bluuebunny/crossref_metadata_2025 huggingface dataset:
Northwest Africa 12279: Evidence for the Interaction Between Early Lunar Mantle Melt and Anorthositic Crust
Authors: Chen Hongyi , Xie Lanfang , Shu Qiao , Miao Bingkui
Published: October 2023

The Mg‐spinel‐bearing rocks are an essential component of the lunar crust. They are widely distributed on the Moon's near and far sides. The study of petrogenesis provides a rare opportunity to understand the early lunar crust‐mantle interaction. Northwest Africa 12279 is a unique Mg‐spinel‐bearing troctolitic anorthosite lunar meteorite that is unbrecciated and pristine. The modal content of the spinel‐bearing troctolitic component is ∼95%. Five hundred sixty spinels larger than 100 μm are investigated in this paper, and 38 of them are found to contain magma melt inclusions. These magma melt inclusions represent the mixed composition between mantle melt and crust material during the crystallization of a spinel. They generally show an immiscible liquid phase separation, which can be divided into a magnesium‐rich and silica‐rich phase. The former is similar in chemical composition to the lunar mantle's peridotite or plutonic ultramafic Mg‐suite. The mantle melt reacts successively with Ferroan Anorthosites in the crust to crystallize Mg‐spinel, plagioclase, olivine, pyroxene, and silica phases. The large grains of euhedral Mg‐spinels with homogeneous chemical composition indicate they are the products of equilibrium crystallization, while plagioclase, olivine, pyroxene, and silica phase are the products of differentiated crystallization of mixed magma. This reaction may represent a typical process of lunar Mg‐suite. This work is the first to find petrological evidence that the melt from the lunar mantle intrudes into the crust and then undergoes a liquid phase immiscible separation to form the Mg‐spinel‐bearing troctolitic anorthosite.
Gestational weight loss and fetal growth in uncomplicated pregnancies among women with obesity: a population-based retrospective cohort study
Authors: Guo Yanfang , Souza Sara C. S. , Bruce Liam , Luo Rong , El-Chaâr Darine , Gaudet Laura M. , Muldoon Katherine , Hawken Steven , Dunn Sandra I. , Dingwall-Harvey Alysha L. J. , Walker Mark C. , Wen Shi Wu , Corsi Daniel J.
Published: October 2023

Objective

The impact of gestational weight loss (GWL) on fetal growth among women with obesity remains unclear. This study aimed to examine the association between weight loss during pregnancy among women with body mass index (BMI) ≥ 30 kg/m2 and the risk of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) neonates.

Methods

We conducted a retrospective, population-based cohort study of women with pre-pregnancy obesity that resulted in a singleton live birth in 2012-2017, using birth registry data in Ontario, Canada. Women with pregnancy complications or health conditions which could cause weight loss were excluded. GWL is defined as negative gestational weight change (≤0 kg). The association between GWL and fetal growth was estimated using generalized estimating equation models and restricted cubic spline regression analysis. Stratified analysis was conducted by obesity class (I:30–34.9 kg/m2, II:35–39.9 kg/m2, and III + : ≥40 kg/m2).

Results

Of the 52,153 eligible women who entered pregnancy with a BMI ≥ 30 kg/m2, 5.3% had GWL. Compared to adequate gestational weight gain, GWL was associated with an increased risk of SGA neonates (aRR:1.45, 95% CI: 1.30–1.60) and a decreased risk of LGA neonates (aRR: 0.81, 95% CI:0.73–0.93). Non-linear L-shaped associations were observed between gestational weight change and SGA neonates, with an increased risk of SGA observed with increased GWL. On the contrary, non-linear S-shaped associations were observed between gestational weight change and LGA neonates, with a decreased risk of LGA observed with increased GWL. Similar findings were observed from the stratified analysis by obesity class.

Conclusion

These findings highlight that GWL in women with obesity may increase the risk of SGA neonates but reduce the risk of LGA neonates. Recommendations of GWL for women with obesity should be interpreted with caution.
Body mass index and waist circumference trajectories across the life course and birth cohorts, 1996–2015 Malaysia: sex and ethnicity matter
Authors: Teh Chien Huey , Rampal Sanjay , Kee Chee Cheong , Azahadi Omar , Tahir Aris
Published: October 2023

Objective

The global obesity epidemic remains a significant threat to public health and the economy. Age-period-cohort (APC) analysis is one method to model the trajectory of obesity. However, there is scarce published evidence of such analyses among the South East Asian population. This study aims to explore the sex and ethnic variations of BMI and waist circumference trajectories over time among non-institutionalized Malaysian adults aged 18 to 80 years.

Methods

Data from four population-based National Health and Morbidity Surveys conducted in 1996, 2006, 2010, and 2015 were pooled. Hierarchical Age-Period-Cohort (HAPC) analysis explored the trajectories of BMI and waist circumference across the life course and birth cohorts by sex and ethnicity. These models assumed no period effect.

Results

Generally, BMI and waist circumference trajectories increased across age and birth cohorts. These trajectories varied by sex and ethnicity. Females have more profound increasing BMI and waist circumference trajectories than their male counterparts as they age and as cohort recency increases. Chinese have less profound BMI and waist circumference increases across the life course and birth cohorts than other ethnic groups.

Conclusions

The profound increasing cohort trajectories of obesity, regardless of sex and ethnicity, are alarming. Future studies should focus on identifying factors associated with the less profound cohort effect among the Chinese to reduce the magnitude of trajectories in obesity, particularly among future generations.
Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia
Authors: Eckardt Jan-Niklas , Stasik Sebastian , Röllig Christoph , Petzold Andreas , Sauer Tim , Scholl Sebastian , Hochhaus Andreas , Crysandt Martina , Brümmendorf Tim H. , Naumann Ralph , Steffen Björn , Kunzmann Volker , Einsele Hermann , Schaich Markus , Burchert Andreas , Neubauer Andreas , Schäfer-Eckart Kerstin , Schliemann Christoph , Krause Stefan W. , Herbst Regina , Hänel Mathias , Hanoun Maher , Kaiser Ulrich , Kaufmann Martin , Rácil Zdenek , Mayer Jiri , Oelschlägel Uta , Berdel Wolfgang E. , Ehninger Gerhard , Serve Hubert , Müller-Tidow Carsten , Platzbecker Uwe , Baldus Claudia D. , Dahl Andreas , Schetelig Johannes , Bornhäuser Martin , Middeke Jan Moritz , Thiede Christian
Published: October 2023

Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.
Macrophage CARD9 mediates cardiac injury following myocardial infarction through regulation of lipocalin 2 expression
Authors: Liu Yan , Shao Yi-hui , Zhang Jun-meng , Wang Ying , Zhou Mei , Li Hui-qin , Zhang Cong-cong , Yu Pei-jie , Gao Shi-juan , Wang Xue-rui , Jia Li-xin , Piao Chun-mei , Du Jie , Li Yu-lin
Published: October 2023

Immune cell infiltration in response to myocyte death regulates extracellular matrix remodeling and scar formation after myocardial infarction (MI). Caspase-recruitment domain family member 9 (CARD9) acts as an adapter that mediates the transduction of pro-inflammatory signaling cascades in innate immunity; however, its role in cardiac injury and repair post-MI remains unclear. We found that Card9 was one of the most upregulated Card genes in the ischemic myocardium of mice. CARD9 expression increased considerably 1 day post-MI and declined by day 7 post-MI. Moreover, CARD9 was mainly expressed in F4/80-positive macrophages. Card9 knockout (KO) led to left ventricular function improvement and infarct scar size reduction in mice 28 days post-MI. Additionally, Card9 KO suppressed cardiomyocyte apoptosis in the border region and attenuated matrix metalloproteinase (MMP) expression. RNA sequencing revealed that Card9 KO significantly suppressed lipocalin 2 (Lcn2) expression post-MI. Both LCN2 and the receptor solute carrier family 22 member 17 (SL22A17) were detected in macrophages. Subsequently, we demonstrated that Card9 overexpression increased LCN2 expression, while Card9 KO inhibited necrotic cell-induced LCN2 upregulation in macrophages, likely through NF-κB. Lcn2 KO showed beneficial effects post-MI, and recombinant LCN2 diminished the protective effects of Card9 KO in vivo. Lcn2 KO reduced MMP9 post-MI, and Lcn2 overexpression increased Mmp9 expression in macrophages. Slc22a17 knockdown in macrophages reduced MMP9 release with recombinant LCN2 treatment. In conclusion, our results demonstrate that macrophage CARD9 mediates the deterioration of cardiac function and adverse remodeling post-MI via LCN2.
Safety and clinical efficacy of sintilimab (anti-PD-1) in pediatric patients with advanced or recurrent malignancies in a phase I study
Authors: Que Yi , Wang Juan , Sun Feifei , Wang Shan , Zhu Jia , Huang Junting , Zhao Zhenzhen , Zhang Li , Liu Juan , Xu Jiaqian , Zhen Zijun , Sun Xiaofei , Lu Suying , Zhang Yizhuo
Published: October 2023

The aim of this phase I study is to evaluate, for the first time, the safety and efficacy of sintilimab in pediatric patients diagnosed with advanced or recurrent malignancies. During the dose escalation phase, patients received a single intravenous infusion of sintilimab at varying doses of 1, 3, and 10 mg/kg. The primary endpoints included the identification of dose-limiting toxicities (DLTs) as well as the evaluation of safety and tolerance. Secondary endpoints focused on assessing objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A total of 29 patients were enrolled, including 10 individuals diagnosed with Hodgkin lymphoma (HL) and 19 patients with various other tumor categories. Notably, diverse pathological types such as thymoma, choroid plexus carcinoma, and NK/T-cell lymphoma were also included in the study cohort. By the safety data cutoff, most adverse events were grade 1 or 2, with grade 3 or higher treatment-related adverse events (TRAE) occurring in 10% of patients. Among the 27 evaluated subjects, four achieved confirmed complete response (CR) while seven patients exhibited confirmed partial response (PR). Additionally, seven patients maintained disease (SD) during the study period. Notably, sintilimab demonstrated remarkable tolerability without DLTs and exhibited promising anti-tumor effects in pediatric HL. Whole-exome sequencing (WES) was conducted in 15 patients to assess the mutational landscape and copy number variation (CNV) status. The completion of this phase I study establishes the foundation for potential combination regimens involving sintilimab in childhood cancer treatment. The trial is registered on ClinicalTrials.gov with the identifier NCT04400851.
Radiotherapy remodels the tumor microenvironment for enhancing immunotherapeutic sensitivity
Authors: Liu Senbo , Wang Wenkang , Hu Shengyun , Jia Bin , Tuo Baojing , Sun Haifeng , Wang Qiming , Liu Yang , Sun Zhenqiang
Published: October 2023

Cancer immunotherapy has transformed traditional treatments, with immune checkpoint blockade being particularly prominent. However, immunotherapy has minimal benefit for patients in most types of cancer and is largely ineffective in some cancers (such as pancreatic cancer and glioma). A synergistic anti-tumor response may be produced through the combined application with traditional tumor treatment methods. Radiotherapy (RT) not only kills tumor cells but also triggers the pro-inflammatory molecules’ release and immune cell infiltration, which remodel the tumor microenvironment (TME). Therefore, the combination of RT and immunotherapy is expected to achieve improved efficacy. In this review, we summarize the effects of RT on cellular components of the TME, including T cell receptor repertoires, different T cell subsets, metabolism, tumor-associated macrophages and other myeloid cells (dendritic cells, myeloid-derived suppressor cells, neutrophils and eosinophils). Meanwhile, non-cellular components such as lactate and extracellular vesicles are also elaborated. In addition, we discuss the impact of different RT modalities on tumor immunity and issues related to the clinical practice of combination therapy.
The risk of withdrawal from hypertension treatment in coastal areas after the Great East Japan Earthquake: the TMM CommCohort Study
Authors: Hatanaka Rieko , Nakaya Naoki , Kogure Mana , Nakaya Kumi , Chiba Ippei , Kanno Ikumi , Hashimoto Hideaki , Nakamura Tomohiro , Nochioka Kotaro , Obara Taku , Hamanaka Yohei , Sugawara Junichi , Kobayashi Tomoko , Uruno Akira , Kodama Eiichi N. , Fuse Nobuo , Kuriyama Shinichi , Hozawa Atsushi
Published: October 2023

This study aimed to examine whether risk of withdrawal from HTTx was higher in coastal areas that were severely damaged by tsunami than in inland areas. We conducted a cross-sectional study of 9218 participants aged ≥20 years in Miyagi, Japan. The odds ratios (ORs) and confidence interval (CI) for withdrawal from HTTx in coastal and inland groups were compared using multivariate logistic regression analysis, adjusting for potential confounders. In total, 194 of 5860 and 146 of 3358 participants in the inland and coastal groups, respectively, withdrew from HTTx treatment. OR (95%CI) of withdrawal from HTTx in the coastal group was 1.46 (1.14–1.86) compared to the inland group. According to housing damage, ORs (95% CI) in the no damage, partially destroyed, and more than half destroyed coastal groups compared with the no damage inland group were 1.62 (1.04–2.50), 1.69 (1.17–2.45), and 1.08 (0.71–1.65), respectively. In conclusion, the risk of HTTx withdrawal for participants whose homes in coastal areas were relatively less damaged was significantly higher compared with those in inland areas, while the risk of HTTx withdrawal for participants whose homes were more than half destroyed was not. Post-disaster administrative support for disaster victims is considered vital for continuation of their treatment.
Terahertz radiation by quantum interference of excitons in a one-dimensional Mott insulator
Authors: Miyamoto Tatsuya , Kondo Akihiro , Inaba Takeshi , Morimoto Takeshi , You Shijia , Okamoto Hiroshi
Published: October 2023

Nearly monocyclic terahertz waves are used for investigating elementary excitations and for controlling electronic states in solids. They are usually generated via second-order optical nonlinearity by injecting a femtosecond laser pulse into a nonlinear optical crystal. In this framework, however, it is difficult to control phase and frequency of terahertz waves. Here, we show that in a one-dimensional Mott insulator of a nickel-bromine chain compound a terahertz wave is generated with high efficiency via strong electron modulations due to quantum interference between odd-parity and even-parity excitons produced by two-color femtosecond pulses. Using this method, one can control all of the phase, frequency, and amplitude of terahertz waves by adjusting the creation-time difference of two excitons with attosecond accuracy. This approach enables to evaluate the phase-relaxation time of excitons under strong electron correlations in Mott insulators. Moreover, phase- and frequency-controlled terahertz pulses are beneficial for coherent electronic-state controls with nearly monocyclic terahertz waves.
High-Q lasing via all-dielectric Bloch-surface-wave platform
Authors: Lee Yang-Chun , Ho Ya-Lun , Lin Bo-Wei , Chen Mu-Hsin , Xing Di , Daiguji Hirofumi , Delaunay Jean-Jacques
Published: October 2023

Controlling the propagation and emission of light via Bloch surface waves (BSWs) has held promise in the field of on-chip nanophotonics. BSW-based optical devices are being widely investigated to develop on-chip integration systems. However, a coherent light source that is based on the stimulated emission of a BSW mode has yet to be developed. Here, we demonstrate lasers based on a guided BSW mode sustained by a gain-medium guiding structure microfabricated on the top of a BSW platform. A long-range propagation length of the BSW mode and a high-quality lasing emission of the BSW mode are achieved. The BSW lasers possess a lasing threshold of 6.7 μJ/mm2 and a very narrow linewidth reaching a full width at half maximum as small as 0.019 nm. Moreover, the proposed lasing scheme exhibits high sensitivity to environmental changes suggesting the applicability of the proposed BSW lasers in ultra-sensitive devices.
Chemo-mechanical forces modulate the topology dynamics of mesoscale DNA assemblies
Authors: Karna Deepak , Mano Eriko , Ji Jiahao , Kawamata Ibuki , Suzuki Yuki , Mao Hanbin
Published: October 2023

The intrinsic complexity of many mesoscale (10–100 nm) cellular machineries makes it challenging to elucidate their topological arrangement and transition dynamics. Here, we exploit DNA origami nanospring as a model system to demonstrate that tens of piconewton linear force can modulate higher-order conformation dynamics of mesoscale molecular assemblies. By switching between two chemical structures (i.e., duplex and tetraplex DNA) in the junctions of adjacent origami modules, the corresponding stretching or compressing chemo-mechanical stress reversibly flips the backbone orientations of the DNA nanosprings. Both coarse-grained molecular dynamics simulations and atomic force microscopy measurements reveal that such a backbone conformational switch does not alter the right-handed chirality of the nanospring helix. This result suggests that mesoscale helical handedness may be governed by the torque, rather than the achiral orientation, of nanospring backbones. It offers a topology-based caging/uncaging concept to present chemicals in response to environmental cues in solution.
Structure of the transcription open complex of distinct σI factors
Authors: Li Jie , Zhang Haonan , Li Dongyu , Liu Ya-Jun , Bayer Edward A. , Cui Qiu , Feng Yingang , Zhu Ping
Published: October 2023

Bacterial σI factors of the σ70-family are widespread in Bacilli and Clostridia and are involved in the heat shock response, iron metabolism, virulence, and carbohydrate sensing. A multiplicity of σI paralogues in some cellulolytic bacteria have been shown to be responsible for the regulation of the cellulosome, a multienzyme complex that mediates efficient cellulose degradation. Here, we report two structures at 3.0 Å and 3.3 Å of two transcription open complexes formed by two σI factors, SigI1 and SigI6, respectively, from the thermophilic, cellulolytic bacterium, Clostridium thermocellum. These structures reveal a unique, hitherto-unknown recognition mode of bacterial transcriptional promoters, both with respect to domain organization and binding to promoter DNA. The key characteristics that determine the specificities of the σI paralogues were further revealed by comparison of the two structures. Consequently, the σI factors represent a distinct set of the σ70-family σ factors, thus highlighting the diversity of bacterial transcription.
Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication
Authors: Chakraborty Chaitali , Nissen Itzel , Vincent Craig A. , Hägglund Anna-Carin , Hörnblad Andreas , Remeseiro Silvia
Published: October 2023

Chromatin organization controls transcription by modulating 3D-interactions between enhancers and promoters in the nucleus. Alterations in epigenetic states and 3D-chromatin organization result in gene expression changes contributing to cancer. Here, we map the promoter-enhancer interactome and regulatory landscape of glioblastoma, the most aggressive primary brain tumour. Our data reveals profound rewiring of promoter-enhancer interactions, chromatin accessibility and redistribution of histone marks in glioblastoma. This leads to loss of long-range regulatory interactions and overall activation of promoters, which orchestrate changes in the expression of genes associated to glutamatergic synapses, axon guidance, axonogenesis and chromatin remodelling. SMAD3 and PITX1 emerge as major transcription factors controlling genes related to synapse organization and axon guidance. Inhibition of SMAD3 and neuronal activity stimulation cooperate to promote proliferation of glioblastoma cells in co-culture with glutamatergic neurons, and in mice bearing patient-derived xenografts. Our findings provide mechanistic insight into the regulatory networks that mediate neurogliomal synaptic communication.
Hyperbranched polymer functionalized flexible perovskite solar cells with mechanical robustness and reduced lead leakage
Authors: Li Zhihao , Jia Chunmei , Wan Zhi , Xue Jiayi , Cao Junchao , Zhang Meng , Li Can , Shen Jianghua , Zhang Chao , Li Zhen
Published: October 2023

Perovskite solar cells (PSCs) are multilayer structures. The interface between electron transport layer and perovskite is the mechanical weakest point in flexible PSCs due to its low fracture energy. Herein, we develop a highly adhesive polyamide-amine-based hyperbranched polymers to reinforce the interface. The interface fracture energy is improved from 1.08 to 2.13 J·m−2 by the hyperbranched polymers with adhesive groups and dynamic hydrogen bond networks. The polymer functionalized perovskite solar cells achieve superior power conversion efficiencies of 25.05% and 23.86% for rigid and flexible devices, respectively. Furthermore, the hyperbranched polymer contains abundant intramolecular cavities that can capture Pb2+. Pb leakage after solar cell damage is effectively suppressed. Our findings provide insights on designing adhesive interface layers towards high-efficiency, mechanical-stable and environment-friendly flexible perovskite solar cells.
A systematic study of key elements underlying molecular property prediction
Authors: Deng Jianyuan , Yang Zhibo , Wang Hehe , Ojima Iwao , Samaras Dimitris , Wang Fusheng
Published: October 2023

Artificial intelligence (AI) has been widely applied in drug discovery with a major task as molecular property prediction. Despite booming techniques in molecular representation learning, key elements underlying molecular property prediction remain largely unexplored, which impedes further advancements in this field. Herein, we conduct an extensive evaluation of representative models using various representations on the MoleculeNet datasets, a suite of opioids-related datasets and two additional activity datasets from the literature. To investigate the predictive power in low-data and high-data space, a series of descriptors datasets of varying sizes are also assembled to evaluate the models. In total, we have trained 62,820 models, including 50,220 models on fixed representations, 4200 models on SMILES sequences and 8400 models on molecular graphs. Based on extensive experimentation and rigorous comparison, we show that representation learning models exhibit limited performance in molecular property prediction in most datasets. Besides, multiple key elements underlying molecular property prediction can affect the evaluation results. Furthermore, we show that activity cliffs can significantly impact model prediction. Finally, we explore into potential causes why representation learning models can fail and show that dataset size is essential for representation learning models to excel.
Overcrowding induces fast colloidal solitons in a slowly rotating potential landscape
Authors: Cereceda-López Eric , Antonov Alexander P. , Ryabov Artem , Maass Philipp , Tierno Pietro
Published: October 2023

Collective particle transport across periodic energy landscapes is ubiquitously present in many condensed matter systems spanning from vortices in high-temperature superconductors, frictional atomic sliding, driven skyrmions to biological and active matter. Here we report the emergence of fast solitons propagating against a rotating optical landscape. These experimentally observed solitons are stable cluster waves that originate from a coordinated particle exchange process which occurs when the number of trapped microparticles exceeds the number of potential wells. The size and speed of individual solitons rapidly increase with the particle diameter as predicted by theory and confirmed by numerical simulations. We show that when several solitons coexist, an effective repulsive interaction can stabilize their propagation along the periodic potential. Our experiments demonstrate a generic mechanism for cluster-mediated transport with potential applications to condensed matter systems on different length scales.
Integrative solution structure of PTBP1-IRES complex reveals strong compaction and ordering with residual conformational flexibility
Authors: Dorn Georg , Gmeiner Christoph , de Vries Tebbe , Dedic Emil , Novakovic Mihajlo , Damberger Fred F. , Maris Christophe , Finol Esteban , Sarnowski Chris P. , Kohlbrecher Joachim , Welsh Timothy J. , Bolisetty Sreenath , Mezzenga Raffaele , Aebersold Ruedi , Leitner Alexander , Yulikov Maxim , Jeschke Gunnar , Allain Frédéric H.-T.
Published: October 2023

RNA-binding proteins (RBPs) are crucial regulators of gene expression, often composed of defined domains interspersed with flexible, intrinsically disordered regions. Determining the structure of ribonucleoprotein (RNP) complexes involving such RBPs necessitates integrative structural modeling due to their lack of a single stable state. In this study, we integrate magnetic resonance, mass spectrometry, and small-angle scattering data to determine the solution structure of the polypyrimidine-tract binding protein 1 (PTBP1/hnRNP I) bound to an RNA fragment from the internal ribosome entry site (IRES) of the encephalomyocarditis virus (EMCV). This binding, essential for enhancing the translation of viral RNA, leads to a complex structure that demonstrates RNA and protein compaction, while maintaining pronounced conformational flexibility. Acting as an RNA chaperone, PTBP1 orchestrates the IRES RNA into a few distinct conformations, exposing the RNA stems outward. This conformational diversity is likely common among RNP structures and functionally important. Our approach enables atomic-level characterization of heterogeneous RNP structures.
Moisture control of tropical cyclones in high-resolution simulations of paleoclimate and future climate
Authors: Raavi Pavan Harika , Chu Jung-Eun , Timmermann Axel , Lee Sun-Seon , Walsh Kevin J. E.
Published: October 2023

The intensity of tropical cyclones (TCs) is expected to increase in response to greenhouse warming. However, how future climate change will affect TC frequencies and tracks is still under debate. Here, to further elucidate the underlying sensitivities and mechanisms, we study TCs response to different past and future climate forcings. Using a high-resolution TC-resolving global Earth system model with 1/4° atmosphere and 1/10° ocean resolution, we conducted a series of paleo-time-slice and future greenhouse warming simulations targeting the last interglacial (Marine Isotope Stage (MIS) 5e, 125 ka), glacial sub-stage MIS5d (115 ka), present-day (PD), and CO2 doubling (2×CO2) conditions. Our analysis reveals that precessional forcing created an interhemispheric difference in simulated TC densities, whereas future CO2 forcing impacts both hemispheres in the same direction. In both cases, we find that TC genesis frequency, density, and intensity are primarily controlled by changes in tropospheric thermal and moisture structure, exhibiting a clear reduction in TC genesis density in warmer hemispheres.
PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
Authors: Niemi Natalie M. , Serrano Lia R. , Muehlbauer Laura K. , Balnis Catherine E. , Wei Lianjie , Smith Andrew J. , Kozul Keri-Lyn , Forny Merima , Connor Olivia M. , Rashan Edrees H. , Shishkova Evgenia , Schueler Kathryn L. , Keller Mark P. , Attie Alan D. , Friedman Jonathan R. , Pagan Julia K. , Coon Joshua J. , Pagliarini David J.
Published: October 2023

PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7-/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function.
Structural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410
Authors: Remm Sille , De Vecchis Dario , Schöppe Jendrik , Hutter Cedric A. J. , Gonda Imre , Hohl Michael , Newstead Simon , Schäfer Lars V. , Seeger Markus A.
Published: October 2023

Mycobacterium tuberculosis is protected from antibiotic therapy by a multi-layered hydrophobic cell envelope. Major facilitator superfamily (MFS) transporter Rv1410 and the periplasmic lipoprotein LprG are involved in transport of triacylglycerides (TAGs) that seal the mycomembrane. Here, we report a 2.7 Å structure of a mycobacterial Rv1410 homologue, which adopts an outward-facing conformation and exhibits unusual transmembrane helix 11 and 12 extensions that protrude ~20 Å into the periplasm. A small, very hydrophobic cavity suitable for lipid transport is constricted by a functionally important ion-lock likely involved in proton coupling. Combining mutational analyses and MD simulations, we propose that TAGs are extracted from the core of the inner membrane into the central cavity via lateral clefts present in the inward-facing conformation. The functional role of the periplasmic helix extensions is to channel the extracted TAG into the lipid binding pocket of LprG.
Developmental atlas of phase-amplitude coupling between physiologic high-frequency oscillations and slow waves
Authors: Sakakura Kazuki , Kuroda Naoto , Sonoda Masaki , Mitsuhashi Takumi , Firestone Ethan , Luat Aimee F. , Marupudi Neena I. , Sood Sandeep , Asano Eishi
Published: October 2023

We investigated the developmental changes in high-frequency oscillation (HFO) and Modulation Index (MI) – the coupling measure between HFO and slow-wave phase. We generated normative brain atlases, using subdural EEG signals from 8251 nonepileptic electrode sites in 114 patients (ages 1.0–41.5 years) who achieved seizure control following resective epilepsy surgery. We observed a higher MI in the occipital lobe across all ages, and occipital MI increased notably during early childhood. The cortical areas exhibiting MI co-growth were connected via the vertical occipital fasciculi and posterior callosal fibers. While occipital HFO rate showed no significant age-association, the temporal, frontal, and parietal lobes exhibited an age-inversed HFO rate. Assessment of 1006 seizure onset sites revealed that z-score normalized MI and HFO rate were higher at seizure onset versus nonepileptic electrode sites. We have publicly shared our intracranial EEG data to enable investigators to validate MI and HFO-centric presurgical evaluations to identify the epileptogenic zone.
Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction
Authors: Sabogal-Guáqueta Angélica María , Marmolejo-Garza Alejandro , Trombetta-Lima Marina , Oun Asmaa , Hunneman Jasmijn , Chen Tingting , Koistinaho Jari , Lehtonen Sarka , Kortholt Arjan , Wolters Justina C. , Bakker Barbara M. , Eggen Bart J. L. , Boddeke Erik , Dolga Amalia
Published: October 2023

Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.
Structure-based development and preclinical evaluation of the SARS-CoV-2 3C-like protease inhibitor simnotrelvir
Authors: Jiang Xiangrui , Su Haixia , Shang Weijuan , Zhou Feng , Zhang Yan , Zhao Wenfeng , Zhang Qiumeng , Xie Hang , Jiang Lei , Nie Tianqing , Yang Feipu , Xiong Muya , Huang Xiaoxing , Li Minjun , Chen Ping , Peng Shaoping , Xiao Gengfu , Jiang Hualiang , Tang Renhong , Zhang Leike , Shen Jingshan , Xu Yechun
Published: October 2023

The persistent pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants accentuates the great demand for developing effective therapeutic agents. Here, we report the development of an orally bioavailable SARS-CoV-2 3C-like protease (3CLpro) inhibitor, namely simnotrelvir, and its preclinical evaluation, which lay the foundation for clinical trials studies as well as the conditional approval of simnotrelvir in combination with ritonavir for the treatment of COVID-19. The structure-based optimization of boceprevir, an approved HCV protease inhibitor, leads to identification of simnotrelvir that covalently inhibits SARS-CoV-2 3CLpro with an enthalpy-driven thermodynamic binding signature. Multiple enzymatic assays reveal that simnotrelvir is a potent pan-CoV 3CLpro inhibitor but has high selectivity. It effectively blocks replications of SARS-CoV-2 variants in cell-based assays and exhibits good pharmacokinetic and safety profiles in male and female rats and monkeys, leading to robust oral efficacy in a male mouse model of SARS-CoV-2 Delta infection in which it not only significantly reduces lung viral loads but also eliminates the virus from brains. The discovery of simnotrelvir thereby highlights the utility of structure-based development of marked protease inhibitors for providing a small molecule therapeutic effectively combatting human coronaviruses.
Extracellular vesicles could be a putative posttranscriptional regulatory mechanism that shapes intracellular RNA levels in Plasmodium falciparum
Authors: Kioko Mwikali , Pance Alena , Mwangi Shaban , Goulding David , Kemp Alison , Rono Martin , Ochola-Oyier Lynette Isabella , Bull Pete C. , Bejon Philip , Rayner Julian C. , Abdi Abdirahman I.
Published: October 2023

Plasmodium falciparum secretes extracellular vesicles (PfEVs) that contain parasite-derived RNA. However, the significance of the secreted RNA remains unexplored. Here, we compare secreted and intracellular RNA from asexual cultures of six P. falciparum lines. We find that secretion of RNA via extracellular vesicles is not only periodic throughout the asexual intraerythrocytic developmental cycle but is also highly conserved across P. falciparum isolates. We further demonstrate that the phases of RNA secreted via extracellular vesicles are discernibly shifted compared to those of the intracellular RNA within the secreting whole parasite. Finally, transcripts of genes with no known function during the asexual intraerythrocytic developmental cycle are enriched in PfEVs compared to the whole parasite. We conclude that the secretion of extracellular vesicles could be a putative posttranscriptional RNA regulation mechanism that is part of or synergise the classic RNA decay processes to maintain intracellular RNA levels in P. falciparum.
Challenging an old paradigm by demonstrating transition metal-like chemistry at a neutral nonmetal center
Authors: Biskup David , Schnakenburg Gregor , Boeré René T. , Espinosa Ferao Arturo , Streubel Rainer K.
Published: October 2023

We describe nonmetal adducts of the phosphorus center of terminal phosphinidene complexes using classical C- and N-ligands from metal coordination chemistry. The nature of the L-P bond has been analyzed by various theoretical methods including a refined method on the variation of the Laplacian of electron density ∇2ρ along the L-P bond path. Studies on thermal stability reveal stark differences between N-ligands such as N-methyl imidazole and C-ligands such as tert-butyl isocyanide, including ligand exchange reactions and a surprising formation of white phosphorus. A milestone is the transformation of a nonmetal-bound isocyanide into phosphaguanidine or an acyclic bisaminocarbene bound to phosphorus; the latter is analogous to the chemistry of transition metal-bound isocyanides, and the former reveals the differences. This example has been studied via cutting-edge DFT calculations leading to two pathways differently favored depending on variations in steric demand. This study reveals the emergence of organometallic from coordination chemistry of a neutral nonmetal center.
Partner choice and cooperation in social dilemmas can increase resource inequality
Authors: Stallen Mirre , Snijder Luuk L. , Gross Jörg , Hilbert Leon P. , De Dreu Carsten K. W.
Published: October 2023

Cooperation is more likely when individuals can choose their interaction partner. However, partner choice may be detrimental in unequal societies, in which individuals differ in available resources and productivity, and thus in their attractiveness as interaction partners. Here we experimentally examine this conjecture in a repeated public goods game. Individuals (n = 336), participating in groups of eight participants, are assigned a high or low endowment and a high or low productivity factor (the value that their cooperation generates), creating four unique participant types. On each round, individuals are either assigned a partner (assigned partner condition) or paired based on their self-indicated preference for a partner type (partner choice condition). Results show that under partner choice, individuals who were assigned a high endowment and high productivity almost exclusively interact with each other, forcing other individuals into less valuable pairs. Consequently, pre-existing resource differences between individuals increase. These findings show how partner choice in social dilemmas can amplify resource inequality.
Chromatin organization drives the search mechanism of nuclear factors
Authors: Mazzocca Matteo , Loffreda Alessia , Colombo Emanuele , Fillot Tom , Gnani Daniela , Falletta Paola , Monteleone Emanuele , Capozi Serena , Bertrand Edouard , Legube Gaelle , Lavagnino Zeno , Tacchetti Carlo , Mazza Davide
Published: October 2023

Nuclear factors rapidly scan the genome for their targets, but the role of nuclear organization in such search is uncharted. Here we analyzed how multiple factors explore chromatin, combining live-cell single-molecule tracking with multifocal structured illumination of DNA density. We find that factors displaying higher bound fractions sample DNA-dense regions more exhaustively. Focusing on the tumor-suppressor p53, we demonstrate that it searches for targets by alternating between rapid diffusion in the interchromatin compartment and compact sampling of chromatin dense regions. Efficient targeting requires balanced interactions with chromatin: fusing p53 with an exogenous intrinsically disordered region potentiates p53-mediated target gene activation at low concentrations, but leads to condensates at higher levels, derailing its search and downregulating transcription. Our findings highlight the role of disordered regions on factors search and showcase a powerful method to generate traffic maps of the eukaryotic nucleus to dissect how its organization guides nuclear factors action.
Structural insights into the allosteric inhibition of P2X4 receptors
Authors: Shen Cheng , Zhang Yuqing , Cui Wenwen , Zhao Yimeng , Sheng Danqi , Teng Xinyu , Shao Miaoqing , Ichikawa Muneyoshi , Wang Jin , Hattori Motoyuki
Published: October 2023

P2X receptors are ATP-activated cation channels, and the P2X4 subtype plays important roles in the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets. Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition.
Bile acids-mediated intracellular cholesterol transport promotes intestinal cholesterol absorption and NPC1L1 recycling
Authors: Xiao Jian , Dong Le-Wei , Liu Shuai , Meng Fan-Hua , Xie Chang , Lu Xiao-Yi , Zhang Weiping J. , Luo Jie , Song Bao-Liang
Published: October 2023

Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the A1272LAL residues dissociates from membrane, exposing the Q1277KR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina
Authors: Gautam Milan , Jozic Antony , Su Grace Li-Na , Herrera-Barrera Marco , Curtis Allison , Arrizabalaga Sebastian , Tschetter Wayne , Ryals Renee C. , Sahay Gaurav
Published: October 2023

Ocular delivery of lipid nanoparticle (LNPs) packaged mRNA can enable efficient gene delivery and editing. We generated LNP variants through the inclusion of positively charged-amine-modified polyethylene glycol (PEG)-lipids (LNPa), negatively charged-carboxyl-(LNPz) and carboxy-ester (LNPx) modified PEG-lipids, and neutral unmodified PEG-lipids (LNP). Subretinal injections of LNPa containing Cre mRNA in the mouse show tdTomato signal in the retinal pigmented epithelium (RPE) like conventional LNPs. Unexpectedly, LNPx and LNPz show 27% and 16% photoreceptor transfection, respectively, with striking localization extending from the photoreceptor synaptic pedicle to the outer segments, displaying pan-retinal distribution in the photoreceptors and RPE. LNPx containing Cas9 mRNA and sgAi9 leads to the formation of an oval elongated structure with a neutral charge resulting in 16.4% editing restricted to RPE. Surface modifications of LNPs with PEG variants can alter cellular tropism of mRNA. LNPs enable genome editing in the retina and in the future can be used to correct genetic mutations that lead to blindness.
Unraveling and leveraging in situ surface amorphization for enhanced hydrogen evolution reaction in alkaline media
Authors: Fu Qiang , Wong Lok Wing , Zheng Fangyuan , Zheng Xiaodong , Tsang Chi Shing , Lai Ka Hei , Shen Wenqian , Ly Thuc Hue , Deng Qingming , Zhao Jiong
Published: October 2023

Surface amorphization provides electrocatalysts with more active sites and flexibility. However, there is still a lack of experimental observations and mechanistic explanations for the in situ amorphization process and its crucial role. Herein, we propose the concept that by in situ reconstructed amorphous surface, metal phosphorus trichalcogenides could intrinsically offer better catalytic performance for the alkaline hydrogen production. Trace Ru (0.81 wt.%) is doped into NiPS3 nanosheets for alkaline hydrogen production. Using in situ electrochemical transmission electron microscopy technique, we confirmed the amorphization process occurred on the edges of NiPS3 is critical for achieving superior activity. Comprehensive characterizations and theoretical calculations reveal Ru primarily stabilized at edges of NiPS3 through in situ formed amorphous layer containing bridging S22− species, which can effectively reduce the reaction energy barrier. This work emphasizes the critical role of in situ formed active layer and suggests its potential for optimizing catalytic activities of electrocatalysts.