sarah , Brülisauer Sonja , Ferreira Natalia Santos , Jiang Yang , Sturla Shana J. , Naegeli Hanspeter
Published: July 2023

To recognize DNA adducts, nucleotide excision repair (NER) deploys the XPC sensor, which detects damage-induced helical distortions, followed by engagement of TFIIH for lesion verification. Accessory players ensure that this factor handover takes place in chromatin where DNA is tightly wrapped around histones. Here, we describe how the histone methyltransferase ASH1L, once activated by MRG15, helps XPC and TFIIH to navigate through chromatin and induce global-genome NER hotspots. Upon UV irradiation, ASH1L adds H3K4me3 all over the genome (except in active gene promoters), thus priming chromatin for XPC relocations from native to damaged DNA. The ASH1L-MRG15 complex further recruits the histone chaperone FACT to DNA lesions. In the absence of ASH1L, MRG15 or FACT, XPC is misplaced and persists on damaged DNA without being able to deliver the lesions to TFIIH. We conclude that ASH1L-MRG15 makes damage verifiable by the NER machinery through the sequential deposition of H3K4me3 and FACT.
Targeted protein degradation reveals BET bromodomains as the cellular target of Hedgehog pathway inhibitor-1
Authors: Bagka Meropi , Choi Hyeonyi , Héritier Margaux , Schwaemmle Hanna , Pasquer Quentin T. L. , Braun Simon M. G. , Scapozza Leonardo , Wu Yibo , Hoogendoorn Sascha
Published: July 2023

Target deconvolution of small molecule hits from phenotypic screens presents a major challenge. Many screens have been conducted to find inhibitors for the Hedgehog signaling pathway – a developmental pathway with many implications in health and disease – yielding many hits but only few identified cellular targets. We here present a strategy for target identification based on Proteolysis-Targeting Chimeras (PROTACs), combined with label-free quantitative proteomics. We develop a PROTAC based on Hedgehog Pathway Inhibitor-1 (HPI-1), a phenotypic screen hit with unknown cellular target. Using this Hedgehog Pathway PROTAC (HPP) we identify and validate BET bromodomains as the cellular targets of HPI-1. Furthermore, we find that HPP-9 is a long-acting Hedgehog pathway inhibitor through prolonged BET bromodomain degradation. Collectively, we provide a powerful PROTAC-based approach for target deconvolution, that answers the longstanding question of the cellular target of HPI-1 and yields a PROTAC that acts on the Hedgehog pathway.
Biomarkers selection and mathematical modeling in biological age estimation
Authors: Bafei Solim Essomandan Clémence , Shen Chong
Published: July 2023

Biological age (BA) is important for clinical monitoring and preventing aging-related disorders and disabilities. Clinical and/or cellular biomarkers are measured and integrated in years using mathematical models to display an individual’s BA. To date, there is not yet a single or set of biomarker(s) and technique(s) that is validated as providing the BA that reflects the best real aging status of individuals. Herein, a comprehensive overview of aging biomarkers is provided and the potential of genetic variations as proxy indicators of the aging state is highlighted. A comprehensive overview of BA estimation methods is also provided as well as a discussion of their performances, advantages, limitations, and potential approaches to overcome these limitations.
Effects of an aged tissue niche on the immune potency of dendritic cells using simulated microgravity
Authors: ElGindi Mei , Sapudom Jiranuwat , Garcia Sabate Anna , Chesney Quartey Brian , Alatoom Aseel , Al-Sayegh Mohamed , Li Rui , Chen Weiqiang , Teo Jeremy
Published: July 2023

Microgravity accelerates the aging of various physiological systems, and it is well acknowledged that aged individuals and astronauts both have increased susceptibility to infections and poor response to vaccination. Immunologically, dendritic cells (DCs) are the key players in linking innate and adaptive immune responses. Their distinct and optimized differentiation and maturation phases play a critical role in presenting antigens and mounting effective lymphocyte responses for long-term immunity. Despite their importance, no studies to date have effectively investigated the effects of microgravity on DCs in their native microenvironment, which is primarily located within tissues. Here, we address a significantly outstanding research gap by examining the effects of simulated microgravity via a random positioning machine on both immature and mature DCs cultured in biomimetic collagen hydrogels, a surrogate for tissue matrices. Furthermore, we explored the effects of loose and dense tissues via differences in collagen concentration. Under these various environmental conditions, the DC phenotype was characterized using surface markers, cytokines, function, and transcriptomic profiles. Our data indicate that aged or loose tissue and exposure to RPM-induced simulated microgravity both independently alter the immunogenicity of immature and mature DCs. Interestingly, cells cultured in denser matrices experience fewer effects of simulated microgravity at the transcriptome level. Our findings are a step forward to better facilitate healthier future space travel and enhance our understanding of the aging immune system on Earth.
Perspective on the current state of the LRRK2 field
Authors: Taymans Jean-Marc , Fell Matt , Greenamyre Tim , Hirst Warren D. , Mamais Adamantios , Padmanabhan Shalini , Peter Inga , Rideout Hardy , Thaler Avner
Published: July 2023

Almost 2 decades after linking LRRK2 to Parkinson’s disease, a vibrant research field has developed around the study of this gene and its protein product. Recent studies have begun to elucidate molecular structures of LRRK2 and its complexes, and our understanding of LRRK2 has continued to grow, affirming decisions made years ago to therapeutically target this enzyme for PD. Markers of LRRK2 activity, with potential to monitor disease progression or treatment efficacy, are also under development. Interestingly, there is a growing understanding of the role of LRRK2 outside of the central nervous system in peripheral tissues such as gut and immune cells that may also contribute to LRRK2 mediated pathology. In this perspective, our goal is to take stock of LRRK2 research by discussing the current state of knowledge and critical open questions in the field.
Chinese Soil Moisture Observation Network and Time Series Data Set for High Resolution Satellite Applications
Authors: Wang Chunmei , Gu Xingfa , Zhou Xiang , Yang Jian , Yu Tao , Tao Zui , Gao Hailiang , Liu Qiyue , Zhan Yulin , Wei Xiangqin , Li Juan , Zhang Lili , Li Lei , Li Bingze , Feng Zhuangzhuang , Wang Xigang , Fu Ruoxi , Zheng Xingming , Wang Chunnuan , Sun Yuan , Li Bin , Dong Wen
Published: July 2023

High-quality ground observation networks are an important basis for scientific research. Here, an automatic soil observation network for high-resolution satellite applications in China (SONTE-China) was established to measure both pixel- and multilayer-based soil moisture and temperature. SONTE-China is distributed across 17 field observation stations with a variety of ecosystems, covering both dry and wet zones. In this paper, the average root mean squared error (RMSE) of station-based soil moisture for well-characterized SONTE-China sites is 0.027 m3/m3 (0.014~0.057 m3/m3) following calibration for specific soil properties. The temporal and spatial characteristics of the observed soil moisture and temperature in SONTE-China conform to the geographical location, seasonality and rainfall of each station. The time series Sentinel-1 C-band radar signal and soil moisture show strong correlations, and the RMSE of the estimated soil moisture from radar data was lower than 0.05 m3/m3 for the Guyuan and Minqin stations. SONTE-China is a soil moisture retrieval algorithm that can validate soil moisture products and provide basic data for weather forecasting, flood forecasting, agricultural drought monitoring and water resource management.
Mutational signatures reveal mutual exclusivity of homologous recombination and mismatch repair deficiencies in colorectal and stomach tumors
Authors: Farmanbar Amir , Kneller Robert , Firouzi Sanaz
Published: July 2023

Decomposing somatic mutation spectra into mutational signatures and their corresponding etiologies provides a powerful approach for investigating the mechanism of DNA damage and repair. Assessing microsatellite (in)stability (MSI/MSS) status and interpreting their clinical relevance in different malignancies offers significant diagnostic and prognostic value. However, little is known about microsatellite (in)stability and its interactions with other DNA repair mechanisms such as homologous recombination (HR) in different cancer types. Based on whole-genome/exome mutational signature analysis, we showed HR deficiency (HRd) and mismatch repair deficiency (MMRd) occur in a significantly mutually exclusive manner in stomach and colorectal adenocarcinomas. ID11 signature with currently unknown etiology was prevalent in MSS tumors, co-occurred with HRd and was mutually exclusive with MMRd. Apolipoprotein B mRNA editing enzyme, Catalytic polypeptide-like (APOBEC) signature co-occurred with HRd and was mutually exclusive with MMRd in stomach tumors. The HRd signature in MSS tumors and the MMRd signature in MSI tumors were the first or second dominant signatures wherever detected. HRd may drive a distinct subgroup of MSS tumors and lead to poor clinical outcome. These analyses offer insight into mutational signatures in MSI and MMS tumors and reveal opportunities for improved clinical diagnosis and personalized treatment of MSS tumors.
Single cell RNA analysis of the left–right organizer transcriptome reveals potential novel heterotaxy genes
Authors: Bellchambers Helen M. , Phatak Amruta R. , Nenni Mardi J. , Padua Maria B. , Gao Hongyu , Liu Yunlong , Ware Stephanie M.
Published: July 2023

The establishment of left–right patterning in mice occurs at a transient structure called the embryonic node or left–right organizer (LRO). Previous analysis of the LRO has proven challenging due to the small cell number and transient nature of this structure. Here, we seek to overcome these difficulties to define the transcriptome of the LRO. Specifically, we used single cell RNA sequencing of 0–1 somite embryos to identify LRO enriched genes which were compared to bulk RNA sequencing of LRO cells isolated by fluorescent activated cell sorting. Gene ontology analysis indicated an enrichment of genes associated with cilia and laterality terms. Furthermore, comparison to previously identified LRO genes identified 127 novel LRO genes, including Ttll3, Syne1 and Sparcl1, for which the expression patterns were validated using whole mount in situ hybridization. This list of novel LRO genes will be a useful resource for further studies on LRO morphogenesis, the establishment of laterality and the genetic causes of heterotaxy.
Study on co-seismic ionospheric disturbance of Alaska earthquake on July 29, 2021 based on GPS TEC
Authors: Ruan Qingshan , Yuan Xitun , Liu Hang , Ge Shuyao
Published: July 2023

With the rapid development of space geodetic information technology, the Global Positioning System (GPS) has been widely used in seismology and space environmental research. Typically, the occurrence of a large earthquake will lead to some changes in the ionosphere, this phenomenon is called coseismic ionospheric disturbances (CIDs). In this contribution, differential slant total electron content (dSTEC) is used to study the anomalous characteristics of the ionosphere. First, based on the ionospheric dSTEC time series and two-dimensional disturbance detection, the temporal and spatial characteristics of ionospheric disturbances can be accurately analysed. Secondly, using wavelet transform spectrum analysis and disturbance propagation velocity, it can be determined that the disturbance sources of this earthquake can be identified as acoustic wave, gravity wave and Rayleigh wave. Finally, in order to further clarify the direction of the earthquake disturbance, this study focuses on proposing an innovative method for the disturbance propagation direction, and determines that there are two directions of the propagation of the CIDs of the Alaski earthquake.
3D-printing-assisted fabrication of hierarchically structured biomimetic surfaces with dual-wettability for water harvesting
Authors: Choi Yeongu , Baek Keuntae , So Hongyun
Published: July 2023

Freshwater acquisition methods under various environments are required because water scarcity has intensified worldwide. Furthermore, as water is an essential resource for humans, a freshwater acquisition method that can be utilized even under harsh conditions, such as waterless and polluted water environments, is highly required. In this study, a three-dimensional (3D) printing-assisted hierarchically structured surface with dual-wettability (i.e., surface with both hydrophobic and hydrophilic region) for fog harvesting was developed by mimicking the biological features (i.e., cactus spines and elytra of Namib Desert beetles) that have effective characteristics for fog harvesting. The cactus-shaped surface exhibited self-transportation ability of water droplet, derived from the Laplace pressure gradient. Additionally, microgrooved patterns of the cactus spines were implemented using the staircase effect of 3D printing. Moreover, a partial metal deposition method using wax-based masking was introduced to realize the dual wettability of the elytra of the Namib Desert beetle. Consequently, the proposed surface exhibited the best performance (average weight of 7.85 g for 10 min) for fog harvesting, which was enhanced by the synergetic effect between the Laplace pressure gradient and surface energy gradient. These results support a novel freshwater production system that can be utilized even in harsh conditions, such as waterless and polluted water environments.
Coupling of nematic in-plane orientational ordering and equilibrium shapes of closed flexible nematic shells
Authors: Mesarec Luka , Góźdź Wojciech , Kralj-Iglič Veronika , Kralj Samo , Iglič Aleš
Published: July 2023

The impact of the intrinsic curvature of in-plane orientationally ordered curved flexible nematic molecules attached to closed 3D flexible shells was studied numerically. A Helfrich-Landau-de Gennes-type mesoscopic approach was adopted where the flexible shell’s curvature field and in-plane nematic field are coupled and concomitantly determined in the process of free energy minimisation. We demonstrate that this coupling has the potential to generate a rich diversity of qualitatively new shapes of closed 3D nematic shells and the corresponding specific in-plane orientational ordering textures, which strongly depend on the shell’s volume-to-surface area ratio, so far not predicted in mesoscopic-type numerical studies of 3D shapes of closed flexible nematic shells.
Plaque burden is associated with minimal intimal coverage following drug-eluting stent implantation in an adult familial hypercholesterolemia swine model
Authors: Razzi Francesca , Dijkstra Jouke , Hoogendoorn Ayla , Witberg Karen , Ligthart Jurgen , Duncker Dirk J. , van Esch Jan , Wentzel Jolanda J. , van Steijn Volkert , van Soest Gijs , Regar Evelyn , van Beusekom Heleen M. M.
Published: July 2023

Safety and efficacy of coronary drug-eluting stents (DES) are often preclinically tested using healthy or minimally diseased swine. These generally show significant fibrotic neointima at follow-up, while in patients, incomplete healing is often observed. The aim of this study was to investigate neointima responses to DES in swine with significant coronary atherosclerosis. Adult familial hypercholesterolemic swine (n = 6) received a high fat diet to develop atherosclerosis. Serial OCT was performed before, directly after, and 28 days after DES implantation (n = 14 stents). Lumen, stent and plaque area, uncovered struts, neointima thickness and neointima type were analyzed for each frame and averaged per stent. Histology was performed to show differences in coronary atherosclerosis. A range of plaque size and severity was found, from healthy segments to lipid-rich plaques. Accordingly, neointima responses ranged from uncovered struts, to minimal neointima, to fibrotic neointima. Lower plaque burden resulted in a fibrotic neointima at follow-up, reminiscent of minimally diseased swine coronary models. In contrast, higher plaque burden resulted in minimal neointima and more uncovered struts at follow-up, similarly to patients’ responses. The presence of lipid-rich plaques resulted in more uncovered struts, which underscores the importance of advanced disease when performing safety and efficacy testing of DES.
Fluorescence lifetime FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators
Authors: Roopnarine Osha , Yuen Samantha L. , Thompson Andrew R. , Roelike Lauren N. , Rebbeck Robyn T. , Bidwell Philip A. , Aldrich Courtney C. , Cornea Razvan L. , Thomas David D.
Published: July 2023

We have used FRET-based biosensors in live cells, in a robust high-throughput screening (HTS) platform, to identify small-molecules that alter the structure and activity of the cardiac sarco/endoplasmic reticulum calcium ATPase (SERCA2a). Our primary aim is to discover drug-like small-molecule activators that improve SERCA’s function for the treatment of heart failure. We have previously demonstrated the use of an intramolecular FRET biosensor, based on human SERCA2a, by screening two different small validation libraries using novel microplate readers that detect the fluorescence lifetime or emission spectrum with high speed, precision, and resolution. Here we report results from FRET-HTS of 50,000 compounds using the same biosensor, with hit compounds functionally evaluated using assays for Ca2+-ATPase activity and Ca2+-transport. We focused on 18 hit compounds, from which we identified eight structurally unique scaffolds and four scaffold classes as SERCA modulators, approximately half of which are activators and half are inhibitors. Five of these compounds were identified as promising SERCA activators, one of which activates Ca2+-transport even more than Ca2+-ATPase activity thus improving SERCA efficiency. While both activators and inhibitors have therapeutic potential, the activators establish the basis for future testing in heart disease models and lead development, toward pharmaceutical therapy for heart failure.
Exploration of sepsis assisting parameters in hospital autopsied-patients: a prospective study
Authors: Inai Kunihiro , Higuchi Shohei , Shimada Akihiro , Hisada Kyoko , Hida Yukio , Hatta Satomi , Kitano Fumihiro , Uno Miyuki , Matsukawa Haruka , Noriki Sakon , Iwasaki Hiromichi , Naiki Hironobu
Published: July 2023

Although Sepsis-3 doesn’t require evidence of bacteremia to diagnose sepsis, clinicians often want to identify the causative pathogen at autopsy. In principle, if the blood cultures are the same at ante- and postmortem, the cause of death is obvious. However, interpretations of postmortem blood cultures are often difficult due to discordance, negativity, mixed infection, and contamination, of pathogens occupying ≥ 50% of the tests. To increase specificity identifying agonal phase sepsis in the situations where blood cultures are discordant, multiple or negative at postmortem, we established a scoring system using blood cultures, procalcitonin (PCN) showing highest sensitivity and specificity for postmortem serum, and bone marrow polyhemophagocytosis (PHP). Histological sepsis showed significantly higher levels of culture score (2.3 ± 1.5 vs. 0.4 ± 0.5, p < 0.001), PHP score (2.5 ± 0.8 vs. 1.0 ± 1.1, p < 0.001), and PCN score (1.8 ± 0.8 vs. 0.8 ± 0.6, p < 0.01) than non-septic patients. Receiver operating characteristic curve analysis indicated that estimation of three scores was the most reliable indicator for recognizing agonal phase sepsis. These findings suggest that the combination of these three inspections enables to determine the pathological diagnoses of sepsis even it is not obvious by discordant, mixed or negative blood cultures.
Study the charging process of moving quantum batteries inside cavity
Authors: Hadipour Maryam , Haseli Soroush , Dolatkhah Hazhir , Rashidi Maryam
Published: July 2023

In quantum mechanics, quantum batteries are devices that can store energy by utilizing the principles of quantum mechanics. While quantum batteries has been investigated largely theoretical, recent research indicates that it may be possible to implement such a device using existing technologies. The environment plays an important role in the charging of quantum batteries. If a strong coupling exists between the environment and the battery, then battery can be charged properly. It has also been demonstrated that quantum battery can be charged even in weak coupling regime just by choosing a suitable initial state for battery and charger. In this study, we investigate the charging process of open quantum batteries mediated by a common dissipative environment. We will consider a wireless-like charging scenario, where there is no external power and direct interaction between charger and battery. Moreover, we consider the case in which the battery and charger move inside the environment with a particular speed. Our results demonstrate that the movement of the quantum battery inside the environment has a negative effect on the performance of the quantum batteries during the charging process. It is also shown that the non-Markovian environment has a positive effect on improving battery performance.
Medical transformer for multimodal survival prediction in intensive care: integration of imaging and non-imaging data
Authors: Khader Firas , Kather Jakob Nikolas , Müller-Franzes Gustav , Wang Tianci , Han Tianyu , Tayebi Arasteh Soroosh , Hamesch Karim , Bressem Keno , Haarburger Christoph , Stegmaier Johannes , Kuhl Christiane , Nebelung Sven , Truhn Daniel
Published: July 2023

When clinicians assess the prognosis of patients in intensive care, they take imaging and non-imaging data into account. In contrast, many traditional machine learning models rely on only one of these modalities, limiting their potential in medical applications. This work proposes and evaluates a transformer-based neural network as a novel AI architecture that integrates multimodal patient data, i.e., imaging data (chest radiographs) and non-imaging data (clinical data). We evaluate the performance of our model in a retrospective study with 6,125 patients in intensive care. We show that the combined model (area under the receiver operating characteristic curve [AUROC] of 0.863) is superior to the radiographs-only model (AUROC = 0.811, p < 0.001) and the clinical data-only model (AUROC = 0.785, p < 0.001) when tasked with predicting in-hospital survival per patient. Furthermore, we demonstrate that our proposed model is robust in cases where not all (clinical) data points are available.
Noninvasive imaging-based machine learning algorithm to identify progressive disease in advanced hepatocellular carcinoma receiving second-line systemic therapy
Authors: Dong Wei , Ji Ye , Pi Shan , Chen Qi-Feng
Published: July 2023

The aim of this study was to predict tyrosine kinase inhibitors (TKI) plus anti-PD-1 antibodies (TKI-PD-1) efficacy as second-line treatment in advanced hepatocellular carcinoma (HCC) using radiomics analysis. From November 2018 to November 2019, a total of 55 patients were included. Radiomic features were obtained from the CT images before treatment and filtered using intraclass correlation coefficients (ICCs) and least absolute shrinkage and selection operator (LASSO) methods. Subsequently, ten prediction algorithms were developed and validated based on radiomic characteristics. The accuracy of the constructed model was measured through area under the receiver operating characteristic curve (AUC) analysis; survival analysis was performed via Kaplan–Meier and Cox regression analyses. Overall, 18 (32.7%) out of 55 patients had progressive disease. Through ICCs and LASSO, ten radiomic features were entered into the algorithm construction and validation. Ten machine learning algorithms showed different accuracies, with the support vector machine (SVM) model having the highest AUC value of 0.933 in the training cohort and 0.792 in the testing cohort. The radiomic features were associated with overall survival. In conclsion, the SVM algorithm is a useful method to predict TKI-PD-1 efficacy in patients with advanced HCC using images taken prior to treatment.
Rapamycin prevents lung injury related to acute spinal cord injury in rats
Authors: Chu Ruiliang , Wang Nan , Bi Yang , Nan Guoxin
Published: July 2023

Severe injury occurs in the lung after acute spinal cord injury (ASCI) and autophagy is inhibited. However, rapamycin-activated autophagy's role and mechanism in lung injury development after ASCI is unknown. Preventing lung injury after ASCI by regulating autophagy is currently a valuable and unknown area. Herein, we aimed to investigate the effect and possible mechanism of rapamycin-activated autophagy on lung damage post-ASCI. An experimental animal study of rapamycin's effect and mechanism on lung damage after ASCI. We randomly divided 144 female wild-type Sprague–Dawley rats into a vehicle sham group (n = 36), a vehicle injury group (n = 36), a rapamycin sham group (n = 36), and a rapamycin injury group (n = 36). The spine was injured at the tenth thoracic vertebra using Allen's method. At 12, 24, 48, and 72 h after surgery, the rats were killed humanely. Lung damage was evaluated via pulmonary gross anatomy, lung pathology, and apoptosis assessment. Autophagy induction was assessed according to LC3, RAB7, and Beclin 1 levels. ULK-1, ULK-1 Ser555, ULK-1 Ser757, AMPK α and AMPK β1/2 were used to investigate the potential mechanism. After rapamycin pretreatment, the lung showed no obvious damage (e.g., cell death, inflammatory exudation, hemorrhage, and pulmonary congestion) at 12 h and 48 h after injury and Beclin1, LC3 and RAB7 levels increased. After rapamycin pretreatment, ULK-1, ULK-1 Ser555, and ULK-1 Ser757 levels increased at 12 h and 48 h after injury compared with the vehicle group, but they decreased at 12 h after injury compared with the rapamycin sham group. After rapamycin pretreatment, AMPKα levels did not change significantly before and after injury; however, at 48 h after injury, its level was elevated significantly compared with that in the vehicle group. Rapamycin can prevent lung injury after ASCI, possibly via upregulation of autophagy through the AMPK–mTORC1–ULK1 regulatory axis.
Response of Fragaria vesca to projected change in temperature, water availability and concentration of CO2 in the atmosphere
Authors: Sammarco Iris , Münzbergová Zuzana , Latzel Vít
Published: July 2023

The high rate of climate change may soon expose plants to conditions beyond their adaptation limits. Clonal plants might be particularly affected due to limited genotypic diversity of their populations, potentially decreasing their adaptability. We therefore tested the ability of a widely distributed predominantly clonally reproducing herb (Fragaria vesca) to cope with periods of drought and flooding in climatic conditions predicted to occur at the end of the twenty-first century, i.e. on average 4 °C warmer and with twice the concentration of CO2in the air (800 ppm) than the current state. We found thatF. vescacan phenotypically adjust to future climatic conditions, although its drought resistance may be reduced. Increased temperature and CO2levels in the air had a far greater effect on growth, phenology, reproduction, and gene expression than the temperature increase itself, and promoted resistance ofF. vescato repeated flooding periods. Higher temperature promoted clonal over sexual reproduction, and increased temperature and CO2concentration in the air triggered change in expression of genes controlling the level of self-pollination. We conclude thatF. vescacan acclimatise to predicted climate change, but the increased ratio of clonal to sexual reproduction and the alteration of genes involved in the self-(in)compatibility system may be associated with reduced genotypic diversity of its populations, which may negatively impact its ability to genetically adapt to novel climate in the long-term.
Molecular characteristics of microsatellite stable early-onset colorectal cancer as predictors of prognosis and immunotherapeutic response
Authors: Lu Can , Zhang Xiaopeng , Schardey Josefine , Wirth Ulrich , Heinrich Kathrin , Massiminio Luca , Cavestro Giulia Martina , Neumann Jens , Bazhin Alexandr V. , Werner Jens , Kühn Florian
Published: July 2023

The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.
Effective impurity behavior emergent from non-Hermitian proximity effect
Authors: Wu Deguang , Chen Jiasong , Su Wei , Wang Rui , Wang Baigeng , Xing D. Y.
Published: July 2023

Non-Hermitian boundaries commonly take place in many open quantum systems locally coupled to a surrounding environment. Here, we reveal a type of non-Hermitian effect induced by non-Hermitian boundaries, the non-Hermitian proximity effect (NHPE), which describes the penetration of non-Hermiticity from the boundary into the bulk. For gapped quantum systems, the NHPE generates in-gap states with imaginary eigenenergies, termed “imaginary in-gap states". The imaginary in-gap states are localized at the system boundary and decay into the bulk, analogous to the behaviors of the conventional impurity states. However, in contrast to impurity states, the imaginary in-gap states exhibit distinct dynamical behaviors under time-evolution. Moreover, they are physically manifested as corner modes under open boundaries, as a combined result of the non-Hermitian skin effect (NHSE) and NHPE. These results not only uncover implicit similarities between quantum systems with non-Hermitian boundaries and impurity physics, but also point to intriguing non-Hermitian phenomena broadly relevant to open quantum systems.