bluuebunny/crossref_metadata_2025 huggingface dataset:
De novo generation of multi-target compounds using deep generative chemistry
Authors: Munson Brenton P. , Chen Michael , Bogosian Audrey , Kreisberg Jason F. , Licon Katherine , Abagyan Ruben , Kuenzi Brent M. , Ideker Trey
Published: May 2024

Polypharmacology drugs—compounds that inhibit multiple proteins—have many applications but are difficult to design. To address this challenge we have developed POLYGON, an approach to polypharmacology based on generative reinforcement learning. POLYGON embeds chemical space and iteratively samples it to generate new molecular structures; these are rewarded by the predicted ability to inhibit each of two protein targets and by drug-likeness and ease-of-synthesis. In binding data for >100,000 compounds, POLYGON correctly recognizes polypharmacology interactions with 82.5% accuracy. We subsequently generatede-novocompounds targeting ten pairs of proteins with documented co-dependency. Docking analysis indicates that top structures bind their two targets with low free energies and similar 3D orientations to canonical single-protein inhibitors. We synthesize 32 compounds targeting MEK1 and mTOR, with most yielding >50% reduction in each protein activity and in cell viability when dosed at 1–10 μM. These results support the potential of generative modeling for polypharmacology.
Primordial germ cell DNA demethylation and development require DNA translesion synthesis
Authors: Shah Pranay , Hill Ross , Dion Camille , Clark Stephen J. , Abakir Abdulkadir , Willems Jeroen , Arends Mark J. , Garaycoechea Juan I. , Leitch Harry G. , Reik Wolf , Crossan Gerry P.
Published: May 2024

Mutations in DNA damage response (DDR) factors are associated with human infertility, which affects up to 15% of the population. The DDR is required during germ cell development and meiosis. One pathway implicated in human fertility is DNA translesion synthesis (TLS), which allows replication impediments to be bypassed. We find that TLS is essential for pre-meiotic germ cell development in the embryo. Loss of the central TLS component, REV1, significantly inhibits the induction of human PGC-like cells (hPGCLCs). This is recapitulated in mice, where deficiencies in TLS initiation (Rev1-/- or PcnaK164R/K164R) or extension (Rev7 -/-) result in a > 150-fold reduction in the number of primordial germ cells (PGCs) and complete sterility. In contrast, the absence of TLS does not impact the growth, function, or homeostasis of somatic tissues. Surprisingly, we find a complete failure in both activation of the germ cell transcriptional program and in DNA demethylation, a critical step in germline epigenetic reprogramming. Our findings show that for normal fertility, DNA repair is required not only for meiotic recombination but for progression through the earliest stages of germ cell development in mammals.
AnnoSpat annotates cell types and quantifies cellular arrangements from spatial proteomics
Authors: Mongia Aanchal , Zohora Fatema Tuz , Burget Noah G. , Zhou Yeqiao , Saunders Diane C. , Wang Yue J. , Brissova Marcela , Powers Alvin C. , Kaestner Klaus H. , Vahedi Golnaz , Naji Ali , Schwartz Gregory W. , Faryabi Robert B.
Published: May 2024

Cellular composition and anatomical organization influence normal and aberrant organ functions. Emerging spatial single-cell proteomic assays such as Image Mass Cytometry (IMC) and Co-Detection by Indexing (CODEX) have facilitated the study of cellular composition and organization by enabling high-throughput measurement of cells and their localization directly in intact tissues. However, annotation of cell types and quantification of their relative localization in tissues remain challenging. To address these unmet needs for atlas-scale datasets like Human Pancreas Analysis Program (HPAP), we develop AnnoSpat (Annotator and Spatial Pattern Finder) that uses neural network and point process algorithms to automatically identify cell types and quantify cell-cell proximity relationships. Our study of data from IMC and CODEX shows the higher performance of AnnoSpat in rapid and accurate annotation of cell types compared to alternative approaches. Moreover, the application of AnnoSpat to type 1 diabetic, non-diabetic autoantibody-positive, and non-diabetic organ donor cohorts recapitulates known islet pathobiology and shows differential dynamics of pancreatic polypeptide (PP) cell abundance and CD8+ T cells infiltration in islets during type 1 diabetes progression.
Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer
Authors: Haderk Franziska , Chou Yu-Ting , Cech Lauren , Fernández-Méndez Celia , Yu Johnny , Olivas Victor , Meraz Ismail M. , Barbosa Rabago Dora , Kerr D. Lucas , Gomez Carlos , Allegakoen David V. , Guan Juan , Shah Khyati N. , Herrington Kari A. , Gbenedio Oghenekevwe M. , Nanjo Shigeki , Majidi Mourad , Tamaki Whitney , Pourmoghadam Yashar K. , Rotow Julia K. , McCoach Caroline E. , Riess Jonathan W. , Gutkind J. Silvio , Tang Tracy T. , Post Leonard , Huang Bo , Santisteban Pilar , Goodarzi Hani , Bandyopadhyay Sourav , Kuo Calvin J. , Roose Jeroen P. , Wu Wei , Blakely Collin M. , Roth Jack A. , Bivona Trever G.
Published: May 2024

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
Adjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus
Authors: Dillard Jacob A. , Taft-Benz Sharon A. , Knight Audrey C. , Anderson Elizabeth J. , Pressey Katia D. , Parotti Breantié , Martinez Sabian A. , Diaz Jennifer L. , Sarkar Sanjay , Madden Emily A. , De la Cruz Gabriela , Adams Lily E. , Dinnon Kenneth H. , Leist Sarah R. , Martinez David R. , Schäfer Alexandra , Powers John M. , Yount Boyd L. , Castillo Izabella N. , Morales Noah L. , Burdick Jane , Evangelista Mia Katrina D. , Ralph Lauren M. , Pankow Nicholas C. , Linnertz Colton L. , Lakshmanane Premkumar , Montgomery Stephanie A. , Ferris Martin T. , Baric Ralph S. , Baxter Victoria K. , Heise Mark T.
Published: May 2024

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection.
Discovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
Authors: Shaw Timothy I. , Wagner Jessica , Tian Liqing , Wickman Elizabeth , Poudel Suresh , Wang Jian , Paul Robin , Koo Selene C. , Lu Meifen , Sheppard Heather , Fan Yiping , O’Neill Francis H. , Lau Ching C. , Zhou Xin , Zhang Jinghui , Gottschalk Stephen
Published: May 2024

Immunotherapy with chimeric antigen receptor T cells for pediatric solid and brain tumors is constrained by available targetable antigens. Cancer-specific exons present a promising reservoir of targets; however, these have not been explored and validated systematically in a pan-cancer fashion. To identify cancer specific exon targets, here we analyze 1532 RNA-seq datasets from 16 types of pediatric solid and brain tumors for comparison with normal tissues using a newly developed workflow. We find 2933 exons in 157 genes encoding proteins of the surfaceome or matrisome with high cancer specificity either at the gene (n = 148) or the alternatively spliced isoform (n = 9) level. Expression of selected alternatively spliced targets, including the EDB domain of fibronectin 1, and gene targets, such as COL11A1, are validated in pediatric patient derived xenograft tumors. We generate T cells expressing chimeric antigen receptors specific for the EDB domain or COL11A1 and demonstrate that these have antitumor activity. The full target list, explorable via an interactive web portal (https://cseminer.stjude.org/), provides a rich resource for developing immunotherapy of pediatric solid and brain tumors using gene or AS targets with high expression specificity in cancer.
Bose-Einstein condensation of non-ground-state caesium atoms
Authors: Horvath Milena , Dhar Sudipta , Das Arpita , Frye Matthew D. , Guo Yanliang , Hutson Jeremy M. , Landini Manuele , Nägerl Hanns-Christoph
Published: May 2024

Bose-Einstein condensates of ultracold atoms serve as low-entropy sources for a multitude of quantum-science applications, ranging from quantum simulation and quantum many-body physics to proof-of-principle experiments in quantum metrology and quantum computing. For stability reasons, in the majority of cases the energetically lowest-lying atomic spin state is used. Here, we report the Bose-Einstein condensation of caesium atoms in the Zeeman-excited mf = 2 state, realizing a non-ground-state Bose-Einstein condensate with tunable interactions and tunable loss. We identify two regions of magnetic field in which the two-body relaxation rate is low enough that condensation is possible. We characterize the phase transition and quantify the loss processes, finding unusually high three-body losses in one of the two regions. Our results open up new possibilities for the mixing of quantum-degenerate gases, for polaron and impurity physics, and in particular for the study of impurity transport in strongly correlated one-dimensional quantum wires.
A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations
Authors: Saldana-Guerrero Ingrid M. , Montano-Gutierrez Luis F. , Boswell Katy , Hafemeister Christoph , Poon Evon , Shaw Lisa E. , Stavish Dylan , Lea Rebecca A. , Wernig-Zorc Sara , Bozsaky Eva , Fetahu Irfete S. , Zoescher Peter , Pötschger Ulrike , Bernkopf Marie , Wenninger-Weinzierl Andrea , Sturtzel Caterina , Souilhol Celine , Tarelli Sophia , Shoeb Mohamed R. , Bozatzi Polyxeni , Rados Magdalena , Guarini Maria , Buri Michelle C. , Weninger Wolfgang , Putz Eva M. , Huang Miller , Ladenstein Ruth , Andrews Peter W. , Barbaric Ivana , Cresswell George D. , Bryant Helen E. , Distel Martin , Chesler Louis , Taschner-Mandl Sabine , Farlik Matthias , Tsakiridis Anestis , Halbritter Florian
Published: May 2024

Early childhood tumours arise from transformed embryonic cells, which often carry large copy number alterations (CNA). However, it remains unclear how CNAs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ female human embryonic stem cell (hESC) differentiation and single-cell transcriptome and epigenome analysis to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNAs impair the specification of trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. This effect is exacerbated upon overexpression of MYCN, whose amplification co-occurs with CNAs in NB. Moreover, CNAs potentiate the pro-tumourigenic effects of MYCN and mutant NC cells resemble NB cells in tumours. These changes correlate with a stepwise aberration of developmental transcription factor networks. Together, our results sketch a mechanistic framework for the CNA-driven initiation of embryonal tumours.
Polymer hetero-electrolyte enabled solid-state 2.4-V Zn/Li hybrid batteries
Authors: Chen Ze , Wang Tairan , Wu Zhuoxi , Hou Yue , Chen Ao , Wang Yanbo , Huang Zhaodong , Schmidt Oliver G. , Zhu Minshen , Fan Jun , Zhi Chunyi
Published: May 2024

The high redox potential of Zn0/2+ leads to low voltage of Zn batteries and therefore low energy density, plaguing deployment of Zn batteries in many energy-demanding applications. Though employing high-voltage cathode like spinel LiNi0.5Mn1.5O4 can increase the voltages of Zn batteries, Zn2+ ions will be immobilized in LiNi0.5Mn1.5O4 once intercalated, resulting in irreversibility. Here, we design a polymer hetero-electrolyte consisting of an anode layer with Zn2+ ions as charge carriers and a cathode layer that blocks the Zn2+ ion shuttle, which allows separated Zn and Li reversibility. As such, the Zn‖LNMO cell exhibits up to 2.4 V discharge voltage and 450 stable cycles with high reversible capacity, which are also attained in a scale-up pouch cell. The pouch cell shows a low self-discharge after resting for 28 days. The designed electrolyte paves the way to develop high-voltage Zn batteries based on reversible lithiated cathodes.
LncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas
Authors: Li Zhaozheng , Zhao Yao , Pan Zhenwei , Cai Benzhi , Zhang Chengwei , Jiao Jundong
Published: May 2024

Arteriovenous fistulas (AVFs) are the most common vascular access points for hemodialysis (HD), but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia (NIH). Our previous studies have revealed a highly conserved LncRNA-LncDACH1 as an important regulator of cardiomyocyte and fibroblast proliferation. Herein, we find that LncDACH1 regulates NIH in AVF in male mice with conditional knockout of smooth muscle cell-specific LncDACH1 and in male mice model of AVF with LncDACH1 overexpression by adeno-associated virus. Mechanistically, silence of LncDACH1 activates p-AKT through promoting the expression of heat shock protein 90 (HSP90) and serine/arginine-rich splicing factor protein kinase 1 (SRPK1). Moreover, LncDACH1 is transcriptionally activated by transcription factor KLF9 that binds directly to the promoter region of the LncDACH1 gene. In this work, during AVF NIH, LncDACH1 is downregulated by KLF9 and promotes NIH through the HSP90/ SRPK1/ AKT signaling axis.
Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers
Authors: Wu Man , Hau Pok Man , Li Linxian , Tsang Chi Man , Yang Yike , Taghbalout Aziz , Chung Grace Tin-Yun , Hui Shin Yee , Tang Wing Chung , Jillette Nathaniel , Zhu Jacqueline Jufen , Lee Horace Hok Yeung , Kong Ee Ling , Chan Melissa Sue Ann , Chan Jason Ying Kuen , Ma Brigette Buig Yue , Chen Mei-Ru , Lee Charles , To Ka Fai , Cheng Albert Wu , Lo Kwok-Wai
Published: May 2024

The unique virus-cell interaction in Epstein-Barr virus (EBV)-associated malignancies implies targeting the viral latent-lytic switch is a promising therapeutic strategy. However, the lack of specific and efficient therapeutic agents to induce lytic cycle in these cancers is a major challenge facing clinical implementation. We develop a synthetic transcriptional activator that specifically activates endogenous BZLF1 and efficiently induces lytic reactivation in EBV-positive cancer cells. A lipid nanoparticle encapsulating nucleoside-modified mRNA which encodes a BZLF1-specific transcriptional activator (mTZ3-LNP) is synthesized for EBV-targeted therapy. Compared with conventional chemical inducers, mTZ3-LNP more efficiently activates EBV lytic gene expression in EBV-associated epithelial cancers. Here we show the potency and safety of treatment with mTZ3-LNP to suppress tumor growth in EBV-positive cancer models. The combination of mTZ3-LNP and ganciclovir yields highly selective cytotoxic effects of mRNA-based lytic induction therapy against EBV-positive tumor cells, indicating the potential of mRNA nanomedicine in the treatment of EBV-associated epithelial cancers.
In vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment
Authors: Meng Xiang , Jia Ruixuan , Zhao Xinping , Zhang Fan , Chen Shaohong , Yu Shicheng , Liu Xiaozhen , Dou Hongliang , Feng Xuefeng , Zhang Jinlu , Wang Ni , Xu Boling , Yang Liping
Published: May 2024

Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drugs. It is caused by mutations in CYP4V2 gene, and about 80% of BCD patients carry mutations in exon 7 to 11. Here, we apply CRISPR/Cas9 mediated homology-independent targeted integration (HITI)-based gene editing therapy in HEK293T cells, BCD patient derived iPSCs, and humanized Cyp4v3 mouse model (h-Cyp4v3mut/mut) using two rAAV2/8 vectors via sub-retinal administration. We find that sgRNA-guided Cas9 generates double-strand cleavage on intron 6 of the CYP4V2 gene, and the HITI donor inserts the carried sequence, part of intron 6, exon 7-11, and a stop codon into the DNA break, achieving precise integration, effective transcription and translation both in vitro and in vivo. HITI-based editing restores the viability of iPSC-RPE cells from BCD patient, improves the morphology, number and metabolism of RPE and photoreceptors in h-Cyp4v3mut/mut mice. These results suggest that HITI-based editing could be a promising therapeutic strategy for those BCD patients carrying mutations in exon 7 to 11, and one injection will achieve lifelong effectiveness.
The DEAD-box RNA helicase PfDOZI imposes opposing actions on RNA metabolism in Plasmodium falciparum
Authors: Min Hui , Liang Xiaoying , Wang Chengqi , Qin Junling , Boonhok Rachasak , Muneer Azhar , Brashear Awtum M. , Li Xiaolian , Minns Allen M. , Adapa Swamy Rakesh , Jiang Rays H. Y. , Ning Gang , Cao Yaming , Lindner Scott E. , Miao Jun , Cui Liwang
Published: May 2024

In malaria parasites, the regulation of mRNA translation, storage and degradation during development and life-stage transitions remains largely unknown. Here, we functionally characterized the DEAD-box RNA helicase PfDOZI inP. falciparum. Disruption ofpfdozienhanced asexual proliferation but reduced sexual commitment and impaired gametocyte development. By quantitative transcriptomics, we show that PfDOZI is involved in the regulation of invasion-related genes and sexual stage-specific genes during different developmental stages. PfDOZI predominantly participates in processing body-like mRNPs in schizonts but germ cell granule-like mRNPs in gametocytes to impose opposing actions of degradation and protection on different mRNA targets. We further show the formation of stress granule-like mRNPs during nutritional deprivation, highlighting an essential role of PfDOZI-associated mRNPs in stress response. We demonstrate that PfDOZI participates in distinct mRNPs to maintain mRNA homeostasis in response to life-stage transition and environmental changes by differentially executing post-transcriptional regulation on the target mRNAs.
Observation of dichotomic field-tunable electronic structure in twisted monolayer-bilayer graphene
Authors: Zhang Hongyun , Li Qian , Park Youngju , Jia Yujin , Chen Wanying , Li Jiaheng , Liu Qinxin , Bao Changhua , Leconte Nicolas , Zhou Shaohua , Wang Yuan , Watanabe Kenji , Taniguchi Takashi , Avila Jose , Dudin Pavel , Yu Pu , Weng Hongming , Duan Wenhui , Wu Quansheng , Jung Jeil , Zhou Shuyun
Published: May 2024

Twisted bilayer graphene (tBLG) provides a fascinating platform for engineering flat bands and inducing correlated phenomena. By designing the stacking architecture of graphene layers, twisted multilayer graphene can exhibit different symmetries with rich tunability. For example, in twisted monolayer-bilayer graphene (tMBG) which breaks the C2z symmetry, transport measurements reveal an asymmetric phase diagram under an out-of-plane electric field, exhibiting correlated insulating state and ferromagnetic state respectively when reversing the field direction. Revealing how the electronic structure evolves with electric field is critical for providing a better understanding of such asymmetric field-tunable properties. Here we report the experimental observation of field-tunable dichotomic electronic structure of tMBG by nanospot angle-resolved photoemission spectroscopy (NanoARPES) with operando gating. Interestingly, selective enhancement of the relative spectral weight contributions from monolayer and bilayer graphene is observed when switching the polarity of the bias voltage. Combining experimental results with theoretical calculations, the origin of such field-tunable electronic structure, resembling either tBLG or twisted double-bilayer graphene (tDBG), is attributed to the selectively enhanced contribution from different stacking graphene layers with a strong electron-hole asymmetry. Our work provides electronic structure insights for understanding the rich field-tunable physics of tMBG.
Low-index mesoscopic surface reconstructions of Au surfaces using Bayesian force fields
Authors: Owen Cameron J. , Xie Yu , Johansson Anders , Sun Lixin , Kozinsky Boris
Published: May 2024

Metal surfaces have long been known to reconstruct, significantly influencing their structural and catalytic properties. Many key mechanistic aspects of these subtle transformations remain poorly understood due to limitations of previous simulation approaches. Using active learning of Bayesian machine-learned force fields trained from ab initio calculations, we enable large-scale molecular dynamics simulations to describe the thermodynamics and time evolution of the low-index mesoscopic surface reconstructions of Au (e.g., the Au(111)-‘Herringbone,’ Au(110)-(1 × 2)-‘Missing-Row,’ and Au(100)-‘Quasi-Hexagonal’ reconstructions). This capability yields direct atomistic understanding of the dynamic emergence of these surface states from their initial facets, providing previously inaccessible information such as nucleation kinetics and a complete mechanistic interpretation of reconstruction under the effects of strain and local deviations from the original stoichiometry. We successfully reproduce previous experimental observations of reconstructions on pristine surfaces and provide quantitative predictions of the emergence of spinodal decomposition and localized reconstruction in response to strain at non-ideal stoichiometries. A unified mechanistic explanation is presented of the kinetic and thermodynamic factors driving surface reconstruction. Furthermore, we study surface reconstructions on Au nanoparticles, where characteristic (111) and (100) reconstructions spontaneously appear on a variety of high-symmetry particle morphologies.
A fast-charging/discharging and long-term stable artificial electrode enabled by space charge storage mechanism
Authors: Zhao Linyi , Wang Tiansheng , Zuo Fengkai , Ju Zhengyu , Li Yuhao , Li Qiang , Zhu Yue , Li Hongsen , Yu Guihua
Published: May 2024

Lithium‐ion batteries with fast-charging/discharging properties are urgently needed for the mass adoption of electric vehicles. Here, we show that fast charging/discharging, long-term stable and high energy charge-storage properties can be realized in an artificial electrode made from a mixed electronic/ionic conductor material (Fe/LixM, where M = O, F, S, N) enabled by a space charge principle. Particularly, the Fe/Li2O electrode is able to be charged/discharged to 126 mAh g−1 in 6 s at a high current density of up to 50 A g−1, and it also shows stable cycling performance for 30,000 cycles at a current density of 10 A g−1, with a mass-loading of ~2.5 mg cm−2 of the electrode materials. This study demonstrates the critical role of the space charge storage mechanism in advancing electrochemical energy storage and provides an unconventional perspective for designing high-performance anode materials for lithium-ion batteries.
Active learning graph neural networks for partial charge prediction of metal-organic frameworks via dropout Monte Carlo
Authors: Thaler Stephan , Mayr Felix , Thomas Siby , Gagliardi Alessio , Zavadlav Julija
Published: May 2024

Metal-organic frameworks (MOF) are an attractive class of porous materials due to their immense design space, allowing for application-tailored properties. Properties of interest, such as gas sorption, can be predicted in silico with molecular mechanics simulations. However, the accuracy is limited by the available empirical force field and partial charge estimation scheme. In this work, we train a graph neural network for partial charge prediction via active learning based on Dropout Monte Carlo. We show that active learning significantly reduces the required amount of labeled MOFs to reach a target accuracy. The obtained model generalizes well to different distributions of MOFs and Zeolites. In addition, the uncertainty predictions of Dropout Monte Carlo enable reliable estimation of the mean absolute error for unseen MOFs. This work paves the way towards accurate molecular modeling of MOFs via next-generation potentials with machine learning predicted partial charges, supporting in-silico material design.
Engineering holography with stabilizer graph codes
Authors: Anglès Munné Gerard , Kasper Valentin , Huber Felix
Published: May 2024

The discovery of holographic codes established a surprising connection between quantum error correction and the anti-de Sitter-conformal field theory correspondence. Recent technological progress in artificial quantum systems renders the experimental realization of such holographic codes now within reach. Formulating the hyperbolic pentagon code in terms of a stabilizer graph code, we give gate sequences that are tailored to systems with long-range interactions. We show how to obtain encoding and decoding circuits for the hyperbolic pentagon code, before focusing on a small instance of the holographic code on twelve qubits. Our approach allows to verify holographic properties by partial decoding operations, recovering bulk degrees of freedom from their nearby boundary.
Phonological awareness mediates the relationship between DCDC2 and reading performance with home environment
Authors: Li Miao , DeMille Mellissa M. C. , Lovett Maureen W. , Bosson-Heenan Joan , Frijters Jan C. , Gruen Jeffrey R. ,   the GRaD Study Consortium, Boada Richard , Gottwald Stephanie , Hill Dina , Jacobson Lisa A. , Willcutt Erik G. , Wolf Maryanne
Published: May 2024

Proficient reading requires critical phonological processing skill that interacts with both genetic and environmental factors. However, the precise nature of the relationships between phonological processing and genetic and environmental factors are poorly understood. We analyzed data from the Genes, Reading and Dyslexia (GRaD) Study on 1419 children ages 8–15 years from African-American and Hispanic-American family backgrounds living in North America. The analyses showed that phonological awareness mediated the relationship between DCDC2-READ1 and reading outcomes when parental education and socioeconomic status was low. The association between READ1 and reading performance is complex, whereby mediation by phonological awareness was significantly moderated by both parental education and socioeconomic status. These results show the importance of home environment and phonological skills when determining associations between READ1 and reading outcomes. This will be an important consideration in the development of genetic screening for risk of reading disability.
Decoding the principle of cell-fate determination for its reverse control
Authors: Lee Jonghoon , Kim Namhee , Cho Kwang-Hyun
Published: May 2024

Understanding and manipulating cell fate determination is pivotal in biology. Cell fate is determined by intricate and nonlinear interactions among molecules, making mathematical model-based quantitative analysis indispensable for its elucidation. Nevertheless, obtaining the essential dynamic experimental data for model development has been a significant obstacle. However, recent advancements in large-scale omics data technology are providing the necessary foundation for developing such models. Based on accumulated experimental evidence, we can postulate that cell fate is governed by a limited number of core regulatory circuits. Following this concept, we present a conceptual control framework that leverages single-cell RNA-seq data for dynamic molecular regulatory network modeling, aiming to identify and manipulate core regulatory circuits and their master regulators to drive desired cellular state transitions. We illustrate the proposed framework by applying it to the reversion of lung cancer cell states, although it is more broadly applicable to understanding and controlling a wide range of cell-fate determination processes.
High production of IL-12 by human dendritic cells stimulated with combinations of pattern-recognition receptor agonists
Authors: Gilmour Brian C. , Corthay Alexandre , Øynebråten Inger
Published: May 2024

The cytokine IL-12p70 is crucial for T helper 1 (Th1) polarization and the generation of type 1 immunity required to fight cancer and pathogens. Therefore, strategies to optimize the production of IL-12p70 by human dendritic cells (DCs) may significantly improve the efficacy of vaccines and immunotherapies. However, the rules governing the production of IL-12p70 remain obscure. Here, we stimulated pattern recognition receptors (PRRs) representing five families of PRRs, to evaluate their ability to elicit high production of IL-12p70 by monocyte-derived DCs. We used ten well-characterized agonists and stimulated DCs in vitro with either single agonists or 27 different combinations. We found that poly(I:C), which engages the RNA-sensing PRRs TLR3 and MDA5, and LPS which stimulates TLR4, were the only agonists that could elicit notable IL-12p70 production when used as single ligands. We identified six different combinations of PRR agonists, all containing either the TLR3/MDA5 agonist poly(I:C) or the TLR7/8 agonist R848, that could synergize to elicit high production of IL-12p70 by human DCs. Five of the six combinations also triggered high production of the antiviral and antitumor cytokine IFNβ. Overall, the tested PRR ligands could be divided into three groups depending on whether they triggered production of both IL-12p70 and IFNβ, only one of the two, or neither. Thus, combinations of PRR agonists were found to increase the production of IL-12p70 by human DCs in a synergistic manner, and we identified six PRR agonist combinations that may represent strong adjuvant candidates, in particular for therapeutic cancer vaccines.
Investigation of scaling inhibition and biofouling potential of different molecular weight fractions of a PAA antiscalant
Authors: Kaushik S. A. , Armbruster D. , Dittmer J. , Bruniecka-Sulewski D. , Wendler B. , Ernst M.
Published: May 2024

This study investigates the scale inhibition performance of a commercial polyacrylic acid-based (PAA) antiscalant used for drinking water production and its molecular weight fractions (≤ 500 Da, ≥ 500 Da). The investigated antiscalant is used to prevent sulfate and carbonate scaling in treatment of drinking water sources by reverse osmosis or nanofiltration (RO/NF). Based on two complementary tests involving determination of induction time in a batch test and rate of flux decline in a lab-scale RO/NF plant, concordant results were obtained, proving that the overall performance of commercial PAA was controlled almost entirely by the higher molecular weight fraction. The low molecular weight fraction, which is potentially more permeable through the NF/RO membrane, showed poor inhibition against both sulfate and carbonate scalants. Furthermore, measurements on the assimilable organic carbon (AOC) by flow cytometry reveals that the low molecular weight PAA fraction has low biological stability, as its potential transport into the permeate of a NF270 nanofiltration membrane was inferred by elevated AOC values in the NF-permeate. These results are crucial information for water utilities, plant engineering, regulatory bodies and public authorities with respect to the possible operation of RO/NF especially in drinking water production.
Transthoracic ultrasound localization microscopy of myocardial vasculature in patients
Authors: Yan Jipeng , Huang Biao , Tonko Johanna , Toulemonde Matthieu , Hansen-Shearer Joseph , Tan Qingyuan , Riemer Kai , Ntagiantas Konstantinos , Chowdhury Rasheda A. , Lambiase Pier D. , Senior Roxy , Tang Meng-Xing
Published: May 2024

Myocardial microvasculature and haemodynamics are indicative of potential microvascular diseases for patients with symptoms of coronary heart disease in the absence of obstructive coronary arteries. However, imaging microvascular structure and flow within the myocardium is challenging owing to the small size of the vessels and the constant movement of the patient’s heart. Here we show the feasibility of transthoracic ultrasound localization microscopy for imaging myocardial microvasculature and haemodynamics in explanted pig hearts and in patients in vivo. Through a customized data-acquisition and processing pipeline with a cardiac phased-array probe, we leveraged motion correction and tracking to reconstruct the dynamics of microcirculation. For four patients, two of whom had impaired myocardial function, we obtained super-resolution images of myocardial vascular structure and flow using data acquired within a breath hold. Myocardial ultrasound localization microscopy may facilitate the understanding of myocardial microcirculation and the management of patients with cardiac microvascular diseases.
Durable lymph-node expansion is associated with the efficacy of therapeutic vaccination
Authors: Najibi Alexander J. , Lane Ryan S. , Sobral Miguel C. , Bovone Giovanni , Kang Shawn , Freedman Benjamin R. , Gutierrez Estupinan Joel , Elosegui-Artola Alberto , Tringides Christina M. , Dellacherie Maxence O. , Williams Katherine , Ijaz Hamza , Müller Sören , Turley Shannon J. , Mooney David J.
Published: May 2024

Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes.
Pemigatinib in previously treated solid tumors with activating FGFR1–FGFR3 alterations: phase 2 FIGHT-207 basket trial
Authors: Rodón Jordi , Damian Silvia , Furqan Muhammad , García-Donas Jesús , Imai Hiroo , Italiano Antoine , Spanggaard Iben , Ueno Makoto , Yokota Tomoya , Veronese Maria Luisa , Oliveira Natalia , Li Xin , Gilmartin Aidan , Schaffer Michael , Goyal Lipika
Published: May 2024

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1–FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1–FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117.
A regionally refined quarter-degree global atmospheric rivers database based on ERA5
Authors: Guan Bin , Waliser Duane E.
Published: May 2024

Atmospheric rivers (ARs) are narrow, elongated, synoptic jets of water vapor that play important roles in the global water cycle. The continually developing Tracking Atmospheric Rivers Globally as Elongated Targets (tARget) algorithm identifies AR objects at individual time steps based on thresholding integrated water vapor transport (IVT) and other requirements, and tracks each AR object in time and space. Building on previous versions of tARget, this paper discusses further refinements to the algorithm to better handle ARs in tropical and polar areas, as well as “zonal” ARs which the previous versions of the algorithm were not designed to capture. This further regionally refined algorithm is applied to the ERA5 reanalysis over 1940–2023 at 6 h intervals and a 0.25° × 0.25° horizontal resolution. The AR detection results are evaluated in terms of key AR characteristics. We anticipate this regionally refined global AR database will aid further understanding of ARs such as AR process studies, evaluation of AR simulations and predictions, and assessment of climate change impacts on ARs.
Assessment of macro, trace and toxic element intake from rice: differences between cultivars, pigmented and non-pigmented rice
Authors: Liu Xingyong , Li Qian , Yin Benlin , Yan Hongmei , Wang Yunmei
Published: May 2024

Pigmented and non-pigmented rice varieties (grown in different areas) were collected in China, Yunnan, to investigate the content of macro-, trace elements and potentially toxic elements (PTEs), and to assess the health risk associated with dietary intake. The order of elemental concentrations in rice was Mn > Zn > Fe > Cu > Se for trace elements, P > K > Mg > Ca > Na for macro elements, and Cr > As > Cd for PTEs. Rice with a high concentration of essential elements also associated with a high content of PTEs. In addition, higher content of Cr, Mn and Na were found in pigmented rice. The health risk assessment showed that the daily intake of all elements was below the tolerable limit (UL). Moreover the intake of Fe, Zn and Se was far from sufficient for the nutrient requirement. The PTEs in rice dominated the health risk. Of concern is that this rice consumption is likely to contribute to carcinogenic risks in the long term and that adults are at higher health risk from pigmented rice compared to non-pigmented rice. This study confirms that the lack of essential micronutrients in rice and the health risk associated with rice diets should remain a concern.
Consumption of red, white, and processed meat and odds of developing kidney damage and diabetic nephropathy (DN) in women: a case control study
Authors: Mirzababaei Atieh , Abaj Faezeh , Roumi Zahra , Khosroshahi Reza Amiri , Aali Yasaman , Clark Cain C. T. , Radmehr Mina , Mirzaei Khadijeh
Published: May 2024

Diabetic nephropathy (DN) is one of the most prevalent and severe complications of diabetes mellitus (DM) and is associated with increased morbidity and mortality. We aimed to investigate the associations between red, processed, and white meat consumption and the odds of developing kidney damage and DN in women. We enrolled 105 eligible women with DN and 105 controls (30–65 years). A validated and reliable food frequency questionnaire (FFQ) was used to evaluate the consumption of red, processed, and white meat. Biochemical variables and anthropometric measurements were assessed for all patients using pre-defined protocols. Binary logistic regression was conducted to examine possible associations. The results of the present study showed that there was a direct significant association between high consumption of red meat and processed meats and odds of microalbuminuria (red meat 2.30, 95% CI 1.25, 4.22; P-value = 0.007, processed meat: OR 2.16, 95% CI 1.18, 3.95; P-value = 0.01), severe albuminuria (red meat OR 3.25, 95% CI 1.38, 7.46; P-value = 0.007, processed meat: OR 2.35, 95% CI 1.01, 5.49; P-value = 0.04), BUN levels (red meat: OR 2.56, 95% CI 1.10, 5.93; P-value = 0.02, processed meat: OR 2.42, 95% CI 1.04, 5.62; P-value = 0.03), and DN (red meat 2.53, 95% CI 1.45, 4.42; P-value = 0.001, processed meat: OR 2.21; 95% CI 1.27, 3.85; P-value = 0.005). In summary, our study suggests that higher consumption of red and processed meat sources may be associated with microalbuminuria, severe albuminuria, higher BUN level, and higher odds of DN.
Enhancing tuberculosis vaccine development: a deconvolution neural network approach for multi-epitope prediction
Authors: Mubarak Auwalu Saleh , Ameen Zubaida Said , Hassan Abdurrahman Shuaibu , Ozsahin Dilber Uzun
Published: May 2024

Tuberculosis (TB) a disease caused by Mycobacterium tuberculosis (Mtb) poses a significant threat to human life, and current BCG vaccinations only provide sporadic protection, therefore there is a need for developing efficient vaccines. Numerous immunoinformatic methods have been utilized previously, here for the first time a deep learning framework based on Deconvolutional Neural Networks (DCNN) and Bidirectional Long Short-Term Memory (DCNN-BiLSTM) was used to predict Mtb Multiepitope vaccine (MtbMEV) subunits against six Mtb H37Rv proteins. The trained model was used to design MEV within a few minutes against TB better than other machine learning models with 99.5% accuracy. The MEV has good antigenicity, and physiochemical properties, and is thermostable, soluble, and hydrophilic. The vaccine's BLAST search ruled out the possibility of autoimmune reactions. The secondary structure analysis revealed 87% coil, 10% beta, and 2% alpha helix, while the tertiary structure was highly upgraded after refinement. Molecular docking with TLR3 and TLR4 receptors showed good binding, indicating high immune reactions. Immune response simulation confirmed the generation of innate and adaptive responses. In-silico cloning revealed the vaccine is highly expressed in E. coli. The results can be further experimentally verified using various analyses to establish a candidate vaccine for future clinical trials.
Association of attenuated leptin signaling pathways with impaired cardiac function under prolonged high-altitude hypoxia
Authors: Wang Jianan , Liu Shiying , Sun Lihong , Kong Zhanping , Chai Jiamin , Wen Jigang , Tian Xuan , Chen Nan , Xu Chengli
Published: May 2024

Cardiovascular function and adipose metabolism were markedly influenced under high altitudes. However, the interplay between adipokines and heart under hypoxia remains to be elucidated. We aim to explore alterations of adipokines and underlying mechanisms in regulating cardiac function under high altitudes. We investigated the cardiopulmonary function and five adipokines in Antarctic expeditioners at Kunlun Station (4,087 m) for 20 days and established rats exposed to hypobaric hypoxia (5,000 m), simulating Kunlun Station. Antarctic expeditioners exhibited elevated heart rate, blood pressure, systemic vascular resistance, and decreased cardiac pumping function. Plasma creatine phosphokinase-MB (CK-MB) and platelet-endothelial cell adhesion molecule-1 (sPecam-1) increased, and leptin, resistin, and lipocalin-2 decreased. Plasma leptin significantly correlated with altered cardiac function indicators. Additionally, hypoxic rats manifested impaired left ventricular systolic and diastolic function, elevated plasma CK-MB and sPecam-1, and decreased plasma leptin. Chronic hypoxia for 14 days led to increased myocyte hypertrophy, fibrosis, apoptosis, and mitochondrial dysfunction, coupled with reduced protein levels of leptin signaling pathways in myocardial tissues. Cardiac transcriptome analysis revealed leptin was associated with downregulated genes involved in rhythm, Na+/K+ transport, and cell skeleton. In conclusion, chronic hypoxia significantly reduced leptin signaling pathways in cardiac tissues along with significant pathological changes, thus highlighting the pivotal role of leptin in regulation of cardiac function under high altitudes.
Joint extraction of wheat germplasm information entity relationship based on deep character and word fusion
Authors: Jia Xiaoxiao , Zheng Guang , Dong Chenyang , Xi Shiyu , Shi Lei , Xiong Shufeng , Ma Xinming , Xi Lei
Published: May 2024

The verified text data of wheat varieties is an important component of wheat germplasm information. To automatically obtain a structured description of the phenotypic and genetic characteristics of wheat varieties, the aim at solve the issues of fuzzy entity boundaries and overlapping relationships in unstructured wheat variety approval data, WGIE-DCWF (joint extraction model of wheat germplasm information entity relationship based on deep character and word fusion) was proposed. The encoding layer of the model deeply fused word semantic information and character information using the Transformer encoder of BERT. This allowed for the cascading fusion of contextual semantic feature information to achieve rich character vector representation and improve the recognition ability of entity features. The triple extraction layer of the model established a cascading pointer network, extracted the head entity, extracted the tail entity according to the relationship category, and decoded the output triplet. This approach improved the model’s capability to extract overlapping relationships. The experimental results demonstrated that the WGIE-DCWF model performed exceptionally well on both the WGD (wheat germplasm dataset) and the public dataset DuIE. The WGIE-DCWF model not only achieved high performance on the evaluation datasets but also demonstrated good generalization. This provided valuable technical support for the construction of a wheat germplasm information knowledge base and is of great significance for wheat breeding, genetic research, cultivation management, and agricultural production.