bluuebunny/crossref_metadata_2025 huggingface dataset:
Data as Assets in Foreign Direct Investment: Is China's National Data Governance Compatible with its International Investment Agreements?
Authors: BIAN Cheng
Published: November 2022

To foreign investors, data, either collected and processed before or after market entry in the host state, can be regarded as a part of the investment and subject to the protection of the applicable international investment agreements (IIAs). China has been developing rigorous and stringent data governance such as data localization requirements and mandatory business-to-government data sharing, and has also concluded the world's second largest IIA regime that provides sweeping investment protection. There is a risk of incompatibility between China's national data policies and its IIA obligations. Foreign investors may challenge China's national laws and practices on data governance, for alleged breaches of investor's protection obligations in Chinese IIAs, or breaches of the data residency provisions in Chinese trade and investment agreements. As a result, potential exists for such claims to be brought against China in investor-state arbitration.
Modeling Viscosity of Volcanic Melts With Artificial Neural Networks
Authors: Langhammer D. , Di Genova D. , Steinle‐Neumann G.
Published: November 2022

Viscosity is of great importance in governing the dynamics of volcanoes, including their eruptive style. The viscosity of a volcanic melt is dominated by temperature and chemical composition, both oxides and water content. The changes in melt structure resulting from the interactions between the various chemical components are complex, and the construction of a physical viscosity model that depends on composition has not yet been achieved. We therefore train an artificial neural network (ANN) on a large database of measured compositions, including water, and viscosities that spans virtually the entire chemical space of terrestrial magmas, as well as some technical and extra‐terrestrial silicate melts. The ANN uses composition, temperature, a structural parameter reflecting melt polymerization and the alkaline ratio as input parameters. It successfully reproduces and predicts measurements in the database with significantly higher accuracy than previous global models for volcanic melt viscosities. Viscosity measurements are restricted to low and high viscosity ranges, which exclude typical eruptive temperatures. Without training data at such conditions, the ANN cannot reliably predict viscosities for this important temperature range. To overcome this limitation, we use the ANN to create synthetic viscosity data in the high and low viscosity range and fit these points using a physically motivated, temperature‐dependent viscosity model. Our study introduces a synthetic data approach for the creation of a physically motivated model predicting volcanic melt viscosities based on ANNs.
Energetic Magnetospheric Particle Fluxes Onto Callisto's Atmosphere
Authors: Liuzzo Lucas , Poppe Andrew R. , Addison Peter , Simon Sven , Nénon Quentin , Paranicas Christopher
Published: November 2022

This study investigates how Callisto's perturbed electromagnetic environment—generated by the moon's interaction with the low‐energy Jovian magnetospheric plasma—affects the dynamics of high‐energy ions and electrons. We constrain how these perturbed fields influence the energetic particle fluxes deposited onto the top of Callisto's atmosphere between energies of 4.5 keV ≤ E ≤ 11.8 MeV. We use a hybrid simulation to model the variability in Callisto's perturbed electromagnetic environment over a synodic period by considering three representative scenarios of the moon's plasma interaction, corresponding to various distances of the moon to the Jovian magnetospheric current sheet. The local field perturbations are maximized near the center of the sheet (forming, e.g., signatures of field‐line pileup, draping, and Alfvén wings) whereas far from the sheet, a mere superposition of the moon's induced dipole with the background field largely explains the perturbations. We then apply a test‐particle approach to investigate the dynamics of energetic electrons and ions (protons, oxygen, and sulfur) while exposed to these fields. Since electron gyroradii are smaller than Callisto, the field perturbations generate small‐scale non‐uniformities in their flux patterns onto the moon, while the ion flux patterns are more homogeneous. Energetic electrons dominate the number flux onto the atmosphere, whereas ions dominate the energy flux. Over a synodic period, the flux patterns onto Callisto's exobase closely resemble those when the moon is near the current sheet center, since the differential energetic particle fluxes in the ambient plasma decrease by an order of magnitude when the moon travels far outside of the sheet.
Frictional Behavior Downdip Along the Subduction Megathrust: Insights From Laboratory Experiments on Exhumed Samples at In Situ Conditions
Authors: den Hartog S. A. M. , Marone C. , Saffer D. M.
Published: November 2022

Subduction megathrusts exhibit a spectrum of slip modes, including catastrophic earthquakes. Although the mechanical and frictional properties of materials sampled from subduction zones have been studied extensively, few datasets have been collected for compositions and at pressure and temperature conditions representative of those in situ. The Nankai subduction zone in southwest Japan is a well‐studied margin, and abundant data provide an opportunity to advance our understanding of fault and earthquake physics. Here, we use samples exhumed in the Shimanto and Sanbagawa Belts on Shikoku Island of southwest Japan that represent analogs for materials along the present‐day megathrust at depths of ∼5–>25 km, and we shear these at their peak in situ pressure‐temperature (P‐T) conditions. Effective normal stresses range from 28 to 192 MPa, and temperatures from 105°C to 470°C. We used pore fluid pressures of 45–240 MPa, corresponding to fluid overpressure ratios λ of 0.65 and 0.90. Slip velocities of 0.1–100 μm/s were used, in order to focus on the nucleation of instability and earthquakes. We found predominantly velocity‐strengthening (inherently stable) behavior under all conditions for λ = 0.65. For λ = 0.90, velocity‐weakening behavior was observed at 350°C, with velocity‐strengthening behavior at lower and higher temperatures. The rate/state frictional stability parameter (a‐b) increases with slip velocity at temperatures up to ∼200°C and remains constant or decreases with slip velocity at higher temperatures. Overall, our results demonstrate the potentially important roles of both temperature and slip velocity in controlling the distribution of stress and frictional rheology along subduction thrusts.
Temperatures and Timescales of Crystallization in the “Mush Zone” Beneath Fast‐Spreading Ocean Ridges
Authors: VanTongeren J. A. , Kelemen P. B. , Grove T. L.
Published: November 2022

Quantifying the timescales of magma solidification and eruption beneath mid‐ocean ridges is critical to understanding how melts are emplaced and crystallized, and how long these magmas and their crystals remain in a semi‐molten “mush‐like” state. Here, we present a new method to quantify the crystallization and solidification temperatures of individual gabbros in the lower crust of the Wadi Tayin massif (Samail ophiolite). Cotectic crystallization temperatures of olivine + plagioclase + clinopyroxene are constrained by our clinopyroxene Mg# thermometer, and supported by clinopyroxene‐olivine Fe‐Mg equilibration temperatures. We find that lower crustal gabbros reach the cotectic at approximately 1,160 ± 16°C, and are fully solidified between 781 and 1011°C, depending on cooling rate. Our results show that lower crustal gabbros spend, on average, 7,500–11,500 years in a partially molten state with no systematic change in duration with depth in the crust. Samples with very fast cooling rates result in solidification only a few tens of meters off‐axis from their emplacement location and likely indicate solidification near the distal edge of the on‐axis melt lens or in off‐axis melt lenses. Incorporating a uniform 1 km wide emplacement region directly on‐axis, as inferred geophysically, and a half‐spreading rate of 55 mm/yr, our results suggest that the Mush Zone at fast‐spreading ridges remains partially molten for 0–3 km away from the ridge axis, but up to 4–7 km considering all possible sources of uncertainty. Both geophysical and geochemical estimates of the Mush Zone are inconsistent with conductive cooling of the lower oceanic crust.
A Proper Use of the Adjacent Land‐Based Observatory Magnetic Field Data to Account for the Geomagnetic Disturbances During Offshore Directional Drilling
Authors: Kruglyakov Mikhail , Kuvshinov Alexey , Nair Manoj
Published: November 2022

Directional drilling in the oil fields relies particularly on the “on‐fly” measurements of the natural magnetic field (measurements while drilling; MWD); the MWD are eventually used to construct the well path. These measurements are the superposition of the signals from the internal, core and crustal, and external, ionospheric and magnetospheric sources and the noise from magnetic elements in the borehole assembly. The internal signals are mostly constant in time and accounted for through the Earth's internal field models. The signals of external origin give rise to diurnal and irregular spatio‐temporal magnetic field variations observable in the MWD. One of the common ways to mitigate the effects of these variations in the MWD is to correct readings for the data from an adjacent land‐based magnetic observatory/site. This method assumes that the land‐based signals are similar to those at the seabed drilling site. In this paper, we show that the sea level and seabed horizontal magnetic fields differ significantly, reaching up to 30% of sea level values in many oceanic regions. We made this inference from the global forward modeling of the magnetic field using realistic models of conducting Earth and time‐varying sources. To perform such modeling, we elaborated a numerical approach to efficiently calculate the spatio‐temporal evolution of the magnetic field. Finally, we propose and validate a formalism allowing researchers to obtain trustworthy seabed signals using measurements at the adjacent land‐based site and exploiting the modeling results, thus without needing additional measurements at the seabed site.
The Origin of the Paleo‐Kuril Arc, NE Japan: Sediment Provenance Change and Its Implications for Plate Configuration in the NW Pacific Region Since the Late Cretaceous
Authors: Harisma H. , Naruse H. , Asanuma H. , Hirata T.
Published: November 2022

The Nemuro Belt is a tectonic belt in the Paleo‐Kuril Arc system, the NW Pacific region. The Paleo‐Kuril Arc has been interpreted as an intraoceanic arc system between the Izanagi and Pacific Plates during the Late Cretaceous, suggesting that the boundary between these plates was a trench. However, this study shows it was a volcanic arc that developed atop a continental margin. To determine the nature of this arc during the Late Cretaceous, U‐Pb ages of detrital zircons from the Nemuro and Urahoro Groups in the Paleo‐Kuril Arc were analyzed. Our results identify two distinct types of detrital zircon U‐Pb age distributions. The first (Type 1) is characterized by multimodal age distributions with peaks ranging from ca. 1.8 Ga to 78 Ma. The other (Type 2) exhibits a unimodal age distribution with a peak at 60‐52 Ma. These different age distributions indicate a provenance transition occurred between the Late Cretaceous and Paleogene. Precambrian zircons in Type 1 sandstones indicate that the Paleo‐Kuril Arc was part of a continental plate, presumably the Okhotsk Block, in NE Asia during the Late Cretaceous. In contrast, Type 2 sandstones were supplied only from the magmatic arc region that the Izanagi‐Pacific Ridge subduction could have activated. This provenance transition suggests the initially continental arc became separated from its continental source at the beginning of the Paleogene.
A Deeper Look Into the 2021 Tyrnavos Earthquake Sequence (TES) Reveals Coseismic Breaching of an Unrecognized Large‐Scale Fault Relay Zone in Continental Greece
Authors: Mouslopoulou Vasiliki , Sudhaus Henriette , Konstantinou Kostas I. , Begg John , Saltogianni Vasso , Männel Benjamin , Andinisari Ratri , Oncken Onno
Published: November 2022

Large magnitude (Mw ∼ ≥6) earthquakes in extensional settings are often associated with simultaneous rupture of multiple normal faults as a result of static and/or dynamic stress transfer. Here, we report details of the coseismic breaching of a previously unrecognized large‐scale fault relay zone in central Greece, through three successive normal fault earthquakes of moderate magnitude (Mw 5.7–6.3) that occurred over a period of ∼10 days in March 2021. Specifically, joint analysis of InSAR, GNSS and seismological data, coupled with detailed field and digital fault mapping, reveals that the Tyrnavos Earthquake Sequence (TES) was accommodated at the northern end of a ∼100 km wide transfer structure, by faults largely unbroken during the Holocene. By contrast, the southern section of this relay zone appears to have accrued significant slip during Holocene. InSAR‐derived displacements agree with the loci of eight subtle, previously undetected, faults that accommodated coseismic and/or syn‐seismic normal fault slip during the TES. Kinematic modeling coupled with fault mapping suggests that all involved faults are interconnected at depth, with their conjugate fault‐intersections acting largely as barriers to coseismic rupture propagation. We also find that the TES mainshocks were characterized by unusually high (>6 MPa) stress‐drop values that scale inversely with rupture length and earthquake magnitude. These findings, collectively suggest that the TES propagated north‐westward to rupture increasingly stronger asperities at fault intersections, transferring slip between the tips of a well‐established, but previously unrecognized, relay structure. Fault relay zones may be prone to high stress‐drop earthquakes and associated elevated seismic hazard.
A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis
Authors: Ma Qizhi , He Xia , Zhang Benxia , Guo Fuchun , Ou Xuejin , Yang Qiyu , Shu Pei , Chen Yue , Li Kai , Gao Ge , Zhu Yajuan , Qin Diyuan , Tang Jie , Li Xiaoyu , Jing Meng , Zhao Jian , Mo Zeming , Liu Ning , Zeng Yao , Zhou Kexun , Feng Mingyang , Liao Weiting , Lei Wanting , Li Qiu , Li Dan , Wang Yongsheng
Published: November 2022

Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).
Organelle-targeted therapies: a comprehensive review on system design for enabling precision oncology
Authors: Yang Jingjing , Griffin Anthony , Qiang Zhe , Ren Jie
Published: November 2022

Cancer is a major threat to human health. Among various treatment methods, precision therapy has received significant attention since the inception, due to its ability to efficiently inhibit tumor growth, while curtailing common shortcomings from conventional cancer treatment, leading towards enhanced survival rates. Particularly, organelle-targeted strategies enable precise accumulation of therapeutic agents in organelles, locally triggering organelle-mediated cell death signals which can greatly reduce the therapeutic threshold dosage and minimize side-effects. In this review, we comprehensively discuss history and recent advances in targeted therapies on organelles, specifically including nucleus, mitochondria, lysosomes and endoplasmic reticulum, while focusing on organelle structures, organelle-mediated cell death signal pathways, and design guidelines of organelle-targeted nanomedicines based on intervention mechanisms. Furthermore, a perspective on future research and clinical opportunities and potential challenges in precision oncology is presented. Through demonstrating recent developments in organelle-targeted therapies, we believe this article can further stimulate broader interests in multidisciplinary research and technology development for enabling advanced organelle-targeted nanomedicines and their corresponding clinic translations.
Constitutive 5-HT2C receptor knock-out facilitates fear extinction through altered activity of a dorsal raphe-bed nucleus of the stria terminalis pathway
Authors: Süß Sandra T. , Olbricht Linda M. , Herlitze Stefan , Spoida Katharina
Published: November 2022

Serotonin 2C receptors (5-HT2CRs) are widely distributed throughout the brain and are strongly implicated in the pathophysiology of anxiety disorders such as post-traumatic stress disorder (PTSD). Although in recent years, a considerable amount of evidence supports 5-HT2CRs facilitating effect on anxiety behavior, the involvement in learned fear responses and fear extinction is rather unexplored. Here, we used a 5-HT2CR knock-out mouse line (2CKO) to gain new insights into the involvement of 5-HT2CRs in the neuronal fear circuitry. Using a cued fear conditioning paradigm, our results revealed that global loss of 5-HT2CRs exclusively accelerates fear extinction, without affecting fear acquisition and fear expression. To investigate the neuronal substrates underlying the extinction enhancing effect, we mapped the immediate-early gene product cFos, a marker for neuronal activity, in the dorsal raphe nucleus (DRN), amygdala and bed nucleus of the stria terminalis (BNST). Surprisingly, besides extinction-associated changes, our results revealed alterations in neuronal activity even under basal home cage conditions in specific subregions of the DRN and the BNST in 2CKO mice. Neuronal activity in the dorsal BNST was shifted in an extinction-supporting direction due to 5-HT2CR knock-out. Finally, the assessment of DRN-BNST connectivity using antero- and retrograde tracing techniques uncovered a discrete serotonergic pathway projecting from the most caudal subregion of the DRN (DRC) to the anterodorsal portion of the BNST (BNSTad). This serotonergic DRC-BNSTad pathway showed increased neuronal activity in 2CKO mice. Thus, our results provide new insights for the fear extinction network by revealing a specific serotonergic DRC-BNSTad pathway underlying a 5-HT2CR-sensitive mechanism with high significance in the treatment of PTSD.
Folate receptor alpha in ovarian cancer tissue and patient serum is associated with disease burden and treatment outcomes
Authors: Bax Heather J. , Chauhan Jitesh , Stavraka Chara , Santaolalla Aida , Osborn Gabriel , Khiabany Atousa , Grandits Melanie , López-Abente Jacobo , Palhares Lais C. G. F. , Chan Wah Hak Charleen , Robinson Alexandra , Pope Amy , Woodman Natalie , Naceur-Lombardelli Cristina , Malas Sadek , Coumbe Jack E. M. , Nakamura Mano , Laddach Roman , Mele Silvia , Crescioli Silvia , Black Anna M. , Lombardi Sara , Canevari Silvana , Figini Mariangela , Sayasneh Ahmad , Tsoka Sophia , FitzGerald Kevin , Gillett Cheryl , Pinder Sarah , Van Hemelrijck Mieke , Kristeleit Rebecca , Ghosh Sharmistha , Montes Ana , Spicer James , Karagiannis Sophia N. , Josephs Debra H.
Published: November 2022

Background

Survival rates for ovarian cancer remain poor, and monitoring and prediction of therapeutic response may benefit from additional markers. Ovarian cancers frequently overexpress Folate Receptor alpha (FRα) and the soluble receptor (sFRα) is measurable in blood. Here we investigated sFRα as a potential biomarker.

Methods

We evaluated sFRα longitudinally, before and during neo-adjuvant, adjuvant and palliative therapies, and tumour FRα expression status by immunohistrochemistry. The impact of free FRα on the efficacy of anti-FRα treatments was evaluated by an antibody-dependent cellular cytotoxicity assay.

Results

Membrane and/or cytoplasmic FRα staining were observed in 52.7% tumours from 316 ovarian cancer patients with diverse histotypes. Circulating sFRα levels were significantly higher in patients, compared to healthy volunteers, specifically in patients sampled prior to neoadjuvant and palliative treatments. sFRα was associated with FRα cell membrane expression in the tumour. sFRα levels decreased alongside concurrent tumour burden in patients receiving standard therapies. High concentrations of sFRα partly reduced anti-FRα antibody tumour cell killing, an effect overcome by increased antibody doses.

Conclusions

sFRα may present a non-invasive marker for tumour FRα expression, with the potential for monitoring patient response to treatment. Larger, prospective studies should evaluate FRα for assessing disease burden and response to systemic treatments.
UK Biobank: a globally important resource for cancer research
Authors: Conroy Megan C. , Lacey Ben , Bešević Jelena , Omiyale Wemimo , Feng Qi , Effingham Mark , Sellers Jonathan , Sheard Simon , Pancholi Mahesh , Gregory Gareth , Busby John , Collins Rory , Allen Naomi E.
Published: November 2022

UK Biobank is a large-scale prospective study with deep phenotyping and genomic data. Its open-access policy allows researchers worldwide, from academia or industry, to perform health research in the public interest. Between 2006 and 2010, the study recruited 502,000 adults aged 40–69 years from the general population of the United Kingdom. At enrolment, participants provided information on a wide range of factors, physical measurements were taken, and biological samples (blood, urine and saliva) were collected for long-term storage. Participants have now been followed up for over a decade with more than 52,000 incident cancer cases recorded. The study continues to be enhanced with repeat assessments, web-based questionnaires, multi-modal imaging, and conversion of the stored biological samples to genomic and other ‘–omic’ data. The study has already demonstrated its value in enabling research into the determinants of cancer, and future planned enhancements will make the resource even more valuable to cancer researchers. Over 26,000 researchers worldwide are currently using the data, performing a wide range of cancer research. UK Biobank is uniquely placed to transform our understanding of the causes of cancer development and progression, and drive improvements in cancer treatment and prevention over the coming decades.
Inhibition of the immunoproteasome modulates innate immunity to ameliorate muscle pathology of dysferlin-deficient BlAJ mice
Authors: Farini A. , Tripodi L. , Villa C. , Napolitano F. , Strati F. , Molinaro D. , Facciotti F. , Cassani B. , Torrente Y.
Published: November 2022

Muscle repair in dysferlinopathies is defective. Although macrophage (Mø)-rich infiltrates are prominent in damaged skeletal muscles of patients with dysferlinopathy, the contribution of the immune system to the disease pathology remains to be fully explored. Numbers of both pro-inflammatory M1 Mø and effector T cells are increased in muscle of dysferlin-deficient BlAJ mice. In addition, symptomatic BlAJ mice have increased muscle production of immunoproteasome. In vitro analyses using bone marrow-derived Mø of BlAJ mice show that immunoproteasome inhibition results in C3aR1 and C5aR1 downregulation and upregulation of M2-associated signaling. Administration of immunoproteasome inhibitor ONX-0914 to BlAJ mice rescues muscle function by reducing muscle infiltrates and fibro-adipogenesis. These findings reveal an important role of immunoproteasome in the progression of muscular dystrophy in BlAJ mouse and suggest that inhibition of immunoproteasome may produce therapeutic benefit in dysferlinopathy.
Pulmonary cancers across different histotypes share hybrid tuft cell/ionocyte-like molecular features and potentially druggable vulnerabilities
Authors: Yamada Yosuke , Belharazem-Vitacolonnna Djeda , Bohnenberger Hanibal , Weiß Christel , Matsui Naoko , Kriegsmann Mark , Kriegsmann Katharina , Sinn Peter , Simon-Keller Katja , Hamilton Gerhard , Graeter Thomas , Preissler Gerhard , Ott German , Schölch Sebastian , Nakajima Naoki , Yoshizawa Akihiko , Haga Hironori , Date Hiroshi , Thomas Roman K. , Petrini Iacopo , Giaccone Giuseppe , Ströbel Philipp , Marx Alexander
Published: November 2022

Tuft cells are chemosensory epithelial cells in the respiratory tract and several other organs. Recent studies revealed tuft cell-like gene expression signatures in some pulmonary adenocarcinomas, squamous cell carcinomas (SQCC), small cell carcinomas (SCLC), and large cell neuroendocrine carcinomas (LCNEC). Identification of their similarities could inform shared druggable vulnerabilities. Clinicopathological features of tuft cell-like (tcl) subsets in various lung cancer histotypes were studied in two independent tumor cohorts using immunohistochemistry (n = 674 and 70). Findings were confirmed, and additional characteristics were explored using public datasets (RNA seq and immunohistochemical data) (n = 555). Drug susceptibilities of tuft cell-like SCLC cell lines were also investigated. By immunohistochemistry, 10–20% of SCLC and LCNEC, and approximately 2% of SQCC expressed POU2F3, the master regulator of tuft cells. These tuft cell-like tumors exhibited “lineage ambiguity” as they co-expressed NCAM1, a marker for neuroendocrine differentiation, and KRT5, a marker for squamous differentiation. In addition, tuft cell-like tumors co-expressed BCL2 and KIT, and tuft cell-like SCLC and LCNEC, but not SQCC, also highly expressed MYC. Data from public datasets confirmed these features and revealed that tuft cell-like SCLC and LCNEC co-clustered on hierarchical clustering. Furthermore, only tuft cell-like subsets among pulmonary cancers significantly expressed FOXI1, the master regulator of ionocytes, suggesting their bidirectional but immature differentiation status. Clinically, tuft cell-like SCLC and LCNEC had a similar prognosis. Experimentally, tuft cell-like SCLC cell lines were susceptible to PARP and BCL2 co-inhibition, indicating synergistic effects. Taken together, pulmonary tuft cell-like cancers maintain histotype-related clinicopathologic characteristics despite overlapping unique molecular features. From a therapeutic perspective, identification of tuft cell-like LCNECs might be crucial given their close kinship with tuft cell-like SCLC.
Onboard early detection and mitigation of lithium plating in fast-charging batteries
Authors: Huang Wenxiao , Ye Yusheng , Chen Hao , Vilá Rafael A. , Xiang Andrew , Wang Hongxia , Liu Fang , Yu Zhiao , Xu Jinwei , Zhang Zewen , Xu Rong , Wu Yecun , Chou Lien-Yang , Wang Hansen , Xu Junwei , Boyle David Tomas , Li Yuzhang , Cui Yi
Published: November 2022

Fast-charging is considered as one of the most desired features needed for lithium-ion batteries to accelerate the mainstream adoption of electric vehicles. However, current battery charging protocols mainly consist of conservative rate steps to avoid potential hazardous lithium plating and its associated parasitic reactions. A highly sensitive onboard detection method could enable battery fast-charging without reaching the lithium plating regime. Here, we demonstrate a novel differential pressure sensing method to precisely detect the lithium plating event. By measuring the real-time change of cell pressure per unit of charge (dP/dQ) and comparing it with the threshold defined by the maximum of dP/dQ during lithium-ion intercalation into the negative electrode, the onset of lithium plating before its extensive growth can be detected with high precision. In addition, we show that by integrating this differential pressure sensing into the battery management system (BMS), a dynamic self-regulated charging protocol can be realized to effectively extinguish the lithium plating triggered by low temperature (0 °C) while the conventional static charging protocol leads to catastrophic lithium plating at the same condition. We propose that differential pressure sensing could serve as an early nondestructive diagnosis method to guide the development of fast-charging battery technologies.
Multi-omics signatures of the human early life exposome
Authors: Maitre Léa , Bustamante Mariona , Hernández-Ferrer Carles , Thiel Denise , Lau Chung-Ho E. , Siskos Alexandros P. , Vives-Usano Marta , Ruiz-Arenas Carlos , Pelegrí-Sisó Dolors , Robinson Oliver , Mason Dan , Wright John , Cadiou Solène , Slama Rémy , Heude Barbara , Casas Maribel , Sunyer Jordi , Papadopoulou Eleni Z. , Gutzkow Kristine B. , Andrusaityte Sandra , Grazuleviciene Regina , Vafeiadi Marina , Chatzi Leda , Sakhi Amrit K. , Thomsen Cathrine , Tamayo Ibon , Nieuwenhuijsen Mark , Urquiza Jose , Borràs Eva , Sabidó Eduard , Quintela Inés , Carracedo Ángel , Estivill Xavier , Coen Muireann , González Juan R. , Keun Hector C. , Vrijheid Martine
Published: November 2022

Environmental exposures during early life play a critical role in life-course health, yet the molecular phenotypes underlying environmental effects on health are poorly understood. In the Human Early Life Exposome (HELIX) project, a multi-centre cohort of 1301 mother-child pairs, we associate individual exposomes consisting of >100 chemical, outdoor, social and lifestyle exposures assessed in pregnancy and childhood, with multi-omics profiles (methylome, transcriptome, proteins and metabolites) in childhood. We identify 1170 associations, 249 in pregnancy and 921 in childhood, which reveal potential biological responses and sources of exposure. Pregnancy exposures, including maternal smoking, cadmium and molybdenum, are predominantly associated with child DNA methylation changes. In contrast, childhood exposures are associated with features across all omics layers, most frequently the serum metabolome, revealing signatures for diet, toxic chemical compounds, essential trace elements, and weather conditions, among others. Our comprehensive and unique resource of all associations (https://helixomics.isglobal.org/) will serve to guide future investigation into the biological imprints of the early life exposome.
Disparate impacts on online information access during the Covid-19 pandemic
Authors: Suh Jina , Horvitz Eric , White Ryen W. , Althoff Tim
Published: November 2022

The COVID-19 pandemic has stimulated important changes in online information access as digital engagement became necessary to meet the demand for health, economic, and educational resources. Our analysis of 55 billion everyday web search interactions during the pandemic across 25,150 US ZIP codes reveals that the extent to which different communities of internet users enlist digital resources varies based on socioeconomic and environmental factors. For example, we find that ZIP codes with lower income intensified their access to health information to a smaller extent than ZIP codes with higher income. We show that ZIP codes with higher proportions of Black or Hispanic residents intensified their access to unemployment resources to a greater extent, while revealing patterns of unemployment site visits unseen by the claims data. Such differences frame important questions on the relationship between differential information search behaviors and the downstream real-world implications on more and less advantaged populations.
Deep learning to decompose macromolecules into independent Markovian domains
Authors: Mardt Andreas , Hempel Tim , Clementi Cecilia , Noé Frank
Published: November 2022

The increasing interest in modeling the dynamics of ever larger proteins has revealed a fundamental problem with models that describe the molecular system as being in a global configuration state. This notion limits our ability to gather sufficient statistics of state probabilities or state-to-state transitions because for large molecular systems the number of metastable states grows exponentially with size. In this manuscript, we approach this challenge by introducing a method that combines our recent progress on independent Markov decomposition (IMD) with VAMPnets, a deep learning approach to Markov modeling. We establish a training objective that quantifies how well a given decomposition of the molecular system into independent subdomains with Markovian dynamics approximates the overall dynamics. By constructing an end-to-end learning framework, the decomposition into such subdomains and their individual Markov state models are simultaneously learned, providing a data-efficient and easily interpretable summary of the complex system dynamics. While learning the dynamical coupling between Markovian subdomains is still an open issue, the present results are a significant step towards learning Ising models of large molecular complexes from simulation data.
Melting of generalized Wigner crystals in transition metal dichalcogenide heterobilayer Moiré systems
Authors: Matty Michael , Kim Eun-Ah
Published: November 2022

Moiré superlattice systems such as transition metal dichalcogenide heterobilayers have garnered significant recent interest due to their promising utility as tunable solid state simulators. Recent experiments on a WSe2/WS2 heterobilayer detected incompressible charge ordered states that one can view as generalized Wigner crystals. The tunability of the transition metal dichalcogenide heterobilayer Moiré system presents an opportunity to study the rich set of possible phases upon melting these charge-ordered states. Here we use Monte Carlo simulations to study these intermediate phases in between incompressible charge-ordered states in the strong coupling limit. We find two distinct stripe solid states to be each preceded by distinct types of nematic states. In particular, we discover microscopic mechanisms that stabilize each of the nematic states, whose order parameter transforms as the two-dimensional E representation of the Moiré lattice point group. Our results provide a testable experimental prediction of where both types of nematic occur, and elucidate the microscopic mechanism driving their formation.
Feedback between mechanosensitive signaling and active forces governs endothelial junction integrity
Authors: McEvoy Eoin , Sneh Tal , Moeendarbary Emad , Javanmardi Yousef , Efimova Nadia , Yang Changsong , Marino-Bravante Gloria E. , Chen Xingyu , Escribano Jorge , Spill Fabian , Garcia-Aznar José Manuel , Weeraratna Ashani T. , Svitkina Tatyana M. , Kamm Roger D. , Shenoy Vivek B.
Published: November 2022

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the regulation of endothelial junctions as dependent on the feedback between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Simulations reveal that active cell tension can stabilize cadherin bonds, but excessive RhoA signaling can drive bond dissociation and junction failure. While actin polymerization aids gap closure, high levels of Rac1 can induce junction weakening. Combining the modeling framework with experiments, our model predicts the influence of pharmacological treatments on the junction state and identifies that a critical balance between RhoA and Rac1 expression is required to maintain junction stability. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.
Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state
Authors: Maiti Atanu , Hedger Adam K. , Myint Wazo , Balachandran Vanivilasini , Watts Jonathan K. , Schiffer Celia A. , Matsuo Hiroshi
Published: November 2022

APOBEC3 proteins (A3s) are enzymes that catalyze the deamination of cytidine to uridine in single-stranded DNA (ssDNA) substrates, thus playing a key role in innate antiviral immunity. However, the APOBEC3 family has also been linked to many mutational signatures in cancer cells, which has led to an intense interest to develop inhibitors of A3’s catalytic activity as therapeutics as well as tools to study A3’s biochemistry, structure, and cellular function. Recent studies have shown that ssDNA containing 2′-deoxy-zebularine (dZ-ssDNA) is an inhibitor of A3s such as A3A, A3B, and A3G, although the atomic determinants of this activity have remained unknown. To fill this knowledge gap, we determined a 1.5 Å resolution structure of a dZ-ssDNA inhibitor bound to active A3G. The crystal structure revealed that the activated dZ-H2O mimics the transition state by coordinating the active site Zn2+ and engaging in additional stabilizing interactions, such as the one with the catalytic residue E259. Therefore, this structure allowed us to capture a snapshot of the A3’s transition state and suggests that developing transition-state mimicking inhibitors may provide a new opportunity to design more targeted molecules for A3s in the future.
PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation
Authors: Madsen Maria Stahl , Broekema Marjoleine F. , Madsen Martin Rønn , Koppen Arjen , Borgman Anouska , Gräwe Cathrin , Thomsen Elisabeth G. K. , Westland Denise , Kranendonk Mariette E. G. , Koerkamp Marian Groot , Hamers Nicole , Bonvin Alexandre M. J. J. , Pittol José M. Ramos , Natarajan Kedar Nath , Kersten Sander , Holstege Frank C. P. , Monajemi Houshang , van Mil Saskia W. C. , Vermeulen Michiel , Kragelund Birthe B. , Cassiman David , Mandrup Susanne , Kalkhoven Eric
Published: November 2022

Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte differentiation, and mutations that interfere with its function cause lipodystrophy. PPARγ is a highly modular protein, and structural studies indicate that PPARγ domains engage in several intra- and inter-molecular interactions. How these interactions modulate PPARγ’s ability to activate target genes in a cellular context is currently poorly understood. Here we take advantage of two previously uncharacterized lipodystrophy mutations, R212Q and E379K, that are predicted to interfere with the interaction of the hinge of PPARγ with DNA and with the interaction of PPARγ ligand binding domain (LBD) with the DNA-binding domain (DBD) of the retinoid X receptor, respectively. Using biochemical and genome-wide approaches we show that these mutations impair PPARγ function on an overlapping subset of target enhancers. The hinge region-DNA interaction appears mostly important for binding and remodelling of target enhancers in inaccessible chromatin, whereas the PPARγ-LBD:RXR-DBD interface stabilizes the PPARγ:RXR:DNA ternary complex. Our data demonstrate how in-depth analyses of lipodystrophy mutants can unravel molecular mechanisms of PPARγ function.
Model spread in tropical low cloud feedback tied to overturning circulation response to warming
Authors: Schiro Kathleen A. , Su Hui , Ahmed Fiaz , Dai Ni , Singer Clare E. , Gentine Pierre , Elsaesser Gregory S. , Jiang Jonathan H. , Choi Yong-Sang , David Neelin J.
Published: November 2022

Among models participating in the Coupled Model Intercomparison Project phase 6 (CMIP6), here we show that the magnitude of the tropical low cloud feedback, which contributes considerably to uncertainty in estimates of climate sensitivity, is intimately linked to tropical deep convection and its effects on the tropical atmospheric overturning circulation. First, a reduction in tropical ascent area and an increased frequency of heavy precipitation result in high cloud reduction and upper-tropospheric drying, which increases longwave cooling and reduces subsidence weakening, favoring low cloud reduction (Radiation-Subsidence Pathway). Second, increased longwave cooling decreases tropospheric stability, which also reduces subsidence weakening and low cloudiness (Stability-Subsidence Pathway). In summary, greater high cloud reduction and upper-tropospheric drying (negative longwave feedback) lead to a more positive cloud feedback among CMIP6 models by contributing to a greater reduction in low cloudiness (positive shortwave feedback). Varying strengths of the two pathways contribute considerably to the intermodel spread in climate sensitivity.
Phosphorylation disrupts long-distance electron transport in cytochrome c
Authors: Gomila Alexandre M. J. , Pérez-Mejías Gonzalo , Nin-Hill Alba , Guerra-Castellano Alejandra , Casas-Ferrer Laura , Ortiz-Tescari Sthefany , Díaz-Quintana Antonio , Samitier Josep , Rovira Carme , De la Rosa Miguel A. , Díaz-Moreno Irene , Gorostiza Pau , Giannotti Marina I. , Lagunas Anna
Published: November 2022

It has been recently shown that electron transfer between mitochondrial cytochrome c and the cytochrome c1 subunit of the cytochrome bc1 can proceed at long-distance through the aqueous solution. Cytochrome c is thought to adjust its activity by changing the affinity for its partners via Tyr48 phosphorylation, but it is unknown how it impacts the nanoscopic environment, interaction forces, and long-range electron transfer. Here, we constrain the orientation and separation between cytochrome c1 and cytochrome c or the phosphomimetic Y48pCMF cytochrome c, and deploy an array of single-molecule, bulk, and computational methods to investigate the molecular mechanism of electron transfer regulation by cytochrome c phosphorylation. We demonstrate that phosphorylation impairs long-range electron transfer, shortens the long-distance charge conduit between the partners, strengthens their interaction, and departs it from equilibrium. These results unveil a nanoscopic view of the interaction between redox protein partners in electron transport chains and its mechanisms of regulation.
Transposable element-mediated rearrangements are prevalent in human genomes
Authors: Balachandran Parithi , Walawalkar Isha A. , Flores Jacob I. , Dayton Jacob N. , Audano Peter A. , Beck Christine R.
Published: November 2022

Transposable elements constitute about half of human genomes, and their role in generating human variation through retrotransposition is broadly studied and appreciated. Structural variants mediated by transposons, which we call transposable element-mediated rearrangements (TEMRs), are less well studied, and the mechanisms leading to their formation as well as their broader impact on human diversity are poorly understood. Here, we identify 493 unique TEMRs across the genomes of three individuals. While homology directed repair is the dominant driver of TEMRs, our sequence-resolved TEMR resource allows us to identify complex inversion breakpoints, triplications or other high copy number polymorphisms, and additional complexities. TEMRs are enriched in genic loci and can create potentially important risk alleles such as a deletion in TRIM65, a known cancer biomarker and therapeutic target. These findings expand our understanding of this important class of structural variation, the mechanisms responsible for their formation, and establish them as an important driver of human diversity.
Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation
Authors: Osseni Alexis , Ravel-Chapuis Aymeric , Belotti Edwige , Scionti Isabella , Gangloff Yann-Gaël , Moncollin Vincent , Mazelin Laetitia , Mounier Remi , Leblanc Pascal , Jasmin Bernard J. , Schaeffer Laurent
Published: November 2022

The absence of dystrophin in Duchenne muscular dystrophy disrupts the dystrophin-associated glycoprotein complex resulting in skeletal muscle fiber fragility and atrophy, associated with fibrosis as well as microtubule and neuromuscular junction disorganization. The specific, non-conventional cytoplasmic histone deacetylase 6 (HDAC6) was recently shown to regulate acetylcholine receptor distribution and muscle atrophy. Here, we report that administration of the HDAC6 selective inhibitor tubastatin A to the Duchenne muscular dystrophy,mdxmouse model increases muscle strength, improves microtubule, neuromuscular junction, and dystrophin-associated glycoprotein complex organization, and reduces muscle atrophy and fibrosis. Interestingly, we found that the beneficial effects of HDAC6 inhibition involve the downregulation of transforming growth factor beta signaling. By increasing Smad3 acetylation in the cytoplasm, HDAC6 inhibition reduces Smad2/3 phosphorylation, nuclear translocation, and transcriptional activity. These findings provide in vivo evidence that Smad3 is a new target of HDAC6 and implicate HDAC6 as a potential therapeutic target in Duchenne muscular dystrophy.
Photocatalytic direct borylation of carboxylic acids
Authors: Wei Qiang , Lee Yuhsuan , Liang Weiqiu , Chen Xiaolei , Mu Bo-shuai , Cui Xi-Yang , Wu Wangsuo , Bai Shuming , Liu Zhibo
Published: November 2022

The preparation of high value-added boronic acids from cheap and plentiful carboxylic acids is desirable. To date, the decarboxylative borylation of carboxylic acids is generally realized through the extra step synthesized redox-active ester intermediate or in situ generated carboxylic acid covalent derivatives above 150 °C reaction temperature. Here, we report a direct decarboxylative borylation method of carboxylic acids enabled by visible-light catalysis and that does not require any extra stoichiometric additives or synthesis steps. This operationally simple process produces CO2 and proceeds under mild reaction conditions, in terms of high step economy and good functional group compatibility. A guanidine-based biomimetic active decarboxylative mechanism is proposed and rationalized by mechanistic studies. The methodology reported herein should see broad application extending beyond borylation.