bluuebunny/crossref_metadata_2025_split huggingface dataset:
Making the global turn matter: strategies and pathways
Authors: Lees Lynn Hollen 
Published: April 2024

Abstract
The survey examines the past, present and future of the urban history field in Britain, mixing memories and reflections. I trace the global turn of that field and the challenges it brings. One argument concerns the impact of a global scale on the methods and the explanatory frameworks used. A second concern is the role of economic history and economic frameworks of analysis in the writing of urban history, and I advocate their continued relevance.
Spontaneous Formation of an Internal Shear Band in Ice Flowing Over Topographically Variable Bedrock
Authors: Liu Emma Weijia , Räss Ludovic , Herman Frédéric , Podladchikov Yury , Suckale Jenny 
Published: April 2024

AbstractIce surface speed increases dramatically from upstream to downstream in many ice streams and glaciers. This speed‐up is thought to be associated with a transition from internal distributed deformation to highly localized deformation or sliding at the ice‐bedrock interface. The physical processes governing this transition remain unclear. Here, we argue that highly localized deformation does not necessarily initiate at the ice‐bedrock interface, but could also take the form of an internal shear band inside the ice flow that connects topographic highs. The power‐law exponent n in the ice rheology amplifies the feedback between shear heating and shear localization, leading to the spontaneous formation of an internal shear band that can create flow separation within the ice. We model the thermomechanical ice flow over a sinusoidal basal topography by building on the high‐resolution Stokes solver FastICE v1.0. We compile a regime diagram summarizing cases in which a sinusoidal topography with a given amplitude and wavelength leads to shear band formation for a given rheology. We compare our model results to borehole measurements from Greenland and find evidence to support the existence of an internal shear band. Our study highlights the importance of re‐evaluating the degree to which internal deformation contributes to total deformation in the ice column and to the flow‐to‐sliding transition.
The Incomplete Record of Autogenic Processes Sets Limits on Signal Detectability
Authors: Griffin C. , Duller R. A. , Straub K. M. 
Published: April 2024

AbstractSpectral analysis is a central tool regularly used by the scientific community to identify the presence of periodic processes within a time series of information, as spectral peaks at an imposed periodicity can be differentiated from internal (autogenic) variance. In scientific disciplines, such as seismology, the time series of information is of high temporal resolution. Hence, although temporal gaps are present, they do not impact the overall noise structure, meaning that the full spectrum of autogenic variance can be reconstructed. However, power spectra generated from stratigraphic information are affected by temporal incompleteness due to varying episodes of erosion and geomorphic stasis, which generate gaps over a range of scales. This removes information related to the natural and autogenic variability present within sediment‐transport systems, which makes it challenging to accurately reconstruct the structure and strength of paleo‐surface processes, which defines the detectability of past environmental signals. We explore how incompleteness impacts the temporal structure of autogenic noise within power spectra, and how this influences the detectability of spectral spikes related to environmental signals. We utilize a sediment flux time series from a physical rice pile and progressively degrade these data to mimic varying degrees of stratigraphic incompleteness. We find that incompleteness strongly influences the timescales and spectral structure of autogenic noise evident, and can render signals over all periodicities undetectable within a highly incomplete time series. This offers the ability to confidently justify the interpretation of subtle environmental signals from field measurements and understand the records that may best preserve paleoenvironmental variability.
Adeno-associated virus as a delivery vector for gene therapy of human diseases
Authors: Wang Jiang-Hui , Gessler Dominic J. , Zhan Wei , Gallagher Thomas L. , Gao Guangping 
Published: April 2024

AbstractAdeno-associated virus (AAV) has emerged as a pivotal delivery tool in clinical gene therapy owing to its minimal pathogenicity and ability to establish long-term gene expression in different tissues. Recombinant AAV (rAAV) has been engineered for enhanced specificity and developed as a tool for treating various diseases. However, as rAAV is being more widely used as a therapy, the increased demand has created challenges for the existing manufacturing methods. Seven rAAV-based gene therapy products have received regulatory approval, but there continue to be concerns about safely using high-dose viral therapies in humans, including immune responses and adverse effects such as genotoxicity, hepatotoxicity, thrombotic microangiopathy, and neurotoxicity. In this review, we explore AAV biology with an emphasis on current vector engineering strategies and manufacturing technologies. We discuss how rAAVs are being employed in ongoing clinical trials for ocular, neurological, metabolic, hematological, neuromuscular, and cardiovascular diseases as well as cancers. We outline immune responses triggered by rAAV, address associated side effects, and discuss strategies to mitigate these reactions. We hope that discussing recent advancements and current challenges in the field will be a helpful guide for researchers and clinicians navigating the ever-evolving landscape of rAAV-based gene therapy.
Mex-3 RNA binding family member A (MEX3A)/circMPP6 complex promotes colorectal cancer progression by inhibiting autophagy
Authors: Chen Ri-Xin , Xu Shui-Dan , Deng Min-Hua , Hao Shi-Hui , Chen Jie-Wei , Ma Xiao-Dan , Zhuang Wei-Tao , Cao Jing-Hua , Lv Yong-Rui , Lin Jin-Long , Li Si-Yu , Qiao Gui-Bin , Xie Dan , Wang Feng-Wei 
Published: April 2024

AbstractRNA-binding proteins (RBPs)-RNA networks have contributed to cancer development. Circular RNAs (circRNAs) are considered as protein recruiters; nevertheless, the patterns of circRNA-protein interactions in colorectal cancer (CRC) are still lacking. Processing bodies (PBs) formed through liquid-liquid phase separation (LLPS) are membrane-less organelles (MLOs) consisting of RBPs and RNA. Previous evidence suggests a connection between PBs dynamics and cancer progression. Despite the increasingly acknowledged crucial role of RBPs and RNA in the accumulation and maintenance of MLOs, there remains a lack of specific research on the interactions between PBs-related RBPs and circRNAs in CRC. Herein, we identify that MEX-3 RNA binding family member A (MEX3A), frequently upregulated in CRC tissues, predicts poorer patient survival. Elevated MEX3A accelerates malignance and inhibits autophagy of CRC cells. Importantly, MEX3A undergoes intrinsically disordered regions (IDRs)-dependent LLPS in the cytoplasm. Specifically, circMPP6 acts as a scaffold to facilitate the interaction between MEX3A and PBs proteins. The MEX3A/circMPP6 complex modulates PBs dynamic and promotes UPF-mediated phosphodiesterase 5A (PDE5A) mRNA degradation, consequently leading to the aggressive properties of CRC cells. Clinically, CRC patients exhibiting high MEX3A expression and low PDE5A expression have the poorest overall survival. Our findings reveal a collaboration between MEX3A and circMPP6 in the regulation of mRNA decay through triggering the PBs aggregation, which provides prognostic markers and/or therapeutic targets for CRC.
XELOX (capecitabine plus oxaliplatin) plus bevacizumab (anti-VEGF-A antibody) with or without adoptive cell immunotherapy in the treatment of patients with previously untreated metastatic colorectal cancer: a multicenter, open-label, randomized, controlled, phase 3 trial
Authors: Pan Qiu-Zhong , Zhao Jing-Jing , Liu Liang , Zhang Dong-Sheng , Wang Li-Ping , Hu Wen-Wei , Weng De-Sheng , Xu Xiang , Li Yi-Zhuo , Tang Yan , Zhang Wei-Hong , Li Jie-Yao , Zheng Xiao , Wang Qi-Jing , Li Yong-Qiang , Xiang Tong , Zhou Li , Yang Shuang-Ning , Wu Chen , Huang Rong-Xing , He Jia , Du Wei-Jiao , Chen Lu-Jun , Wu Yue-Na , Xu Bin , Shen Qiong , Zhang Yi , Jiang Jing-Ting , Ren Xiu-Bao , Xia Jian-Chuan 
Published: April 2024

AbstractFluoropyrimidine-based combination chemotherapy plus targeted therapy is the standard initial treatment for unresectable metastatic colorectal cancer (mCRC), but the prognosis remains poor. This phase 3 trial (ClinicalTrials.gov: NCT03950154) assessed the efficacy and adverse events (AEs) of the combination of PD-1 blockade-activated DC-CIK (PD1-T) cells with XELOX plus bevacizumab as a first-line therapy in patients with mCRC. A total of 202 participants were enrolled and randomly assigned in a 1:1 ratio to receive either first-line XELOX plus bevacizumab (the control group, n = 102) or the same regimen plus autologous PD1-T cell immunotherapy (the immunotherapy group, n = 100) every 21 days for up to 6 cycles, followed by maintenance treatment with capecitabine and bevacizumab. The main endpoint of the trial was progression-free survival (PFS). The median follow-up was 19.5 months. Median PFS was 14.8 months (95% CI, 11.6–18.0) for the immunotherapy group compared with 9.9 months (8.0–11.8) for the control group (hazard ratio [HR], 0.60 [95% CI, 0.40–0.88]; p = 0.009). Median overall survival (OS) was not reached for the immunotherapy group and 25.6 months (95% CI, 18.3–32.8) for the control group (HR, 0.57 [95% CI, 0.33–0.98]; p = 0.043). Grade 3 or higher AEs occurred in 20.0% of patients in the immunotherapy group and 23.5% in the control groups, with no toxicity-associated deaths reported. The addition of PD1-T cells to first-line XELOX plus bevacizumab demonstrates significant clinical improvement of PFS and OS with well tolerability in patients with previously untreated mCRC.
Overcoming barriers to single-cell RNA sequencing adoption in low- and middle-income countries
Authors: Boakye Serebour Tracy , Cribbs Adam P. , Baldwin Mathew J. , Masimirembwa Collen , Chikwambi Zedias , Kerasidou Angeliki , Snelling Sarah J. B. 
Published: April 2024

AbstractThe advent of single-cell resolution sequencing and spatial transcriptomics has enabled the delivery of cellular and molecular atlases of tissues and organs, providing new insights into tissue health and disease. However, if the full potential of these technologies is to be equitably realised, ancestrally inclusivity is paramount. Such a goal requires greater inclusion of both researchers and donors in low- and middle-income countries (LMICs). In this perspective, we describe the current landscape of ancestral inclusivity in genomic and single-cell transcriptomic studies. We discuss the collaborative efforts needed to scale the barriers to establishing, expanding, and adopting single-cell sequencing research in LMICs and to enable globally impactful outcomes of these technologies.
Machine-learning potentials for nanoscale simulations of tensile deformation and fracture in ceramics
Authors: Lin Shuyao , Casillas-Trujillo Luis , Tasnádi Ferenc , Hultman Lars , Mayrhofer Paul H. , Sangiovanni Davide G. , Koutná Nikola 
Published: April 2024

AbstractMachine-learning interatomic potentials (MLIPs) offer a powerful avenue for simulations beyond length and timescales of ab initio methods. Their development for investigation of mechanical properties and fracture, however, is far from trivial since extended defects—governing plasticity and crack nucleation in most materials—are too large to be included in the training set. Using TiB2 as a model ceramic material, we propose a training strategy for MLIPs suitable to simulate mechanical response of monocrystals until failure. Our MLIP accurately reproduces ab initio stresses and fracture mechanisms during room-temperature uniaxial tensile deformation of TiB2 at the atomic scale ( ≈ 103 atoms). More realistic tensile tests (low strain rate, Poisson’s contraction) at the nanoscale ( ≈ 104–106 atoms) require MLIP up-fitting, i.e., learning from additional ab initio configurations. Consequently, we elucidate trends in theoretical strength, toughness, and crack initiation patterns under different loading directions. As our MLIP is specifically trained to modelling tensile deformation, we discuss its limitations for description of different loading conditions and lattice structures with various Ti/B stoichiometries. Finally, we show that our MLIP training procedure is applicable to diverse ceramic systems. This is demonstrated by developing MLIPs which are subsequently validated by simulations of uniaxial strain and fracture in TaB2, WB2, ReB2, TiN, and Ti2AlB2.
Organic carbon source controlled microbial olivine dissolution in small-scale flow-through bioreactors, for CO2 removal
Authors: Corbett Thomas D. W. , Westholm Marcus , Rosling Anna , Calogiuri Tullia , Poetra Reinaldy , Niron Harun , Hagens Mathilde , Vidal Alix , Van Groenigen Jan Willem , Hartmann Jens , Janssens Ivan A. , Rieder Lukas , Struyf Eric , Van Tendeloo Michiel , Vlaeminck Siegfried E. , Vicca Sara , Neubeck Anna 
Published: April 2024

AbstractThe development of carbon dioxide removal methods, coupled with decreased CO2 emissions, is fundamental to achieving the targets outlined in the Paris Agreement limiting global warming to 1.5 °C. Here we are investigating the importance of the organic carbon feedstock to support silicate mineral weathering in small-scale flow through bioreactors and subsequent CO2 sequestration. Here, we combine two bacteria and two fungi, widely reported for their weathering potential, in simple flow through bioreactors (columns) consisting of forsterite and widely available, cheap organic carbon sources (wheat straw, bio-waste digestate of pig manure and biowaste, and manure compost), over six weeks. Compared to their corresponding abiotic controls, the inoculated straw and digestate columns release more total alkalinity (~2 times more) and produce greater dissolved and solid inorganic carbon (29% for straw and 13% for digestate), suggesting an increase in CO2 sequestration because of bio-enhanced silicate weathering. Microbial biomass is higher in the straw columns compared to the digestate and manure compost columns, with a phospholipid fatty acid derived total microbial biomass 10 x greater than the other biotic columns. Scanning Electron Microscopy imaging shows the most extensive colonisation and biofilm formation on the mineral surfaces in the straw columns. The biotic straw and digestate columns sequester 50 and 14 mg C more than their abiotic controls respectively, while there is no difference in the manure columns. The selection of organic carbon sources to support microbial communities in the flow through bioreactors controlls the silicate weathering rates and CO2 sequestration.
Logic programming-based Minimal Cut Sets reveal consortium-level therapeutic targets for chronic wound infections
Authors: Mahout Maxime , Carlson Ross P. , Simon Laurent , Peres Sabine 
Published: April 2024

AbstractMinimal Cut Sets (MCSs) identify sets of reactions which, when removed from a metabolic network, disable certain cellular functions. The traditional search for MCSs within genome-scale metabolic models (GSMMs) targets cellular growth, identifies reaction sets resulting in a lethal phenotype if disrupted, and retrieves a list of corresponding gene, mRNA, or enzyme targets. Using the dual link between MCSs and Elementary Flux Modes (EFMs), our logic programming-based tool aspefm was able to compute MCSs of any size from GSMMs in acceptable run times. The tool demonstrated better performance when computing large-sized MCSs than the mixed-integer linear programming methods. We applied the new MCSs methodology to a medically-relevant consortium model of two cross-feeding bacteria, Staphylococcus aureus and Pseudomonas aeruginosa. aspefm constraints were used to bias the computation of MCSs toward exchanged metabolites that could complement lethal phenotypes in individual species. We found that interspecies metabolite exchanges could play an essential role in rescuing single-species growth, for instance inosine could complement lethal reaction knock-outs in the purine synthesis, glycolysis, and pentose phosphate pathways of both bacteria. Finally, MCSs were used to derive a list of promising enzyme targets for consortium-level therapeutic applications that cannot be circumvented via interspecies metabolite exchange.
Automatic design of gene regulatory mechanisms for spatial pattern formation
Authors: Mousavi Reza , Lobo Daniel 
Published: April 2024

Abstract
Gene regulatory mechanisms (GRMs) control the formation of spatial and temporal expression patterns that can serve as regulatory signals for the development of complex shapes. Synthetic developmental biology aims to engineer such genetic circuits for understanding and producing desired multicellular spatial patterns. However, designing synthetic GRMs for complex, multi-dimensional spatial patterns is a current challenge due to the nonlinear interactions and feedback loops in genetic circuits. Here we present a methodology to automatically design GRMs that can produce any given two-dimensional spatial pattern. The proposed approach uses two orthogonal morphogen gradients acting as positional information signals in a multicellular tissue area or culture, which constitutes a continuous field of engineered cells implementing the same designed GRM. To efficiently design both the circuit network and the interaction mechanisms—including the number of genes necessary for the formation of the target spatial pattern—we developed an automated algorithm based on high-performance evolutionary computation. The tolerance of the algorithm can be configured to design GRMs that are either simple to produce approximate patterns or complex to produce precise patterns. We demonstrate the approach by automatically designing GRMs that can produce a diverse set of synthetic spatial expression patterns by interpreting just two orthogonal morphogen gradients. The proposed framework offers a versatile approach to systematically design and discover complex genetic circuits producing spatial patterns.
A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids
Authors: Hong Fenglin , Aldhous Timothy P. , Kemmitt Paul D. , Bower John F. 
Published: April 2024

AbstractHomochiral α-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the α-stereocentre. By contrast, and despite their importance, α-amino acids possessing β-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N–H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or α-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled α-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres.
The covariance environment defines cellular niches for spatial inference
Authors: Haviv Doron , Remšík Ján , Gatie Mohamed , Snopkowski Catherine , Takizawa Meril , Pereira Nathan , Bashkin John , Jovanovich Stevan , Nawy Tal , Chaligne Ronan , Boire Adrienne , Hadjantonakis Anna-Katerina , Pe’er Dana 
Published: April 2024

Abstract
A key challenge of analyzing data from high-resolution spatial profiling technologies is to suitably represent the features of cellular neighborhoods or niches. Here we introduce the covariance environment (COVET), a representation that leverages the gene–gene covariate structure across cells in the niche to capture the multivariate nature of cellular interactions within it. We define a principled optimal transport-based distance metric between COVET niches that scales to millions of cells. Using COVET to encode spatial context, we developed environmental variational inference (ENVI), a conditional variational autoencoder that jointly embeds spatial and single-cell RNA sequencing data into a latent space. ENVI includes two decoders: one to impute gene expression across the spatial modality and a second to project spatial information onto single-cell data. ENVI can confer spatial context to genomics data from single dissociated cells and outperforms alternatives for imputing gene expression on diverse spatial datasets.
Self-pigmenting textiles grown from cellulose-producing bacteria with engineered tyrosinase expression
Authors: Walker Kenneth T. , Li Ivy S. , Keane Jennifer , Goosens Vivianne J. , Song Wenzhe , Lee Koon-Yang , Ellis Tom 
Published: April 2024

AbstractEnvironmental concerns are driving interest in postpetroleum synthetic textiles produced from microbial and fungal sources. Bacterial cellulose (BC) is a promising sustainable leather alternative, on account of its material properties, low infrastructure needs and biodegradability. However, for alternative textiles like BC to be fully sustainable, alternative ways to dye textiles need to be developed alongside alternative production methods. To address this, we genetically engineer Komagataeibacter rhaeticus to create a bacterial strain that grows self-pigmenting BC. Melanin biosynthesis in the bacteria from recombinant tyrosinase expression achieves dark black coloration robust to material use. Melanated BC production can be scaled up for the construction of prototype fashion products, and we illustrate the potential of combining engineered self-pigmentation with tools from synthetic biology, through the optogenetic patterning of gene expression in cellulose-producing bacteria. With this study, we demonstrate that combining genetic engineering with current and future methods of textile biofabrication has the potential to create a new class of textiles.