bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of Scintillation Events With Basis on L1 Transmissions From Geostationary SBAS Satellites
Authors: Moraes Alison , Sousasantos Jonas , Costa Emanoel , Pereira Bruno Augusto , Rodrigues Fabiano , Galera Monico João Francisco
Published: January 2024

Signals recorded by two stations in the Brazilian region: [Fortaleza (3.74°S, 38.57°W) and Inconfidentes (22.31°S, 46.32°W)], receiving L1 transmissions from different geostationary satellites, were used to evaluate the amplitude scintillation index S4 and several characteristics of scintillation events (continuous record with S4 > 0.2) during nighttime hours (18:00 LT–02:00 LT) in the years 2014–2016. The effects from solar activity, season, and local time on the number of scintillation events per night, maximum scintillation, scintillation event duration, and spacing between consecutive events will be discussed. The results indicate that: (a) scintillation occurs from September to March in both links; (b) the most likely numbers of observed scintillation events per night were two or three, particularly during the first 2 years; (c) on average, the first scintillation event usually had larger maximum S4 values when compared to those of the later ones along the night; (d) the first scintillation event had a longer mean duration than the succeeding ones in a given night; (e) the durations of scintillation events, regardless of their numbers per night and the location, decreased with local time; (f) the opposite dependence of spacings between consecutive events on local time was observed; (g) the cumulative distribution functions of the scintillation onset time indicated a strong dependence on the dip latitude of the station; and (h) early occurrences of onset times are directly related to the increased probability of the occurrence of multiple scintillation events.
Japan’s SLIM Spacecraft Lands on the Moon
Authors: Cartier Kimberly
Published: January 2024

The mission hopes to advance space exploration using a lightweight lander and a high-precision landing system.
The Climate Crisis Briefly Crashes the New Hampshire GOP Primary
Authors: Cartier Kimberly
Published: January 2024

Republican candidates repeated earlier promises to expand domestic fossil fuel production and fight programs that promote race- and gender-based equity in schools.
Abnormal developmental of structural covariance networks in young adults with heavy cannabis use: a 3-year follow-up study
Authors: Xu Hui , Li Jiahao , Huang Huan , Yin Bo , Li Dan-Dong
Published: January 2024

Heavy cannabis use (HCU) exerts adverse effects on the brain. Structural covariance networks (SCNs) that illustrate coordinated regional maturation patterns are extensively employed to examine abnormalities in brain structure. Nevertheless, the unexplored aspect remains the developmental alterations of SCNs in young adults with HCU for three years, from the baseline (BL) to the 3-year follow-up (FU). These changes demonstrate dynamic development and hold potential as biomarkers. A total of 20 young adults with HCU and 22 matched controls were recruited. All participants underwent magnetic resonance imaging (MRI) scans at both the BL and FU and were evaluated using clinical measures. Both groups used cortical thickness (CT) and cortical surface area (CSA) to construct structural covariance matrices. Subsequently, global and nodal network measures of SCNs were computed based on these matrices. Regarding global network measures, the BL assessment revealed significant deviations in small-worldness and local efficiency of CT and CSA in young adults with HCU compared to controls. However, no significant differences between the two groups were observed at the FU evaluation. Young adults with HCU displayed changes in nodal network measures across various brain regions during the transition from BL to FU. These alterations included abnormal nodal degree, nodal efficiency, and nodal betweenness in widespread areas such as the entorhinal cortex, superior frontal gyrus, and parahippocampal cortex. These findings suggest that the topography of CT and CSA plays a role in the typical structural covariance topology of the brain. Furthermore, these results indicate the effect of HCU on the developmental changes of SCNs in young adults.
Results of a randomised Phase II trial of olaparib, chemotherapy or olaparib and cediranib in patients with platinum-resistant ovarian cancer
Authors: Nicum Shibani , McGregor Naomi , Austin Rachel , Collins Linda , Dutton Susan , McNeish Iain , Glasspool Rosalind , Hall Marcia , Roux Rene , Michael Agnieszka , Clamp Andrew , Jayson Gordon , Kristeleit Rebecca , Banerjee Susana , Mansouri Anita
Published: January 2024

Background

OCTOVA compared the efficacy of olaparib (O) versus weekly paclitaxel (wP) or olaparib + cediranib (O + C) in recurrent ovarian cancer (OC).

Aims

The main aim of the OCTOVA trial was to determine the progression-free survival (PFS) of olaparib (O) versus the oral combination of olaparib plus cediranib (O + C) and weekly paclitaxel (wP) in recurrent ovarian cancer (OC).

Methods

In total, 139 participants who had relapsed within 12 months of platinum therapy were randomised to O (300 mg twice daily), wP (80 mg/m2 d1,8,15, q28) or O + C (300 mg twice daily/20 mg daily, respectively). The primary endpoint was progression-free survival (PFS) of olaparib (O) versus olaparib plus cediranib (O + C) or weekly paclitaxel (wP). The sample size was calculated to observe a PFS hazard ratio (HR) 0.64 in favour of O + C compared to O (20% one-sided type I error, 80% power).

Results

The majority had platinum-resistant disease (90%), 22% prior PARPi, 34% prior anti-angiogenic therapy, 30% germline BRCA1/2 mutations. The PFS was increased for O + C vs O (O + C 5.4 mo (2.3, 9.6): O 3.7 mo (1.8, 7.6) HR = 0.73; 60% CI: 0.59, 0.89; P = 0.1) and no different between wP and O (wP 3.9 m (1.9, 9.1); O 3.7 mo (1.8, 7.6) HR = 0.89, 60% CI: 0.72, 1.09; P = 0.69). The main treatment-related adverse events included manageable diarrhoea (4% Grade 3) and hypertension (4% Grade 3) in the O + C arm.

Discussion

OCTOVA demonstrated the activity of O + C in women with recurrent disease, offering a potential non-chemotherapy option.

Trial registration

ISRCTN14784018, registered on 19th January 2018 http://www.isrctn.com/ISRCTN14784018.
The LKB1–TSSK1B axis controls YAP phosphorylation to regulate the Hippo–YAP pathway
Authors: Kim Cho-Long , Lim Su-Bin , Choi Sue-Hee , Kim Dong Hyun , Sim Ye Eun , Jo Eun-Hye , Kim Keeeun , Lee Keesook , Park Hee-Sae , Lim Su Bin , Kang Li-Jung , Jeong Han-Sol , Lee Youngsoo , Hansen Carsten G. , Mo Jung-Soon
Published: January 2024

The Hippo pathway’s main effector, Yes-associated protein (YAP), plays a crucial role in tumorigenesis as a transcriptional coactivator. YAP’s phosphorylation by core upstream components of the Hippo pathway, such as mammalian Ste20 kinase 1/2 (MST1/2), mitogen-activated protein kinase kinase kinase kinases (MAP4Ks), and their substrate, large tumor suppressor 1/2 (LATS1/2), influences YAP’s subcellular localization, stability, and transcriptional activity. However, recent research suggests the existence of alternative pathways that phosphorylate YAP, independent of these core upstream Hippo pathway components, raising questions about additional means to inactivate YAP. In this study, we present evidence demonstrating that TSSK1B, a calcium/calmodulin-dependent protein kinase (CAMK) superfamily member, is a negative regulator of YAP, suppressing cellular proliferation and oncogenic transformation. Mechanistically, TSSK1B inhibits YAP through two distinct pathways. Firstly, the LKB1–TSSK1B axis directly phosphorylates YAP at Ser94, inhibiting the YAP–TEAD complex’s formation and suppressing its target genes’ expression. Secondly, the TSSK1B–LATS1/2 axis inhibits YAP via phosphorylation at Ser127. Our findings reveal the involvement of TSSK1B-mediated molecular mechanisms in the Hippo–YAP pathway, emphasizing the importance of multilevel regulation in critical cellular decision-making processes.
Fatty acid metabolism of immune cells: a new target of tumour immunotherapy
Authors: Zhang Sheng , Lv Kebing , Liu Zhen , Zhao Ran , Li Fei
Published: January 2024

Metabolic competition between tumour cells and immune cells for limited nutrients is an important feature of the tumour microenvironment (TME) and is closely related to the outcome of tumour immune escape. A large number of studies have proven that tumour cells need metabolic reprogramming to cope with acidification and hypoxia in the TME while increasing energy uptake to support their survival. Among them, synthesis, oxidation and uptake of fatty acids (FAs) in the TME are important manifestations of lipid metabolic adaptation. Although different immune cell subsets often show different metabolic characteristics, various immune cell functions are closely related to fatty acids, including providing energy, providing synthetic materials and transmitting signals. In the face of the current situation of poor therapeutic effects of tumour immunotherapy, combined application of targeted immune cell fatty acid metabolism seems to have good therapeutic potential, which is blocked at immune checkpoints. Combined application of adoptive cell therapy and cancer vaccines is reflected. Therefore, it is of great interest to explore the role of fatty acid metabolism in immune cells to discover new strategies for tumour immunotherapy and improve anti-tumour immunity.
Breakthrough of solid tumor treatment: CAR-NK immunotherapy
Authors: Wang Wenkang , Liu Yang , He Zhen , Li Lifeng , Liu Senbo , Jiang Mingqiang , Zhao Bing , Deng Meng , Wang Wendong , Mi Xuefang , Sun Zhenqiang , Ge Xin
Published: January 2024

As the latest and most anticipated method of tumor immunotherapy, CAR-NK therapy has received increasing attention in recent years, and its safety and high efficiency have irreplaceable advantages over CAR-T. Current research focuses on the application of CAR-NK in hematological tumors, while there are fewer studies on solid tumor. This article reviews the process of constructing CAR-NK, the effects of hypoxia and metabolic factors, NK cell surface receptors, cytokines, and exosomes on the efficacy of CAR-NK in solid tumor, and the role of CAR-NK in various solid tumor. The mechanism of action and the research status of the potential of CAR-NK in the treatment of solid tumor in clinical practice, and put forward the advantages, limitations and future problems of CAR-NK in the treatment of solid tumor.
Ramping dynamics and theta oscillations reflect dissociable signatures during rule-guided human behavior
Authors: Weber Jan , Solbakk Anne-Kristin , Blenkmann Alejandro O. , Llorens Anais , Funderud Ingrid , Leske Sabine , Larsson Pål Gunnar , Ivanovic Jugoslav , Knight Robert T. , Endestad Tor , Helfrich Randolph F.
Published: January 2024

Contextual cues and prior evidence guide human goal-directed behavior. The neurophysiological mechanisms that implement contextual priors to guide subsequent actions in the human brain remain unclear. Using intracranial electroencephalography (iEEG), we demonstrate that increasing uncertainty introduces a shift from a purely oscillatory to a mixed processing regime with an additional ramping component. Oscillatory and ramping dynamics reflect dissociable signatures, which likely differentially contribute to the encoding and transfer of different cognitive variables in a cue-guided motor task. The results support the idea that prefrontal activity encodes rules and ensuing actions in distinct coding subspaces, while theta oscillations synchronize the prefrontal-motor network, possibly to guide action execution. Collectively, our results reveal how two key features of large-scale neural population activity, namely continuous ramping dynamics and oscillatory synchrony, jointly support rule-guided human behavior.
Interindividual- and blood-correlated sweat phenylalanine multimodal analytical biochips for tracking exercise metabolism
Authors: Zhong Bowen , Qin Xiaokun , Xu Hao , Liu Lingchen , Li Linlin , Li Zhexin , Cao Limin , Lou Zheng , Jackman Joshua A. , Cho Nam-Joon , Wang Lili
Published: January 2024

In situ monitoring of endogenous amino acid loss through sweat can provide physiological insights into health and metabolism. However, existing amino acid biosensors are unable to quantitatively assess metabolic status during exercise and are rarely used to establish blood-sweat correlations because they only detect a single concentration indicator and disregard sweat rate. Here, we present a wearable multimodal biochip integrated with advanced electrochemical electrodes and multipurpose microfluidic channels that enables simultaneous quantification of multiple sweat indicators, including phenylalanine and chloride, as well as sweat rate. This combined measurement approach reveals a negative correlation between sweat phenylalanine levels and sweat rates among individuals, which further enables identification of individuals at high metabolic risk. By tracking phenylalanine fluctuations induced by protein intake during exercise and normalizing the concentration indicator by sweat rates to reduce interindividual variability, we demonstrate a reliable method to correlate and analyze sweat-blood phenylalanine levels for personal health monitoring.
Engineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
Authors: Gurbatri Candice R. , Radford Georgette A. , Vrbanac Laura , Im Jongwon , Thomas Elaine M. , Coker Courtney , Taylor Samuel R. , Jang YoungUk , Sivan Ayelet , Rhee Kyu , Saleh Anas A. , Chien Tiffany , Zandkarimi Fereshteh , Lia Ioana , Lannagan Tamsin R. M. , Wang Tongtong , Wright Josephine A. , Kobayashi Hiroki , Ng Jia Q. , Lawrence Matt , Sammour Tarik , Thomas Michelle , Lewis Mark , Papanicolas Lito , Perry Joanne , Fitzsimmons Tracy , Kaazan Patricia , Lim Amanda , Stavropoulos Alexandra M. , Gouskos Dion A. , Marker Julie , Ostroff Cheri , Rogers Geraint , Arpaia Nicholas , Worthley Daniel L. , Woods Susan L. , Danino Tal
Published: January 2024

Bioengineered probiotics enable new opportunities to improve colorectal cancer (CRC) screening, prevention and treatment. Here, first, we demonstrate selective colonization of colorectal adenomas after oral delivery of probiotic E. coli Nissle 1917 (EcN) to a genetically-engineered murine model of CRC predisposition and orthotopic models of CRC. We next undertake an interventional, double-blind, dual-centre, prospective clinical trial, in which CRC patients take either placebo or EcN for two weeks prior to resection of neoplastic and adjacent normal colorectal tissue (ACTRN12619000210178). We detect enrichment of EcN in tumor samples over normal tissue from probiotic-treated patients (primary outcome of the trial). Next, we develop early CRC intervention strategies. To detect lesions, we engineer EcN to produce a small molecule, salicylate. Oral delivery of this strain results in increased levels of salicylate in the urine of adenoma-bearing mice, in comparison to healthy controls. To assess therapeutic potential, we engineer EcN to locally release a cytokine, GM-CSF, and blocking nanobodies against PD-L1 and CTLA-4 at the neoplastic site, and demonstrate that oral delivery of this strain reduces adenoma burden by ~50%. Together, these results support the use of EcN as an orally-deliverable platform to detect disease and treat CRC through the production of screening and therapeutic molecules.
Cell state dependent effects of Bmal1 on melanoma immunity and tumorigenicity
Authors: Zhang Xue , Pant Shishir M. , Ritch Cecily C. , Tang Hsin-Yao , Shao Hongguang , Dweep Harsh , Gong Yao-Yu , Brooks Rebekah , Brafford Patricia , Wolpaw Adam J. , Lee Yool , Weeraratna Ashani , Sehgal Amita , Herlyn Meenhard , Kossenkov Andrew , Speicher David , Sorger Peter K. , Santagata Sandro , Dang Chi V.
Published: January 2024

The circadian clock regulator Bmal1 modulates tumorigenesis, but its reported effects are inconsistent. Here, we show that Bmal1 has a context-dependent role in mouse melanoma tumor growth. Loss of Bmal1 in YUMM2.1 or B16-F10 melanoma cells eliminates clock function and diminishes hypoxic gene expression and tumorigenesis, which could be rescued by ectopic expression of HIF1α in YUMM2.1 cells. By contrast, over-expressed wild-type or a transcriptionally inactive mutant Bmal1 non-canonically sequester myosin heavy chain 9 (Myh9) to increase MRTF-SRF activity and AP-1 transcriptional signature, and shift YUMM2.1 cells from a Sox10high to a Sox9high immune resistant, mesenchymal cell state that is found in human melanomas. Our work describes a link between Bmal1, Myh9, mouse melanoma cell plasticity, and tumor immunity. This connection may underlie cancer therapeutic resistance and underpin the link between the circadian clock, MRTF-SRF and the cytoskeleton.
Machine learning-based high-frequency neuronal spike reconstruction from low-frequency and low-sampling-rate recordings
Authors: Hong Nari , Kim Boil , Lee Jaewon , Choe Han Kyoung , Jin Kyong Hwan , Kang Hongki
Published: January 2024

Recording neuronal activity using multiple electrodes has been widely used to understand the functional mechanisms of the brain. Increasing the number of electrodes allows us to decode more variety of functionalities. However, handling massive amounts of multichannel electrophysiological data is still challenging due to the limited hardware resources and unavoidable thermal tissue damage. Here, we present machine learning (ML)-based reconstruction of high-frequency neuronal spikes from subsampled low-frequency band signals. Inspired by the equivalence between high-frequency restoration and super-resolution in image processing, we applied a transformer ML model to neuronal data recorded from both in vitro cultures and in vivo male mouse brains. Even with the x8 downsampled datasets, our trained model reasonably estimated high-frequency information of spiking activity, including spike timing, waveform, and network connectivity. With our ML-based data reduction applicable to existing multichannel recording hardware while achieving neuronal signals of broad bandwidths, we expect to enable more comprehensive analysis and control of brain functions.
LDLR is used as a cell entry receptor by multiple alphaviruses
Authors: Zhai Xiaofeng , Li Xiaoling , Veit Michael , Wang Ningning , Wang Yu , Merits Andres , Jiang Zhiwen , Qin Yan , Zhang Xiaoguang , Qi Kaili , Jiao Houqi , He Wan-Ting , Chen Ye , Mao Yang , Su Shuo
Published: January 2024

Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.
Distinguishing examples while building concepts in hippocampal and artificial networks
Authors: Kang Louis , Toyoizumi Taro
Published: January 2024

The hippocampal subfield CA3 is thought to function as an auto-associative network that stores experiences as memories. Information from these experiences arrives directly from the entorhinal cortex as well as indirectly through the dentate gyrus, which performs sparsification and decorrelation. The computational purpose for these dual input pathways has not been firmly established. We model CA3 as a Hopfield-like network that stores both dense, correlated encodings and sparse, decorrelated encodings. As more memories are stored, the former merge along shared features while the latter remain distinct. We verify our model’s prediction in rat CA3 place cells, which exhibit more distinct tuning during theta phases with sparser activity. Finally, we find that neural networks trained in multitask learning benefit from a loss term that promotes both correlated and decorrelated representations. Thus, the complementary encodings we have found in CA3 can provide broad computational advantages for solving complex tasks.
Unraveling the crucial role of trace oxygen in organic semiconductors
Authors: Huang Yinan , Wu Kunjie , Sun Yajing , Hu Yongxu , Wang Zhongwu , Yuan Liqian , Wang Shuguang , Ji Deyang , Zhang Xiaotao , Dong Huanli , Gong Zhongmiao , Li Zhiyun , Weng Xuefei , Huang Rong , Cui Yi , Chen Xiaosong , Li Liqiang , Hu Wenping
Published: January 2024

Optoelectronic properties of semiconductors are significantly modified by impurities at trace level. Oxygen, a prevalent impurity in organic semiconductors (OSCs), has long been considered charge-carrier traps, leading to mobility degradation and stability problems. However, this understanding relies on the conventional deoxygenation methods, by which oxygen residues in OSCs are inevitable. It implies that the current understanding is questionable. Here, we develop a non-destructive deoxygenation method (i.e., de-doping) for OSCs by a soft plasma treatment, and thus reveal that trace oxygen significantly pre-empties the donor-like traps in OSCs, which is the origin of p-type characteristics exhibited by the majority of these materials. This insight is completely opposite to the previously reported carrier trapping and can clarify some previously unexplained organic electronics phenomena. Furthermore, the de-doping results in the disappearance of p-type behaviors and significant increase of n-type properties, while re-doping (under light irradiation in O2) can controllably reverse the process. Benefiting from this, the key electronic characteristics (e.g., polarity, conductivity, threshold voltage, and mobility) can be precisely modulated in a nondestructive way, expanding the explorable property space for all known OSC materials.
Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
Authors: Yang Xue , Wang Jianming , Chang Chun-Yuan , Zhou Fan , Liu Juan , Xu Huiting , Ibrahim Maria , Gomez Maria , Guo Grace L. , Liu Hao , Zong Wei-Xing , Wondisford Fredric E. , Su Xiaoyang , White Eileen , Feng Zhaohui , Hu Wenwei
Published: January 2024

Cancer cachexia is a systemic metabolic syndrome characterized by involuntary weight loss, and muscle and adipose tissue wasting. Mechanisms underlying cachexia remain poorly understood. Leukemia inhibitory factor (LIF), a multi-functional cytokine, has been suggested as a cachexia-inducing factor. In a transgenic mouse model with conditional LIF expression, systemic elevation of LIF induces cachexia. LIF overexpression decreases de novo lipogenesis and disrupts lipid homeostasis in the liver. Liver-specific LIF receptor knockout attenuates LIF-induced cachexia, suggesting that LIF-induced functional changes in the liver contribute to cachexia. Mechanistically, LIF overexpression activates STAT3 to downregulate PPARα, a master regulator of lipid metabolism, leading to the downregulation of a group of PPARα target genes involved in lipogenesis and decreased lipogenesis in the liver. Activating PPARα by fenofibrate, a PPARα agonist, restores lipid homeostasis in the liver and inhibits LIF-induced cachexia. These results provide valuable insights into cachexia, which may help develop strategies to treat cancer cachexia.
Connective tissue inspired elastomer-based hydrogel for artificial skin via radiation-indued penetrating polymerization
Authors: Tian Yuan , Wang Zhihao , Cao Shuiyan , Liu Dong , Zhang Yukun , Chen Chong , Jiang Zhiwen , Ma Jun , Wang Yunlong
Published: January 2024

Robust hydrogels offer a candidate for artificial skin of bionic robots, yet few hydrogels have a comprehensive performance comparable to real human skin. Here, we present a general method to convert traditional elastomers into tough hydrogels via a unique radiation-induced penetrating polymerization method. The hydrogel is composed of the original hydrophobic crosslinking network from elastomers and grafted hydrophilic chains, which act as elastic collagen fibers and water-rich substances. Therefore, it successfully combines the advantages of both elastomers and hydrogels and provides similar Young’s modulus and friction coefficients to human skin, as well as better compression and puncture load capacities than double network and polyampholyte hydrogels. Additionally, responsive abilities can be introduced during the preparation process, granting the hybrid hydrogels shape adaptability. With these unique properties, the hybrid hydrogel can be a candidate for artificial skin, fluid flow controller, wound dressing layer and many other bionic application scenarios.
Proteomic analysis of SARS-CoV-2 particles unveils a key role of G3BP proteins in viral assembly
Authors: Murigneux Emilie , Softic Laurent , Aubé Corentin , Grandi Carmen , Judith Delphine , Bruce Johanna , Le Gall Morgane , Guillonneau François , Schmitt Alain , Parissi Vincent , Berlioz-Torrent Clarisse , Meertens Laurent , Hansen Maike M. K. , Gallois-Montbrun Sarah
Published: January 2024

Considerable progress has been made in understanding the molecular host-virus battlefield during SARS-CoV-2 infection. Nevertheless, the assembly and egress of newly formed virions are less understood. To identify host proteins involved in viral morphogenesis, we characterize the proteome of SARS-CoV-2 virions produced from A549-ACE2 and Calu-3 cells, isolated via ultracentrifugation on sucrose cushion or by ACE-2 affinity capture. Bioinformatic analysis unveils 92 SARS-CoV-2 virion-associated host factors, providing a valuable resource to better understand the molecular environment of virion production. We reveal that G3BP1 and G3BP2 (G3BP1/2), two major stress granule nucleators, are embedded within virions and unexpectedly favor virion production. Furthermore, we show that G3BP1/2 participate in the formation of cytoplasmic membrane vesicles, that are likely virion assembly sites, consistent with a proviral role of G3BP1/2 in SARS-CoV-2 dissemination. Altogether, these findings provide new insights into host factors required for SARS-CoV-2 assembly with potential implications for future therapeutic targeting.
i-shaped antibody engineering enables conformational tuning of biotherapeutic receptor agonists
Authors: Romei Matthew G. , Leonard Brandon , Katz Zachary B. , Le Daniel , Yang Yanli , Day Eric S. , Koo Christopher W. , Sharma Preeti , Bevers III Jack , Kim Ingrid , Dai Huiguang , Farahi Farzam , Lin May , Shaw Andrey S. , Nakamura Gerald , Sockolosky Jonathan T. , Lazar Greg A.
Published: January 2024

The ability to leverage antibodies to agonize disease relevant biological pathways has tremendous potential for clinical investigation. Yet while antibodies have been successful as antagonists, immune mediators, and targeting agents, they are not readily effective at recapitulating the biology of natural ligands. Among the important determinants of antibody agonist activity is the geometry of target receptor engagement. Here, we describe an engineering approach inspired by a naturally occurring Fab-Fab homotypic interaction that constrains IgG in a unique i-shaped conformation. i-shaped antibody (iAb) engineering enables potent intrinsic agonism of five tumor necrosis factor receptor superfamily (TNFRSF) targets. When applied to bispecific antibodies against the heterodimeric IL-2 receptor pair, constrained bispecific IgG formats recapitulate IL-2 agonist activity. iAb engineering provides a tool to tune agonist antibody function and this work provides a framework for the development of intrinsic antibody agonists with the potential for generalization across broad receptor classes.
Scattered tree death contributes to substantial forest loss in California
Authors: Cheng Yan , Oehmcke Stefan , Brandt Martin , Rosenthal Lisa , Das Adrian , Vrieling Anton , Saatchi Sassan , Wagner Fabien , Mugabowindekwe Maurice , Verbruggen Wim , Beier Claus , Horion Stéphanie
Published: January 2024

In recent years, large-scale tree mortality events linked to global change have occurred around the world. Current forest monitoring methods are crucial for identifying mortality hotspots, but systematic assessments of isolated or scattered dead trees over large areas are needed to reduce uncertainty on the actual extent of tree mortality. Here, we mapped individual dead trees in California using sub-meter resolution aerial photographs from 2020 and deep learning-based dead tree detection. We identified 91.4 million dead trees over 27.8 million hectares of vegetated areas (16.7-24.7% underestimation bias when compared to field data). Among these, a total of 19.5 million dead trees appeared isolated, and 60% of all dead trees occurred in small groups ( ≤ 3 dead trees within a 30 × 30 m grid), which is largely undetected by other state-level monitoring methods. The widespread mortality of individual trees impacts the carbon budget and sequestration capacity of California forests and can be considered a threat to forest health and a fuel source for future wildfires.
Global-scale magnetosphere convection driven by dayside magnetic reconnection
Authors: Dai Lei , Zhu Minghui , Ren Yong , Gonzalez Walter , Wang Chi , Sibeck David , Samsonov Andrey , Escoubet Philippe , Tang Binbin , Zhang Jiaojiao , Branduardi-Raymont Graziella
Published: January 2024

Plasma convection on a global scale is a fundamental feature of planetary magnetosphere. The Dungey cycle explains that steady-state convection within the closed part of the magnetosphere relies on magnetic reconnection in the nightside magnetospheric tail. Nevertheless, time-dependent models of the Dungey cycle suggest an alternative scenario where magnetospheric convection can be solely driven by dayside magnetic reconnection. In this study, we provide direct evidence supporting the scenario of dayside-driven magnetosphere convection. The driving process is closely connected to the evolution of Region 1 and Region 2 field-aligned currents. Our global simulations demonstrate that intensified magnetospheric convection and field-aligned currents progress from the dayside to the nightside within 10–20 minutes, following a southward turning of the interplanetary magnetic field. Observational data within this short timescale also reveal enhancements in both magnetosphere convection and the ionosphere’s two-cell convection. These findings provide insights into the mechanisms driving planetary magnetosphere convection, with implications for the upcoming Solar-Wind-Magnetosphere-Ionosphere Link Explorer (SMILE) mission.
A magnetic multi-layer soft robot for on-demand targeted adhesion
Authors: Chen Ziheng , Wang Yibin , Chen Hui , Law Junhui , Pu Huayan , Xie Shaorong , Duan Feng , Sun Yu , Liu Na , Yu Jiangfan
Published: January 2024

Magnetic soft robots have shown great potential for biomedical applications due to their high shape reconfigurability, motion agility, and multi-functionality in physiological environments. Magnetic soft robots with multi-layer structures can enhance the loading capacity and function complexity for targeted delivery. However, the interactions between soft entities have yet to be fully investigated, and thus the assembly of magnetic soft robots with on-demand motion modes from multiple film-like layers is still challenging. Herein, we model and tailor the magnetic interaction between soft film-like layers with distinct in-plane structures, and then realize multi-layer soft robots that are capable of performing agile motions and targeted adhesion. Each layer of the robot consists of a soft magnetic substrate and an adhesive film. The mechanical properties and adhesion performance of the adhesive films are systematically characterized. The robot is capable of performing two locomotion modes, i.e., translational motion and tumbling motion, and also the on-demand separation with one side layer adhered to tissues. Simulation results are presented, which have a good qualitative agreement with the experimental results. The feasibility of using the robot to perform multi-target adhesion in a stomach is validated in both ex-vivo and in-vivo experiments.
Sub-micro porous thin polymer membranes for discriminating H2 and CO2
Authors: Yan Xueru , Song Tianqi , Li Min , Wang Zhi , Liu Xinlei
Published: January 2024

Polymeric membranes with high permeance and remarkable selectivity for simultaneous H2 purification and CO2 capture under industry-relevant conditions are absent. Herein, sub-micro pores with precise molecular sieving capability are created in ultra-thin (13–30 nm) polymer membranes via controllable transformation of amine-linked polymer (ALP) films into benzimidazole-and-amine-linked polymer (BIALP) layers. The BIALP membranes exhibit stable unprecedented H2/CO2 selectivity of 120 with a H2 permeance of 315 GPU. Furthermore, high pressure (up to 11 bar) and thermal (up to 300 °C) resistance is delivered. This work provides a concept on designing porous polymeric membranes for precise molecular discrimination.
A mesocortical glutamatergic pathway modulates neuropathic pain independent of dopamine co-release
Authors: Li Miao , Yang Guang
Published: January 2024

Dysfunction in the mesocortical pathway, connecting the ventral tegmental area (VTA) to the prefrontal cortex, has been implicated in chronic pain. While extensive research has focused on the role of dopamine, the contribution of glutamatergic signaling in pain modulation remains unknown. Using in vivo calcium imaging, we observe diminished VTA glutamatergic activity targeting the prelimbic cortex (PL) in a mouse model of neuropathic pain. Optogenetic activation of VTA glutamatergic terminals in the PL alleviates neuropathic pain, whereas inhibiting these terminals in naïve mice induces pain-like responses. Importantly, this pain-modulating effect is independent of dopamine co-release, as demonstrated by CRISPR/Cas9-mediated gene deletion. Furthermore, we show that VTA neurons primarily project to excitatory neurons in the PL, and their activation restores PL outputs to the anterior cingulate cortex, a key region involved in pain processing. These findings reveal a distinct mesocortical glutamatergic pathway that critically modulates neuropathic pain independent of dopamine signaling.
Structure-guided discovery of anti-CRISPR and anti-phage defense proteins
Authors: Duan Ning , Hand Emily , Pheko Mannuku , Sharma Shikha , Emiola Akintunde
Published: January 2024

Bacteria use a variety of defense systems to protect themselves from phage infection. In turn, phages have evolved diverse counter-defense measures to overcome host defenses. Here, we use protein structural similarity and gene co-occurrence analyses to screen >66 million viral protein sequences and >330,000 metagenome-assembled genomes for the identification of anti-phage and counter-defense systems. We predict structures for ~300,000 proteins and perform large-scale, pairwise comparison to known anti-CRISPR (Acr) and anti-phage proteins to identify structural homologs that otherwise may not be uncovered using primary sequence search. This way, we identify a Bacteroidota phage Acr protein that inhibits Cas12a, and an Akkermansia muciniphila anti-phage defense protein, termed BxaP. Gene bxaP is found in loci encoding Bacteriophage Exclusion (BREX) and restriction-modification defense systems, but confers immunity independently. Our work highlights the advantage of combining protein structural features and gene co-localization information in studying host-phage interactions.
Enhancing tumor-specific recognition of programmable synthetic bacterial consortium for precision therapy of colorectal cancer
Authors: Zhou Tuoyu , Wu Jingyuan , Tang Haibo , Liu Dali , Jeon Byong-Hun , Jin Weilin , Wang Yiqing , Zheng Yuanzhang , Khan Aman , Han Huawen , Li Xiangkai
Published: January 2024

Probiotics hold promise as a potential therapy for colorectal cancer (CRC), but encounter obstacles related to tumor specificity, drug penetration, and dosage adjustability. In this study, genetic circuits based on the E. coli Nissle 1917 (EcN) chassis were developed to sense indicators of tumor microenvironment and control the expression of therapeutic payloads. Integration of XOR gate amplify gene switch into EcN biosensors resulted in a 1.8-2.3-fold increase in signal output, as confirmed by mathematical model fitting. Co-culturing programmable EcNs with CRC cells demonstrated a significant reduction in cellular viability ranging from 30% to 50%. This approach was further validated in a mouse subcutaneous tumor model, revealing 47%-52% inhibition of tumor growth upon administration of therapeutic strains. Additionally, in a mouse tumorigenesis model induced by AOM and DSS, the use of synthetic bacterial consortium (SynCon) equipped with multiple sensing modules led to approximately 1.2-fold increased colon length and 2.4-fold decreased polyp count. Gut microbiota analysis suggested that SynCon maintained the abundance of butyrate-producing bacteria Lactobacillaceae NK4A136, whereas reducing the level of gut inflammation-related bacteria Bacteroides. Taken together, engineered EcNs confer the advantage of specific recognition of CRC, while SynCon serves to augment the synergistic effect of this approach.
Molecular identification with atomic force microscopy and conditional generative adversarial networks
Authors: Carracedo-Cosme Jaime , Pérez Rubén
Published: January 2024

Frequency modulation (FM) atomic force microscopy (AFM) with metal tips functionalized with a CO molecule at the tip apex (referred as High-Resolution AFM, HR-AFM) has provided access to the internal structure of molecules with totally unprecedented resolution. We propose a model to extract the chemical information from those AFM images in order to achieve a complete identification of the imaged molecule. Our Conditional Generative Adversarial Network (CGAN) converts a stack of constant-height HR-AFM images at various tip-sample distances into a ball-and-stick depiction, where balls of different color and size represent the chemical species and sticks represent the bonds, providing complete information on the structure and chemical composition. The CGAN has been trained and tested with the QUAM-AFM data set, that contains simulated AFM images for a collection of 686000 organic molecules that include all the chemical species relevant in organic chemistry. Tests with a large set of theoretical images and few experimental examples demonstrate the accuracy and potential of our approach for molecular identification.
Candidate ferroelectrics via ab initio high-throughput screening of polar materials
Authors: Ricci Francesco , Reyes-Lillo Sebastian E. , Mack Stephanie A. , Neaton Jeffrey B.
Published: January 2024

Ferroelectrics are a class of polar and switchable functional materials with diverse applications, from microelectronics to energy conversion. Computational searches for new ferroelectric materials have been constrained by accurate prediction of the polarization and switchability with electric field, properties that, in principle, require a comparison with a nonpolar phase whose atomic-scale unit cell is continuously deformable from the polar ground state. For most polar materials, such a higher-symmetry nonpolar phase does not exist or is unknown. Here, we introduce a general high-throughput workflow that screens polar materials as potential ferroelectrics. We demonstrate our workflow on 1978 polar structures in the Materials Project database, for which we automatically generate a nonpolar reference structure using pseudosymmetries, and then compute the polarization difference and energy barrier between polar and nonpolar phases, comparing the predicted values to known ferroelectrics. Focusing on a subset of 182 potential ferroelectrics, we implement a systematic ranking strategy that prioritizes candidates with large polarization and small polar-nonpolar energy differences. To assess stability and synthesizability, we combine information including the computed formation energy above the convex hull, the Inorganic Crystal Structure Database id number, a previously reported machine learning-based synthesizability score, and ab initio phonon band structures. To distinguish between previously reported ferroelectrics, materials known for alternative applications, and lesser-known materials, we combine this ranking with a survey of the existing literature on these candidates through Google Scholar and Scopus databases, revealing ~130 promising materials uninvestigated as ferroelectric. Our workflow and large-scale high-throughput screening lays the groundwork for the discovery of novel ferroelectrics, revealing numerous candidates materials for future experimental and theoretical endeavors.
Adaptive finite differencing in high accuracy electronic structure calculations
Authors: Briggs E. L. , Lu Wenchang , Bernholc J.
Published: January 2024

A multi-order Adaptive Finite Differencing (AFD) method is developed for the kinetic energy operator in real-space, grid-based electronic structure codes. It uses atomic pseudo orbitals produced by the corresponding pseudopotential codes to optimize the standard finite difference (SFD) operators for improved precision. Results are presented for a variety of test systems and Bravais lattice types, including the well-known Δ test for 71 elements in the periodic table, the Mott insulator NiO, and borax decahydrate, which contains covalent, ionic, and hydrogen bonds. The tests show that an 8th-order AFD operator leads to the same average Δ value as that achieved by plane-wave codes and is typically far more accurate and has a much lower computational cost than a 12th-order SFD operator. The scalability of real-space electronic calculations is demonstrated for a 2016-atom NiO cell, for which the computational time decreases nearly linearly when scaled from 18 to 144 CPU-GPU nodes.
On the dynamical stability of copper-doped lead apatite
Authors: Kim Sun-Woo , Wang Kang , Chen Siyu , Conway Lewis J. , Pascut G. Lucian , Errea Ion , Pickard Chris J. , Monserrat Bartomeu
Published: January 2024

The recent claim of room temperature superconductivity in a copper-doped lead apatite compound, called LK-99, has sparked remarkable interest and controversy. Subsequent experiments have largely failed to reproduce the claimed superconductivity, while theoretical works have identified multiple key features including strong electronic correlation, structural instabilities, and dopability constraints. A puzzling claim of several recent theoretical studies is that both parent and copper-doped lead apatite structures are dynamically unstable at the harmonic level, questioning decades of experimental reports of the parent compound structures and the recently proposed copper-doped structures. In this work, we demonstrate that both parent and copper-doped lead apatite structures are dynamically stable at room temperature. Anharmonic phonon–phonon interactions play a key role in stabilizing some copper-doped phases, while most phases are largely stable even at the harmonic level. We also show that dynamical stability depends on both volume and correlation strength, suggesting controllable ways of exploring the copper-doped lead apatite structural phase diagram. Our results fully reconcile the theoretical description of the structures of both parent and copper-doped lead apatite with the experiment.
CSF α-synuclein seed amplification kinetic profiles are associated with cognitive decline in Parkinson’s disease
Authors: Brockmann Kathrin , Lerche Stefanie , Baiardi Simone , Rossi Marcello , Wurster Isabel , Quadalti Corinne , Roeben Benjamin , Mammana Angela , Zimmermann Milan , Hauser Ann‑Kathrin , Deuschle Christian , Schulte Claudia , Liepelt-Scarfone Inga , Gasser Thomas , Parchi Piero
Published: January 2024

Seed amplification assays have been implemented in Parkinson’s disease to reveal disease-specific misfolded alpha-synuclein aggregates in biospecimens. While the assays’ qualitative dichotomous seeding response is valuable to stratify and enrich cohorts for alpha-synuclein pathology in general, more quantitative parameters that are associated with clinical dynamics of disease progression and that might potentially serve as exploratory outcome measures in clinical trials targeting alpha-synuclein would add important information. To evaluate whether the seeding kinetic parameters time required to reach the seeding threshold (LAG phase), the peak of fluorescence response (Imax), and the area under the curve (AUC) are associated with clinical trajectories, we analyzed LAG, Imax, and AUC in relation to the development of cognitive decline in a longitudinal cohort of 199 people with Parkinson’s disease with positive CSF alpha-synuclein seeding status. Patients were stratified into tertiles based on their individual CSF alpha-synuclein seeding kinetic properties. The effect of the kinetic parameters on longitudinal development of cognitive impairment defined by MoCA ≤25 was analyzed by Cox-Regression. Patients with a higher number of positive seeding replicates and tertile groups of shorter LAG, higher Imax, and higher AUC showed a higher prevalence of and a shorter duration until cognitive impairment longitudinally (3, 6, and 3 years earlier with p ≤ 0.001, respectively). Results remained similar in separate subgroup analyses of patients with and without GBA mutation. We conclude that a more prominent alpha-synuclein seeding kinetic profile translates into a more rapid development of cognitive decline.
hUC-MSCs-derived MFGE8 ameliorates locomotor dysfunction via inhibition of ITGB3/ NF-κB signaling in an NMO mouse model
Authors: Xu Huiming , Jiang Wei , Li Xuejia , Jiang Jiaohua , Afridi Shabbir Khan , Deng Longhui , Li Rui , Luo Ermei , Zhang Zhaoqing , Huang Yu-Wen Alvin , Cui Yaxiong , So Kwok-Fai , Chen Haijia , Qiu Wei , Tang Changyong
Published: January 2024

Neuromyelitis optica (NMO) is a severe autoimmune inflammatory disease of the central nervous system that affects motor function and causes relapsing disability. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been used extensively in the treatment of various inflammatory diseases, due to their potent regulatory roles that can mitigate inflammation and repair damaged tissues. However, their use in NMO is currently limited, and the mechanism underlying the beneficial effects of hUC-MSCs on motor function in NMO remains unclear. In this study, we investigate the effects of hUC-MSCs on the recovery of motor function in an NMO systemic model. Our findings demonstrate that milk fat globule epidermal growth 8 (MFGE8), a key functional factor secreted by hUC-MSCs, plays a critical role in ameliorating motor impairments. We also elucidate that the MFGE8/Integrin αvβ3/NF-κB signaling pathway is partially responsible for structural and functional recovery, in addition to motor functional enhancements induced by hUC-MSC exposure. Taken together, these findings strongly support the involvement of MFGE8 in mediating hUC-MSCs-induced improvements in motor functional recovery in an NMO mouse model. In addition, this provides new insight on the therapeutic potential of hUC-MSCs and the mechanisms underlying their beneficial effects in NMO.