bluuebunny/crossref_metadata_2025 huggingface dataset:
Is combined antidepressant medication (ADM) and psychotherapy better than either monotherapy at preventing suicide attempts and other psychiatric serious adverse events for depressed patients? A rare events meta-analysis
Authors: Zainal Nur Hani
Published: November 2023

Antidepressant medication (ADM)-only, psychotherapy-only, and their combination are the first-line treatment options for major depressive disorder (MDD). Previous meta-analyses of randomized controlled trials (RCTs) established that psychotherapy and combined treatment were superior to ADM-only for MDD treatment remission or response. The current meta-analysis extended previous ones by determining the comparative efficacy of ADM-only, psychotherapy-only, and combined treatment on suicide attempts and other serious psychiatric adverse events (i.e. psychiatric emergency department [ED] visit, psychiatric hospitalization, and/or suicide death; SAEs). Peto odds ratios (ORs) and their 95% confidence intervals were computed from the present random-effects meta-analysis. Thirty-four relevant RCTs were included. Psychotherapy-only was stronger than combined treatment (1.9% v. 3.7%; OR 1.96 [1.20–3.20], p = 0.012) and ADM-only (3.0% v. 5.6%; OR 0.45 [0.30–0.67], p = 0.001) in decreasing the likelihood of SAEs in the primary and trim-and-fill sensitivity analyses. Combined treatment was better than ADM-only in reducing the probability of SAEs (6.0% v. 8.7%; OR 0.74 [0.56–0.96], p = 0.029), but this comparative efficacy finding was non-significant in the sensitivity analyses. Subgroup analyses revealed the advantage of psychotherapy-only over combined treatment and ADM-only for reducing SAE risk among children and adolescents and the benefit of combined treatment over ADM-only among adults. Overall, psychotherapy and combined treatment outperformed ADM-only in reducing the likelihood of SAEs, perhaps by conferring strategies to enhance reasons for living. Plausibly, psychotherapy should be prioritized for high-risk youths and combined treatment for high-risk adults with MDD.
Voluntary and cued language switching in late bilingual speakers
Authors: Mooijman Saskia , Schoonen Rob , Ruiter Marina B. , Roelofs Ardi
Published: November 2023

Previous research examining the factors that determine language choice and voluntary switching mainly involved early bilinguals. Here, using picture naming, we investigated language choice and switching in late Dutch–English bilinguals. We found that naming was overall slower in cued than in voluntary switching, but switch costs occurred in both types of switching. The magnitude of switch costs differed depending on the task and language, and was moderated by L2 proficiency. Self-rated rather than objectively assessed proficiency predicted voluntary switching and ease of lexical access was associated with language choice. Between-language and within-language switch costs were not correlated. These results highlight self-rated proficiency as a reliable predictor of voluntary switching, with language modulating switch costs. As in early bilinguals, ease of lexical access was related to word-level language choice of late bilinguals.
Devonian to Early Carboniferous Retreating—Advancing Subduction Switch in the Northwestern Patagonia Accretionary Orogen: U‐Pb and Lu‐Hf Isotopic Insights
Authors: Marcos Paulo , Renda Emiliano M. , González Pablo D. , Oriolo Sebastián , Scivetti Nicolás , Benedini Leonardo , Geraldes Mauro , Gregori Daniel , Yoya María Belén , Bahía Marcos
Published: November 2023

In this contribution, we present new early middle Devonian igneous and metaigneous units with a major juvenile magmatic source input in the North Patagonian Massif, which were discovered through U‐Pb and Lu‐Hf zircon analyses. Afterward, we assessed their tectonic implications for northwestern Patagonia and then for southern South America, combining our results with available database information consisting of igneous crystallization ages and isotopic data of the Devonian to early Carboniferous magmatic units, tectonic‐metamorphic analyses, and thermochronologic record. This study allows for distinguishing retreating and advancing subduction switching in northwestern Patagonia (38°30′ to 44°S) and a contrasting coetaneous evolution for basement outcrops exposed further north (27°30′ and 37°30′S). The early middle Devonian (400–380 Ma) northwestern Patagonian magmatism is characterized by widespread magmatism and positive εHf–εNd linked to forearc and backarc magmatism that evolved within a retreating subduction stage. A tectonic switching toward advancing orogeny stage began in the late Devonian, evidenced by a lull in magmatic activity with a negative εHf–εNd trend, possibly contemporaneous with the first tectonic‐metamorphic event in western Patagonia. An early Carboniferous magmatic gap, followed by the subsequent development of the main foliation in the basement during the Carboniferous‐Permian period, denotes the acme of this contractional stage. In contrast, the Devonian period in the northern segment is characterized by mostly negative εHf–εNd values, reverse shear zone activity in the foreland, and an inboard magmatism migration, evidencing a compressive tectonic setting that changed to an extensional configuration in the early Carboniferous with widespread arc magmatism development.
Deformation Mechanisms, Microstructures, and Seismic Anisotropy of Wadsleyite in the Earth's Transition Zone
Authors: Ledoux Estelle E. , Saki Morvarid , Gay Jeffrey P. , Krug Matthias , Castelnau Olivier , Zhou Wen‐Yi , Zhang Jin S. , Chantel Julien , Hilairet Nadège , Bykov Maxim , Bykova Elena , Aprilis Georgios , Svitlyk Volodymyr , Garbarino Gaston , Sanchez‐Valle Carmen , Thomas Christine , Speziale Sergio , Merkel Sébastien
Published: November 2023

Wadsleyite is the dominant mineral of the upper portion of the Earth's mantle transition zone (MTZ). As such, understanding plastic deformation of wadsleyite is relevant for the interpretation of observations of seismic signals from this region in terms of mantle flow. Despite its relevance, however, the deformation mechanisms of wadsleyite and their effects on microstructures and anisotropy are still poorly understood. Here, we present the results of new deformation experiments on polycrystalline wadsleyite at temperatures of 1400–1770 K and pressures between 12.3 and 20.3 GPa in the laser‐heated diamond anvil cell. We rely on multigrain X‐ray crystallography to follow the evolution of individual grain orientations and extract lattice preferred orientations at the sample scale at different steps of the experiments. A comparison of experimental results of our work and the literature with polycrystal plasticity simulations, indicates that 〈111〉{101} is the most active slip system of dislocations in wadsleyite at all investigated conditions. Secondary slip systems such as [001](010), [100](001), and [100]{0kl}, however, play a critical role in the resulting microstructures and their activity depends on both temperature and water content, from which we extract an updated deformation map of wadsleyite at MTZ conditions. Lastly, we propose several seismic anisotropy models of the upper part of the MTZ, depending on temperature, geophysical context, and levels of hydration that will be useful for the interpretation of seismic signals from the MTZ in terms of mantle flow and water content.
Lithospheric Structure Controls Sequentially Active Detachment Faulting at the Longqi Segment on the Southwest Indian Ridge
Authors: Chen Ming , Tao Chunhui , Rüpke Lars H. , Liu Yunlong , Wang Hanchuang , Liu Sibiao
Published: November 2023

Oceanic detachment faulting, a major mode of seafloor accretion at slow and ultraslow spreading ridges, is thought to occur during magma‐poor phases and be abandoned when magmatism increases. In this framework, detachment faulting is the result of temporal variations in magma flux, which is inconsistent with recent geophysical observations at the Longqi segment on the Southwest Indian Ridge (49°42′E). In this paper, we focus on this sequentially active detachment faulting system that includes an old, inactive detachment fault and a younger, active detachment fault. We investigate the mechanisms controlling the temporal evolution of this tectonomagmatic system by using 2D mid‐ocean ridge spreading models that simulate faulting and magma intrusion into a visco‐elasto‐plastic continuum. Our models show that temporal variations in magma flux alone are insufficient to match the inferred temporal evolution of the sequentially active detachment system. Rather we find that sequentially active detachment faulting spontaneously occurs at the Longqi segment as a function of lithospheric thickness. This finding is in agreement with an analytical model, which shows that a thicker axial lithosphere results in a smaller fault heave and that a flatter angle in lithosphere thickening away from the accretion axis stabilizes the active fault. A thicker axial lithosphere and its flatter off‐axis angle combined have the potential to modulate sequentially active detachment faulting at the Longqi segment. Our results thus suggest that temporal changes of magmatism are not necessary for the development and abandonment of detachment faults at ultraslow spreading ridges.
Subseasonal Clustering of Atmospheric Rivers Over the Western United States
Authors: Slinskey Emily A. , Hall Alex , Goldenson Naomi , Loikith Paul C. , Norris Jesse
Published: November 2023

The serial occurrence of atmospheric rivers (ARs) along the US West Coast can lead to prolonged and exacerbated hydrologic impacts, threatening flood‐control and water‐supply infrastructure due to soil saturation and diminished recovery time between storms. Here a statistical approach for quantifying subseasonal temporal clustering among extreme events is applied to a 41‐year (1979–2019) wintertime AR catalog across the western United States (US). Observed AR occurrence, compared against a randomly distributed AR timeseries with the same average event density, reveals temporal clustering at a greater‐than‐random rate across the western US with a distinct geographical pattern. Compared to the Pacific Northwest, significant AR clusters over the northern Coastal Range of California and Sierra Nevada are more frequent and occur over longer time periods. Clusters along the California Coastal Range typically persist for 2 weeks, are composed of 4–5 ARs per cluster, and account for over 85% of total AR occurrence. Across the northwest Coast‐Cascade Ranges, clusters account for ∼50% of total AR occurrence, typically last 8–10 days, and contain 3–4 individual AR events. Based on precipitation data from a high‐resolution dynamical downscaling of reanalysis, the fractions of total and extreme hourly precipitation attributable to AR clusters are largest along the northern California coast and in the Sierra Nevada. Interannual variability among clusters highlights their importance for determining whether a particular water year is anomalously wet or dry. The mechanisms behind this unusual clustering are unclear and require further research.
High Resolution Mapping of Nitrate Loads of a Reservoir Using an Uncrewed Surface Vehicle: Potential Opportunities and Challenges
Authors: Lee Kwang‐Hun , Ali Shahid , Kim Yena , Lee Kitack , Kwon Sae Yun , Kam Jonghun
Published: November 2023

Reliable nutrient load estimation of a reservoir is challenging due to inconsistent spatial extent and temporal frequency of water quality and quantity measurements. This study aims to collect consistent spatial extent and temporal frequency of water depths and nitrate concentrations of a reservoir in South Korea using uncrewed surface vehicle (USV). In this study, reservoir nitrate loads were estimated using four methods to examine how spatial variation in water depth and nitrate concentrations affected load estimates. Based on dual measurements of water depth and nitrate concentration, reservoir nitrate loads across 30 sampling dates (0.7 million tons of fresh water on average) ranged from one to four tons. Results showed that a point measurement of water depths and nitrate concentrations can cause up to −17% of underestimation of nitrate loads, particularly after intense rainfall events. This study highlights potential opportunities and challenges of the USV‐based dual monitoring systems for water quality and quantity.
The effects of experience of discrimination and acculturation during pregnancy on the developing offspring brain
Authors: Spann Marisa N. , Alleyne Kiarra , Holland Cristin M. , Davids Antonette , Pierre-Louis Arline , Bang Claire , Oyeneye Victoria , Kiflom Rebecca , Shea Eileen , Cheng Bin , Peterson Bradley S. , Monk Catherine , Scheinost Dustin
Published: November 2023

The experience of ethnic, racial, and structural inequalities is increasingly recognized as detrimental to health, and early studies suggest that its experience in pregnant mothers may affect the developing fetus. We characterized discrimination and acculturation experiences in a predominantly Hispanic sample of pregnant adolescent women and assessed their association with functional connectivity in their neonate’s brain. We collected self-report measures of acculturation, discrimination, maternal distress (i.e., perceived stress, childhood trauma, and depressive symptoms), and socioeconomic status in 165 women. Then, we performed a data-driven clustering of acculturation, discrimination, perceived stress, depressive symptoms, trauma, and socioeconomic status variables during pregnancy to determine whether discrimination or acculturation clustered into distinct factors. Discrimination and acculturation styles loaded onto different factors from perceived stress, depressive symptoms, trauma, and socioeconomic status, suggesting that they were distinct from other factors in our sample. We associated these data-driven maternal phenotypes (discrimination and acculturation styles) with measures of resting-state functional MRI connectivity of the infant amygdala (n = 38). Higher maternal report of assimilation was associated with weaker connectivity between their neonate’s amygdala and bilateral fusiform gyrus. Maternal experience of discrimination was associated with weaker connectivity between the amygdala and prefrontal cortex and stronger connectivity between the amygdala and fusiform of their neonate. Cautiously, the results may suggest a similarity to self-contained studies with adults, noting that the experience of discrimination and acculturation may influence amygdala circuitry across generations. Further prospective studies are essential that consider a more diverse population of minoritized individuals and with a comprehensive assessment of ethnic, racial, and structural factors.
mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions
Authors: Cosialls Emma , Pacreau Emeline , Duruel Clémence , Ceccacci Sara , Elhage Rima , Desterke Christophe , Roger Kevin , Guerrera Chiara , Ducloux Romane , Souquere Sylvie , Pierron Gérard , Nemazanyy Ivan , Kelly Mairead , Dalmas Elise , Chang Yunhua , Goffin Vincent , Mehrpour Maryam , Hamaï Ahmed
Published: November 2023

Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment.
BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury
Authors: Zhang Wen , Liu Kai , Ren Guang-Ming , Wang Yu , Wang Ting , Liu Xian , Li Dong-Xu , Xiao Yang , Chen Xu , Li Ya-Ting , Zhan Yi-Qun , Xiang Shen-Si , Chen Hui , Gao Hui-Ying , Zhao Ke , Yu Miao , Ge Chang-Hui , Li Chang-Yan , Ge Zhi-Qiang , Yang Xiao-Ming , Yin Rong-Hua
Published: November 2023

BRISC (BRCC3 isopeptidase complex) is a deubiquitinating enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1β, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.
Single cell dynamics of tumor specificity vs bystander activity in CD8+ T cells define the diverse immune landscapes in colorectal cancer
Authors: Borràs Daniel Morales , Verbandt Sara , Ausserhofer Markus , Sturm Gregor , Lim Jinyeong , Verge Gil Arasa , Vanmeerbeek Isaure , Laureano Raquel S. , Govaerts Jannes , Sprooten Jenny , Hong Yourae , Wall Rebecca , De Hertogh Gert , Sagaert Xavier , Bislenghi Gabriele , D’Hoore André , Wolthuis Albert , Finotello Francesca , Park Woong-Yang , Naulaerts Stefan , Tejpar Sabine , Garg Abhishek D.
Published: November 2023

CD8+ T cell activation via immune checkpoint blockade (ICB) is successful in microsatellite instable (MSI) colorectal cancer (CRC) patients. By comparison, the success of immunotherapy against microsatellite stable (MSS) CRC is limited. Little is known about the most critical features of CRC CD8+ T cells that together determine the diverse immune landscapes and contrasting ICB responses. Hence, we pursued a deep single cell mapping of CRC CD8+ T cells on transcriptomic and T cell receptor (TCR) repertoire levels in a diverse patient cohort, with additional surface proteome validation. This revealed that CRC CD8+ T cell dynamics are underscored by complex interactions between interferon-γ signaling, tumor reactivity, TCR repertoire, (predicted) TCR antigen-specificities, and environmental cues like gut microbiome or colon tissue-specific ‘self-like’ features. MSI CRC CD8+ T cells showed tumor-specific activation reminiscent of canonical ‘T cell hot’ tumors, whereas the MSS CRC CD8+ T cells exhibited tumor unspecific or bystander-like features. This was accompanied by inflammation reminiscent of ‘pseudo-T cell hot’ tumors. Consequently, MSI and MSS CRC CD8+ T cells showed overlapping phenotypic features that differed dramatically in their TCR antigen-specificities. Given their high discriminating potential for CD8+ T cell features/specificities, we used the single cell tumor-reactive signaling modules in CD8+ T cells to build a bulk tumor transcriptome classification for CRC patients. This “Immune Subtype Classification” (ISC) successfully distinguished various tumoral immune landscapes that showed prognostic value and predicted immunotherapy responses in CRC patients. Thus, we deliver a unique map of CRC CD8+ T cells that drives a novel tumor immune landscape classification, with relevance for immunotherapy decision-making.
Hippocampal firing fields anchored to a moving object predict homing direction during path-integration-based behavior
Authors: Najafian Jazi Maryam , Tymorek Adrian , Yen Ting-Yun , Jose Kavarayil Felix , Stingl Moritz , Chau Sherman Richard , Baskurt Benay , García Vilela Celia , Allen Kevin
Published: November 2023

Homing based on path integration (H-PI) is a form of navigation in which an animal uses self-motion cues to keep track of its position and return to a starting point. Despite evidence for a role of the hippocampus in homing behavior, the hippocampal spatial representations associated with H-PI are largely unknown. Here we developed a homing task (AutoPI task) that required a mouse to find a randomly placed lever on an arena before returning to its home base. Recordings from the CA1 area in male mice showed that hippocampal neurons remap between random foraging and AutoPI task, between trials in light and dark conditions, and between search and homing behavior. During the AutoPI task, approximately 25% of the firing fields were anchored to the lever position. The activity of 24% of the cells with a lever-anchored field predicted the homing direction of the animal on each trial. Our results demonstrate that the activity of hippocampal neurons with object-anchored firing fields predicts homing behavior.
Altered corollary discharge signaling in the auditory cortex of a mouse model of schizophrenia predisposition
Authors: Rummell Brian P. , Bikas Solmaz , Babl Susanne S. , Gogos Joseph A. , Sigurdsson Torfi
Published: November 2023

The ability to distinguish sensations that are self-generated from those caused by external events is disrupted in schizophrenia patients. However, the neural circuit abnormalities underlying this sensory impairment and its relationship to the risk factors for the disease is not well understood. To address this, we examined the processing of self-generated sounds in male Df(16)A+/− mice, which model one of the largest genetic risk factors for schizophrenia, the 22q11.2 microdeletion. We find that auditory cortical neurons in Df(16)A+/− mice fail to attenuate their responses to self-generated sounds, recapitulating deficits seen in schizophrenia patients. Notably, the auditory cortex of Df(16)A+/− mice displayed weaker motor-related signals and received fewer inputs from the motor cortex, suggesting an anatomical basis underlying the sensory deficit. These results provide insights into the mechanisms by which a major genetic risk factor for schizophrenia disrupts the top-down processing of sensory information.
Lead-free Zr-doped ceria ceramics with low permittivity displaying giant electrostriction
Authors: Varenik Maxim , Xu Boyuan , Li Junying , Gaver Elad , Wachtel Ellen , Ehre David , Routh Prahlad K. , Khodorov Sergey , Frenkel Anatoly I. , Qi Yue , Lubomirsky Igor
Published: November 2023

Electrostrictors, materials developing mechanical strain proportional to the square of the applied electric field, present many advantages for mechanical actuation as they convert electrical energy into mechanical, but not vice versa. Both high relative permittivity and reliance on Pb as the key component in commercial electrostrictors pose serious practical and health problems. Here we describe a low relative permittivity (<250) ceramic, ZrxCe1-xO2 (x < 0.2), that displays electromechanical properties rivaling those of the best performing electrostrictors: longitudinal electrostriction strain coefficient ~10−16 m2/V2; relaxation frequency ≈ a few kHz; and strain ≥0.02%. Combining X-ray absorption spectroscopy, atomic-level modeling and electromechanical measurements, here we show that electrostriction in ZrxCe1-xO2 is enabled by elastic dipoles produced by anharmonic motion of the smaller isovalent dopant (Zr). Unlike the elastic dipoles in aliovalent doped ceria, which are present even in the absence of an applied elastic or electric field, the elastic dipoles in ZrxCe1-xO2 are formed only under applied anisotropic field. The local descriptors of electrostrictive strain, namely, the cation size mismatch and dynamic anharmonicity, are sufficiently versatile to guide future searches in other polycrystalline solids.
PAX3-FOXO1 dictates myogenic reprogramming and rhabdomyosarcoma identity in endothelial progenitors
Authors: Searcy Madeline B. , Larsen Randolph K. , Stevens Bradley T. , Zhang Yang , Jin Hongjian , Drummond Catherine J. , Langdon Casey G. , Gadek Katherine E. , Vuong Kyna , Reed Kristin B. , Garcia Matthew R. , Xu Beisi , Kimbrough Darden W. , Adkins Grace E. , Djekidel Nadhir , Porter Shaina N. , Schreiner Patrick A. , Pruett-Miller Shondra M. , Abraham Brian J. , Rehg Jerold E. , Hatley Mark E.
Published: November 2023

Fusion-positive rhabdomyosarcoma (FP-RMS) driven by the expression of the PAX3-FOXO1 (P3F) fusion oncoprotein is an aggressive subtype of pediatric rhabdomyosarcoma. FP-RMS histologically resembles developing muscle yet occurs throughout the body in areas devoid of skeletal muscle highlighting that FP-RMS is not derived from an exclusively myogenic cell of origin. Here we demonstrate that P3F reprograms mouse and human endothelial progenitors to FP-RMS. We show that P3F expression in aP2-Cre expressing cells reprograms endothelial progenitors to functional myogenic stem cells capable of regenerating injured muscle fibers. Further, we describe a FP-RMS mouse model driven by P3F expression and Cdkn2a loss in endothelial cells. Additionally, we show that P3F expression in TP53-null human iPSCs blocks endothelial-directed differentiation and guides cells to become myogenic cells that form FP-RMS tumors in immunocompromised mice. Together these findings demonstrate that FP-RMS can originate from aberrant development of non-myogenic cells driven by P3F.
Interferon stimulated immune profile changes in a humanized mouse model of HBV infection
Authors: Wang Yaping , Guo Liliangzi , Shi Jingrong , Li Jingyun , Wen Yanling , Gu Guoming , Cui Jianping , Feng Chengqian , Jiang Mengling , Fan Qinghong , Tang Jingyan , Chen Sisi , Zhang Jun , Zheng Xiaowen , Pan Meifang , Li Xinnian , Sun Yanxia , Zhang Zheng , Li Xian , Hu Fengyu , Zhang Liguo , Tang Xiaoping , Li Feng
Published: November 2023

The underlying mechanism of chronic hepatitis B virus (HBV) functional cure by interferon (IFN), especially in patients with low HBsAg and/or young ages, is still unresolved due to the lack of surrogate models. Here, we generate a type I interferon receptor humanized mouse (huIFNAR mouse) through a CRISPR/Cas9-based knock-in strategy. Then, we demonstrate that human IFN stimulates gene expression profiles in huIFNAR peripheral blood mononuclear cells (PBMCs) are similar to those in human PBMCs, supporting the representativeness of this mouse model for functionally analyzing human IFN in vivo. Next, we reveal the tissue-specific gene expression atlas across multiple organs in response to human IFN treatment; this pattern has not been reported in healthy humans in vivo. Finally, by using the AAV-HBV model, we test the antiviral effects of human interferon. Fifteen weeks of human PEG-IFNα2 treatment significantly reduces HBsAg and HBeAg and even achieves HBsAg seroconversion. We observe that activation of intrahepatic monocytes and effector memory CD8 T cells by human interferon may be critical for HBsAg suppression. Our huIFNAR mouse can authentically respond to human interferon stimulation, providing a platform to study interferon function in vivo. PEG-IFNα2 treatment successfully suppresses intrahepatic HBV replication and achieves HBsAg seroconversion.
A generalized Knudsen theory for gas transport with specular and diffuse reflections
Authors: Qian JianHao , Wu HengAn , Wang FengChao
Published: November 2023

Gas permeation through nanopores is a long-standing research interest because of its importance in fundamental science and many technologies. The free molecular flow is conventionally described by Knudsen theory, under the diffuse reflection assumption. Recent experiments reported ballistic molecular transport of gases, which urges for the development of theoretical tools to address the predominant specular reflections on atomically smooth surfaces. Here we develop a generalized Knudsen theory, which is applicable to various boundary conditions covering from the extreme specular reflection to the complete diffuse reflection. Our model overcomes the limitation of Smoluchowski model, which predicts the gas flow rate diverging to infinity for specular reflection. It emphasizes that the specular reflection can reduce the dissipation flow rate. Our model is validated using molecular dynamics simulations in various scenarios. The proposed model provides insights into the gas transport under confinement and extends Knudsen theory to free molecular flow with specular reflections.
A cost comparison of various hourly-reliable and net-zero hydrogen production pathways in the United States
Authors: Bracci Justin M. , Sherwin Evan D. , Boness Naomi L. , Brandt Adam R.
Published: November 2023

Hydrogen (H2) as an energy carrier may play a role in various hard-to-abate subsectors, but to maximize emission reductions, supplied hydrogen must be reliable, low-emission, and low-cost. Here, we build a model that enables direct comparison of the cost of producing net-zero, hourly-reliable hydrogen from various pathways. To reach net-zero targets, we assume upstream and residual facility emissions are mitigated using negative emission technologies. For the United States (California, Texas, and New York), model results indicate next-decade hybrid electricity-based solutions are lower cost ($2.02-$2.88/kg) than fossil-based pathways with natural gas leakage greater than 4% ($2.73-$5.94/kg). These results also apply to regions outside of the U.S. with a similar climate and electric grid. However, when omitting the net-zero emission constraint and considering the U.S. regulatory environment, electricity-based production only achieves cost-competitiveness with fossil-based pathways if embodied emissions of electricity inputs are not counted under U.S. Tax Code Section 45V guidance.
Mercury deposition and redox transformation processes in peatland constrained by mercury stable isotopes
Authors: Li Chuxian , Jiskra Martin , Nilsson Mats B. , Osterwalder Stefan , Zhu Wei , Mauquoy Dmitri , Skyllberg Ulf , Enrico Maxime , Peng Haijun , Song Yu , Björn Erik , Bishop Kevin
Published: November 2023

Peatland vegetation takes up mercury (Hg) from the atmosphere, typically contributing to net production and export of neurotoxic methyl-Hg to downstream ecosystems. Chemical reduction processes can slow down methyl-Hg production by releasing Hg from peat back to the atmosphere. The extent of these processes remains, however, unclear. Here we present results from a comprehensive study covering concentrations and isotopic signatures of Hg in an open boreal peatland system to identify post-depositional Hg redox transformation processes. Isotope mass balances suggest photoreduction of HgII is the predominant process by which 30% of annually deposited Hg is emitted back to the atmosphere. Isotopic analyses indicate that above the water table, dark abiotic oxidation decreases peat soil gaseous Hg0 concentrations. Below the water table, supersaturation of gaseous Hg is likely created more by direct photoreduction of rainfall rather than by reduction and release of Hg from the peat soil. Identification and quantification of these light-driven and dark redox processes advance our understanding of the fate of Hg in peatlands, including the potential for mobilization and methylation of HgII.
Single cell transcriptomics shows that malaria promotes unique regulatory responses across multiple immune cell subsets
Authors: Dooley Nicholas L. , Chabikwa Tinashe G. , Pava Zuleima , Loughland Jessica R. , Hamelink Julianne , Berry Kiana , Andrew Dean , Soon Megan S. F. , SheelaNair Arya , Piera Kim A. , William Timothy , Barber Bridget E. , Grigg Matthew J. , Engwerda Christian R. , Lopez J. Alejandro , Anstey Nicholas M. , Boyle Michelle J.
Published: November 2023

Plasmodium falciparum malaria drives immunoregulatory responses across multiple cell subsets, which protects from immunopathogenesis, but also hampers the development of effective anti-parasitic immunity. Understanding malaria induced tolerogenic responses in specific cell subsets may inform development of strategies to boost protective immunity during drug treatment and vaccination. Here, we analyse the immune landscape with single cell RNA sequencing during P. falciparum malaria. We identify cell type specific responses in sub-clustered major immune cell types. Malaria is associated with an increase in immunosuppressive monocytes, alongside NK and γδ T cells which up-regulate tolerogenic markers. IL-10-producing Tr1 CD4 T cells and IL-10-producing regulatory B cells are also induced. Type I interferon responses are identified across all cell types, suggesting Type I interferon signalling may be linked to induction of immunoregulatory networks during malaria. These findings provide insights into cell-specific and shared immunoregulatory changes during malaria and provide a data resource for further analysis.
Polyethyleneimine-coated MXene quantum dots improve cotton tolerance to Verticillium dahliae by maintaining ROS homeostasis
Authors: Qiu Ping , Li Jiayue , Zhang Lin , Chen Kun , Shao Jianmin , Zheng Baoxin , Yuan Hang , Qi Jie , Yue Lin , Hu Qin , Ming Yuqing , Liu Shiming , Long Lu , Gu Jiangjiang , Zhang Xianlong , Lindsey Keith , Gao Wei , Wu Honghong , Zhu Longfu
Published: November 2023

Verticillium dahliae is a soil-borne hemibiotrophic fungal pathogen that threatens cotton production worldwide. In this study, we assemble the genomes of two V. dahliae isolates: the more virulence and defoliating isolate V991 and nondefoliating isolate 1cd3-2. Transcriptome and comparative genomics analyses show that genes associated with pathogen virulence are mostly induced at the late stage of infection (Stage II), accompanied by a burst of reactive oxygen species (ROS), with upregulation of more genes involved in defense response in cotton. We identify the V991-specific virulence gene SP3 that is highly expressed during the infection Stage II. V. dahliae SP3 knock-out strain shows attenuated virulence and triggers less ROS production in cotton plants. To control the disease, we employ polyethyleneimine-coated MXene quantum dots (PEI-MQDs) that possess the ability to remove ROS. Cotton seedlings treated with PEI-MQDs are capable of maintaining ROS homeostasis with enhanced peroxidase, catalase, and glutathione peroxidase activities and exhibit improved tolerance to V. dahliae. These results suggest that V. dahliae trigger ROS production to promote infection and scavenging ROS is an effective way to manage this disease. This study reveals a virulence mechanism of V. dahliae and provides a means for V. dahliae resistance that benefits cotton production.
Facile access to benzofuran derivatives through radical reactions with heteroatom-centered super-electron-donors
Authors: Jiang Shichun , Wang Wei , Mou Chengli , Zou Juan , Jin Zhichao , Hao Gefei , Chi Yonggui Robin
Published: November 2023

The development of suitable electron donors is critical to single-electron-transfer (SET) processes. The use of heteroatom-centered anions as super-electron-donors (SEDs) for direct SET reactions has rarely been studied. Here we show that heteroatom anions can be applied as SEDs to initiate radical reactions for facile synthesis of 3-substituted benzofurans. Phosphines, thiols and anilines bearing different substitution patterns work well in this inter-molecular radical coupling reaction and the 3-functionalized benzofuran products bearing heteroatomic functionalities are given in moderate to excellent yields. The reaction mechanism is elucidated via control experiments and computational methods. The afforded products show promising applications in both organic synthesis and pesticide development.
Structural and dynamic mechanisms for coupled folding and tRNA recognition of a translational T-box riboswitch
Authors: Niu Xiaolin , Xu Zhonghe , Zhang Yufan , Zuo Xiaobing , Chen Chunlai , Fang Xianyang
Published: November 2023

T-box riboswitches are unique riboregulators where gene regulation is mediated through interactions between two highly structured RNAs. Despite extensive structural insights, how RNA-RNA interactions drive the folding and structural transitions of T-box to achieve functional conformations remains unclear. Here, by combining SAXS, single-molecule FRET and computational modeling, we elaborate the folding energy landscape of a translational T-box aptamer consisting of stems I, II and IIA/B, which Mg2+-induced global folding and tRNA binding are cooperatively coupled. smFRET measurements reveal that high Mg2+ stabilizes IIA/B and its stacking on II, which drives the pre-docking of I and II into a competent conformation, subsequent tRNA binding promotes docking of I and II to form a high-affinity tRNA binding groove, of which the essentiality of IIA/B and S-turn in II is substantiated with mutational analysis. We highlight a delicate balance among Mg2+, the intra- and intermolecular RNA-RNA interactions in modulating RNA folding and function.
M. mazei glutamine synthetase and glutamine synthetase-GlnK1 structures reveal enzyme regulation by oligomer modulation
Authors: Schumacher Maria A. , Salinas Raul , Travis Brady A. , Singh Rajiv Ranjan , Lent Nicholas
Published: November 2023

Glutamine synthetases (GS) play central roles in cellular nitrogen assimilation. Although GS active-site formation requires the oligomerization of just two GS subunits, all GS form large, multi-oligomeric machines. Here we describe a structural dissection of the archaeal Methanosarcina mazei (Mm) GS and its regulation. We show that Mm GS forms unstable dodecamers. Strikingly, we show this Mm GS oligomerization property is leveraged for a unique mode of regulation whereby labile Mm GS hexamers are stabilized by binding the nitrogen regulatory protein, GlnK1. Our GS-GlnK1 structure shows that GlnK1 functions as molecular glue to affix GS hexamers together, stabilizing formation of GS active-sites. These data, therefore, reveal the structural basis for a unique form of enzyme regulation by oligomer modulation.
Deep learning of human polyadenylation sites at nucleotide resolution reveals molecular determinants of site usage and relevance in disease
Authors: Stroup Emily Kunce , Ji Zhe
Published: November 2023

The genomic distribution of cleavage and polyadenylation (polyA) sites should be co-evolutionally optimized with the local gene structure. Otherwise, spurious polyadenylation can cause premature transcription termination and generate aberrant proteins. To obtain mechanistic insights into polyA site optimization across the human genome, we develop deep/machine learning models to identify genome-wide putative polyA sites at unprecedented nucleotide-level resolution and calculate their strength and usage in the genomic context. Our models quantitatively measure position-specific motif importance and their crosstalk in polyA site formation and cleavage heterogeneity. The intronic site expression is governed by the surrounding splicing landscape. The usage of alternative polyA sites in terminal exons is modulated by their relative locations and distance to downstream genes. Finally, we apply our models to reveal thousands of disease- and trait-associated genetic variants altering polyadenylation activity. Altogether, our models represent a valuable resource to dissect molecular mechanisms mediating genome-wide polyA site expression and characterize their functional roles in human diseases.
Mucosal-associated invariant T cells contribute to suppression of inflammatory myeloid cells in immune-mediated kidney disease
Authors: Gnirck Ann-Christin , Philipp Marie-Sophie , Waterhölter Alex , Wunderlich Malte , Shaikh Nikhat , Adamiak Virginia , Henneken Lena , Kautz Tobias , Xiong Tingting , Klaus Daniela , Tomczyk Pascal , Al-Bahra Mohamad M. , Menche Dirk , Walkenhorst Mark , Lantz Olivier , Willing Anne , Friese Manuel A. , Huber Tobias B. , Krebs Christian F. , Panzer Ulf , Kurts Christian , Turner Jan-Eric
Published: November 2023

Mucosal-associated invariant T (MAIT) cells have been implicated in various inflammatory diseases of barrier organs, but so far, their role in kidney disease is unclear. Here we report that MAIT cells that recognize their prototypical ligand, the vitamin B2 intermediate 5-OP-RU presented by MR1, reside in human and mouse kidneys. Single cell RNAseq analysis reveals several intrarenal MAIT subsets, and one, carrying the genetic fingerprint of tissue-resident MAIT17 cells, is activated and expanded in a murine model of crescentic glomerulonephritis (cGN). An equivalent subset is also present in kidney biopsies of patients with anti-neutrophil cytoplasmatic antibody (ANCA)-associated cGN. MAIT cell-deficient MR1 mice show aggravated disease, whereas B6-MAITCAST mice, harboring higher MAIT cell numbers, are protected from cGN. The expanded MAIT17 cells express anti-inflammatory mediators known to suppress cGN, such as CTLA-4, PD-1, and TGF-β. Interactome analysis predicts CXCR6 – CXCL16-mediated cross-talk with renal mononuclear phagocytes, known to drive cGN progression. In line, we find that cGN is aggravated upon CXCL16 blockade. Finally, we present an optimized 5-OP-RU synthesis method which we apply to attenuating cGN in mice. In summary, we propose that CXCR6+ MAIT cells might play a protective role in cGN, implicating them as a potential target for anti-inflammatory therapies.
Pan-genome analysis of 13 Malus accessions reveals structural and sequence variations associated with fruit traits
Authors: Wang Ting , Duan Shiyao , Xu Chen , Wang Yi , Zhang Xinzhong , Xu Xuefeng , Chen Liyang , Han Zhenhai , Wu Ting
Published: November 2023

Structural variations (SVs) and copy number variations (CNVs) contribute to trait variations in fleshy-fruited species. Here, we assemble 10 genomes of genetically diverse Malus accessions, including the ever-green cultivar ‘Granny Smith’ and the widely cultivated cultivar ‘Red Fuji’. Combining with three previously reported genomes, we assemble the pan-genome of Malus species and identify 20,220 CNVs and 317,393 SVs. We also observe CNVs that are positively correlated with expression levels of the genes they are associated with. Furthermore, we show that the noncoding RNA generated from a 209 bp insertion in the intron of mitogen-activated protein kinase homology encoding gene, MMK2, regulates the gene expression and affects fruit coloration. Moreover, we identify overlapping SVs associated with fruit quality and biotic resistance. This pan-genome uncovers possible contributions of CNVs to gene expression and highlights the role of SVs in apple domestication and economically important traits.
Impulsive-compulsive behaviour in early Parkinson’s disease is determined by apathy and dopamine receptor D3 polymorphism
Authors: Theis Hendrik , Prange Stéphane , Bischof Gérard N. , Hoenig Merle C. , Tittgemeyer Marc , Timmermann Lars , Fink Gereon R. , Drzezga Alexander , Eggers Carsten , van Eimeren Thilo
Published: November 2023

Impulsive-compulsive behaviour (ICB) is a frequently observed non-motor symptom in early Parkinson’s disease after initiating dopamine replacement therapy. At the opposite end of the motivated behaviour spectrum, apathy occurs in early Parkinson’s disease even before dopamine replacement is started. The co-occurrence of these behavioural conditions in Parkinson’s disease raises questions about their relationship and underlying pathophysiological determinants. In previous imaging or genetic studies, both conditions have been associated with the limbic dopaminergic system. The risk variant of the Ser9Gly polymorphism of the dopamine receptor D3 (DRD3) is linked to increased dopamine affinity in the limbic striatum. With this in mind, we investigated how ICB expression is explained by apathy and DRD3 polymorphisms and their effects on grey matter volume and dopamine synthesis capacity. Fifty-four patients with early Parkinson’s disease took part in anatomical T1-weighted MRI. Forty of them also underwent dynamic PET imaging using [18F]DOPA to measure striatal dopamine synthesis capacity. Further, Ser9Gly (rs6280) gene polymorphism influencing the DRD3 dopamine-binding affinity was determined in all patients. The severity of impulsive-compulsive behaviour and apathy was assessed using the Questionnaire for Impulsive-Compulsive Disorders Rating Scale and the Apathy Evaluation Scale. ICB and the severity of apathy were indeed positively correlated. Apathy and the DRD3 polymorphism were interactive risk factors for ICB severity. Apathy was significantly linked to atrophy of the bilateral putamen. Patients with the DRD3 risk type had reduced dopamine synthesis capacity in the putamen and limbic striatum, apathy was associated with reduced dopamine synthesis capacity in the limbic striatum. The results of [18F]DOPA reached only trend significance. Apathy in drug-naïve PD patients might be a consequence of impaired striatal dopaminergic tone. This may represent a predisposing factor for the development of ICB after the initiation of dopamine replacement therapy. The risk type of DRD3 could further amplify this predisposition due to its higher affinity to dopamine.