bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survey of perspectives of people with inherited retinal diseases on ocular gene therapy in Australia
Authors: Mack Heather G. , Britten-Jones Alexis Ceecee , McGuinness Myra B. , Chen Fred K. , Grigg John R. , Jamieson Robyn V. , Edwards Thomas L. , De Roach John , O’Hare Fleur , Martin Keith R. , Ayton Lauren N. 
Published: October 2022

AbstractMany gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p < 0.001) and outcomes (p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.
Opportunities and challenges with the German act for the protection of children with variations of sex development
Authors: Danon Limor Meoded , Schweizer Katinka , Thies Barbara 
Published: October 2022

AbstractIn May 2021, the German parliament passed a long-debated law to protect children with variations of sex development/sex characteristics from medically unnecessary surgeries until they are old enough to decide for themselves. This law joins similar laws passed in other countries in recent years and recognizes the rights of people with variations of sex development to self-determination and bodily autonomy. In this article, we discuss the notion of bodily autonomy and examine details of the German legislation in the context of psychosocial care. We focus on the following questions: (1) How may the law help to preserve the genital integrity and future bodily autonomy of newborns with variations of sex development (VSD)? (2) What are the opportunities and challenges of this law? (3) What strategies are needed to implement the law in ways that include medical professionals’ knowledge and skills, parental cooperation, and protection for the genital integrity as well as the future genital autonomy of newborns with VSD? We make two main arguments. On the one hand, this law has created a space for a new discourse and discussion on VSD in German society and enables the “wait and see” approach. This approach challenges the traditional “psychosocial emergency” policy aimed at quickly “repairing” atypical genitalia. On the other hand, the law is characterized by significant challenges. For example, it does not address the meaning of bodily autonomy in the context of newborns and their families with VSD, and it overlooks the important distinction between genital appearance, genital function, and gender identity. We offer various educational strategies that can be implemented with different target groups in Germany to meet these challenges and ensure the adequate implementation of this law.
The design and evaluation of hybrid controlled trials that leverage external data and randomization
Authors: Ventz Steffen , Khozin Sean , Louv Bill , Sands Jacob , Wen Patrick Y. , Rahman Rifaquat , Comment Leah , Alexander Brian M. , Trippa Lorenzo 
Published: October 2022

AbstractPatient-level data from completed clinical studies or electronic health records can be used in the design and analysis of clinical trials. However, these external data can bias the evaluation of the experimental treatment when the statistical design does not appropriately account for potential confounders. In this work, we introduce a hybrid clinical trial design that combines the use of external control datasets and randomization to experimental and control arms, with the aim of producing efficient inference on the experimental treatment effects. Our analysis of the hybrid trial design includes scenarios where the distributions of measured and unmeasured prognostic patient characteristics differ across studies. Using simulations and datasets from clinical studies in extensive-stage small cell lung cancer and glioblastoma, we illustrate the potential advantages of hybrid trial designs compared to externally controlled trials and randomized trial designs.
Adsorbate chemical environment-based machine learning framework for heterogeneous catalysis
Authors: Ghanekar Pushkar G. , Deshpande Siddharth , Greeley Jeffrey 
Published: October 2022

AbstractHeterogeneous catalytic reactions are influenced by a subtle interplay of atomic-scale factors, ranging from the catalysts’ local morphology to the presence of high adsorbate coverages. Describing such phenomena via computational models requires generation and analysis of a large space of atomic configurations. To address this challenge, we present Adsorbate Chemical Environment-based Graph Convolution Neural Network (ACE-GCN), a screening workflow that accounts for atomistic configurations comprising diverse adsorbates, binding locations, coordination environments, and substrate morphologies. Using this workflow, we develop catalyst surface models for two illustrative systems: (i) NO adsorbed on a Pt3Sn(111) alloy surface, of interest for nitrate electroreduction processes, where high adsorbate coverages combined with low symmetry of the alloy substrate produce a large configurational space, and (ii) OH* adsorbed on a stepped Pt(221) facet, of relevance to the Oxygen Reduction Reaction, where configurational complexity results from the presence of irregular crystal surfaces, high adsorbate coverages, and directionally-dependent adsorbate-adsorbate interactions. In both cases, the ACE-GCN model, trained on a fraction (~10%) of the total DFT-relaxed configurations, successfully describes trends in the relative stabilities of unrelaxed atomic configurations sampled from a large configurational space. This approach is expected to accelerate development of rigorous descriptions of catalyst surfaces under in-situ conditions.
CD36-mediated metabolic crosstalk between tumor cells and macrophages affects liver metastasis
Authors: Yang Ping , Qin Hong , Li Yiyu , Xiao Anhua , Zheng Enze , Zeng Han , Su Chunxiao , Luo Xiaoqing , Lu Qiannan , Liao Meng , Zhao Lei , Wei Li , Varghese Zac , Moorhead John F. , Chen Yaxi , Ruan Xiong Z. 
Published: October 2022

AbstractLiver metastasis is highly aggressive and treatment-refractory, partly due to macrophage-mediated immune suppression. Understanding the mechanisms leading to functional reprogramming of macrophages in the tumor microenvironment (TME) will benefit cancer immunotherapy. Herein, we find that the scavenger receptor CD36 is upregulated in metastasis-associated macrophages (MAMs) and deletion of CD36 in MAMs attenuates liver metastasis in mice. MAMs contain more lipid droplets and have the unique capability in engulfing tumor cell-derived long-chain fatty acids, which are carried by extracellular vesicles. The lipid-enriched vesicles are preferentially partitioned into macrophages via CD36, that fuel macrophages and trigger their tumor-promoting activities. In patients with liver metastases, high expression of CD36 correlates with protumoral M2-type MAMs infiltration, creating a highly immunosuppressive TME. Collectively, our findings uncover a mechanism by which tumor cells metabolically interact with macrophages in TME, and suggest a therapeutic potential of targeting CD36 as immunotherapy for liver metastasis.
XPF activates break-induced telomere synthesis
Authors: Guh Chia-Yu , Shen Hong-Jhih , Chen Liv WeiChien , Chiu Pei-Chen , Liao I-Hsin , Lo Chen-Chia , Chen Yunfei , Hsieh Yu-Hung , Chang Ting-Chia , Yen Chien-Ping , Chen Yi-Yun , Chen Tom Wei-Wu , Chen Liuh-Yow , Wu Ching-Shyi , Egly Jean-Marc , Chu Hsueh-Ping Catherine 
Published: October 2022

AbstractAlternative Lengthening of Telomeres (ALT) utilizes a recombination mechanism and break-induced DNA synthesis to maintain telomere length without telomerase, but it is unclear how cells initiate ALT. TERRA, telomeric repeat-containing RNA, forms RNA:DNA hybrids (R-loops) at ALT telomeres. We show that depleting TERRA using an RNA-targeting Cas9 system reduces ALT-associated PML bodies, telomere clustering, and telomere lengthening. TERRA interactome reveals that TERRA interacts with an extensive subset of DNA repair proteins in ALT cells. One of TERRA interacting proteins, the endonuclease XPF, is highly enriched at ALT telomeres and recruited by telomeric R-loops to induce DNA damage response (DDR) independent of CSB and SLX4, and thus triggers break-induced telomere synthesis and lengthening. The attraction of BRCA1 and RAD51 at telomeres requires XPF in FANCM-deficient cells that accumulate telomeric R-loops. Our results suggest that telomeric R-loops activate DDR via XPF to promote homologous recombination and telomere replication to drive ALT.
Triangular lattice quantum dimer model with variable dimer density
Authors: Yan Zheng , Samajdar Rhine , Wang Yan-Cheng , Sachdev Subir , Meng Zi Yang 
Published: October 2022

AbstractQuantum dimer models are known to host topological quantum spin liquid phases, and it has recently become possible to simulate such models with Rydberg atoms trapped in arrays of optical tweezers. Here, we present large-scale quantum Monte Carlo simulation results on an extension of the triangular lattice quantum dimer model with terms in the Hamiltonian annihilating and creating single dimers. We find distinct odd and even $${{\mathbb{Z}}}_{2}$$

Z

2

spin liquids, along with several phases with no topological order: a staggered crystal, a nematic phase, and a trivial symmetric phase with no obvious broken symmetry. We also present dynamic spectra of the phases, and note implications for experiments on Rydberg atoms.
Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics
Authors: Fraser Cameron S. , Spetz Johan K. E. , Qin Xingping , Presser Adam , Choiniere Jonathan , Li Chendi , Yu Stacey , Blevins Frances , Hata Aaron N. , Miller Jeffrey W. , Bradshaw Gary A. , Kalocsay Marian , Sanchorawala Vaishali , Sarosiek Shayna , Sarosiek Kristopher A. 
Published: October 2022

AbstractImmunoglobulin light chain (AL) amyloidosis is an incurable hematologic disorder typically characterized by the production of amyloidogenic light chains by clonal plasma cells. These light chains misfold and aggregate in healthy tissues as amyloid fibrils, leading to life-threatening multi-organ dysfunction. Here we show that the clonal plasma cells in AL amyloidosis are highly primed to undergo apoptosis and dependent on pro-survival proteins MCL-1 and BCL-2. Notably, this MCL-1 dependency is indirectly targeted by the proteasome inhibitor bortezomib, currently the standard of care for this disease and the related plasma cell disorder multiple myeloma, due to upregulation of pro-apoptotic Noxa and its inhibitory binding to MCL-1. BCL-2 inhibitors sensitize clonal plasma cells to multiple front-line therapies including bortezomib, dexamethasone and lenalidomide. Strikingly, in mice bearing AL amyloidosis cell line xenografts, single agent treatment with the BCL-2 inhibitor ABT-199 (venetoclax) produces deeper remissions than bortezomib and triples median survival. Mass spectrometry-based proteomic analysis reveals rewiring of signaling pathways regulating apoptosis, proliferation and mitochondrial metabolism between isogenic AL amyloidosis and multiple myeloma cells that divergently alter their sensitivity to therapies. These findings provide a roadmap for the use of BH3 mimetics to exploit endogenous and induced apoptotic vulnerabilities in AL amyloidosis.
The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury
Authors: Bretheau Floriane , Castellanos-Molina Adrian , Bélanger Dominic , Kusik Maxime , Mailhot Benoit , Boisvert Ana , Vallières Nicolas , Lessard Martine , Gunzer Matthias , Liu Xiaoyu , Boilard Éric , Quan Ning , Lacroix Steve 
Published: October 2022

AbstractSpinal cord injury (SCI) triggers neuroinflammation, and subsequently secondary degeneration and oligodendrocyte (OL) death. We report that the alarmin interleukin (IL)−1α is produced by damaged microglia after SCI. Intra-cisterna magna injection of IL-1α in mice rapidly induces neutrophil infiltration and OL death throughout the spinal cord, mimicking the injury cascade seen in SCI sites. These effects are abolished through co-treatment with the IL-1R1 antagonist anakinra, as well as in IL-1R1-knockout mice which demonstrate enhanced locomotor recovery after SCI. Conditional restoration of IL-1R1 expression in astrocytes or endothelial cells (ECs), but not in OLs or microglia, restores IL-1α-induced effects, while astrocyte- or EC-specific Il1r1 deletion reduces OL loss. Conditioned medium derived from IL-1α-stimulated astrocytes results in toxicity for OLs; further, IL-1α-stimulated astrocytes generate reactive oxygen species (ROS), and blocking ROS production in IL-1α-treated or SCI mice prevented OL loss. Thus, after SCI, microglia release IL-1α, inducing astrocyte- and EC-mediated OL degeneration.
Topological zero-dimensional defect and flux states in three-dimensional insulators
Authors: Schindler Frank , Tsirkin Stepan S. , Neupert Titus , Andrei Bernevig B. , Wieder Benjamin J. 
Published: October 2022

AbstractIn insulating crystals, it was previously shown that defects with two fewer dimensions than the bulk can bind topological electronic states. We here further extend the classification of topological defect states by demonstrating that the corners of crystalline defects with integer Burgers vectors can bind 0D higher-order end (HEND) states with anomalous charge and spin. We demonstrate that HEND states are intrinsic topological consequences of the bulk electronic structure and introduce new bulk topological invariants that are predictive of HEND dislocation states in solid-state materials. We demonstrate the presence of first-order 0D defect states in PbTe monolayers and HEND states in 3D SnTe crystals. We relate our analysis to magnetic flux insertion in insulating crystals. We find that π-flux tubes in inversion- and time-reversal-symmetric (helical) higher-order topological insulators bind Kramers pairs of spin-charge-separated HEND states, which represent observable signatures of anomalous surface half quantum spin Hall states.
Self-organization of an inhomogeneous memristive hardware for sequence learning
Authors: Payvand Melika , Moro Filippo , Nomura Kumiko , Dalgaty Thomas , Vianello Elisa , Nishi Yoshifumi , Indiveri Giacomo 
Published: October 2022

AbstractLearning is a fundamental component of creating intelligent machines. Biological intelligence orchestrates synaptic and neuronal learning at multiple time scales to self-organize populations of neurons for solving complex tasks. Inspired by this, we design and experimentally demonstrate an adaptive hardware architecture Memristive Self-organizing Spiking Recurrent Neural Network (MEMSORN). MEMSORN incorporates resistive memory (RRAM) in its synapses and neurons which configure their state based on Hebbian and Homeostatic plasticity respectively. For the first time, we derive these plasticity rules directly from the statistical measurements of our fabricated RRAM-based neurons and synapses. These "technologically plausible” learning rules exploit the intrinsic variability of the devices and improve the accuracy of the network on a sequence learning task by 30%. Finally, we compare the performance of MEMSORN to a fully-randomly-set-up spiking recurrent network on the same task, showing that self-organization improves the accuracy by more than 15%. This work demonstrates the importance of the device-circuit-algorithm co-design approach for implementing brain-inspired computing hardware.
Ancient marine sediment DNA reveals diatom transition in Antarctica
Authors: Armbrecht Linda , Weber Michael E. , Raymo Maureen E. , Peck Victoria L. , Williams Trevor , Warnock Jonathan , Kato Yuji , Hernández-Almeida Iván , Hoem Frida , Reilly Brendan , Hemming Sidney , Bailey Ian , Martos Yasmina M. , Gutjahr Marcus , Percuoco Vincent , Allen Claire , Brachfeld Stefanie , Cardillo Fabricio G. , Du Zhiheng , Fauth Gerson , Fogwill Chris , Garcia Marga , Glüder Anna , Guitard Michelle , Hwang Ji-Hwan , Iizuka Mutsumi , Kenlee Bridget , O’Connell Suzanne , Pérez Lara F. , Ronge Thomas A. , Seki Osamu , Tauxe Lisa , Tripathi Shubham , Zheng Xufeng 
Published: October 2022

AbstractAntarctica is one of the most vulnerable regions to climate change on Earth and studying the past and present responses of this polar marine ecosystem to environmental change is a matter of urgency. Sedimentary ancient DNA (sedaDNA) analysis can provide such insights into past ecosystem-wide changes. Here we present authenticated (through extensive contamination control and sedaDNA damage analysis) metagenomic marine eukaryote sedaDNA from the Scotia Sea region acquired during IODP Expedition 382. We also provide a marine eukaryote sedaDNA record of ~1 Mio. years and diatom and chlorophyte sedaDNA dating back to ~540 ka (using taxonomic marker genes SSU, LSU, psbO). We find evidence of warm phases being associated with high relative diatom abundance, and a marked transition from diatoms comprising <10% of all eukaryotes prior to ~14.5 ka, to ~50% after this time, i.e., following Meltwater Pulse 1A, alongside a composition change from sea-ice to open-ocean species. Our study demonstrates that sedaDNA tools can be expanded to hundreds of thousands of years, opening the pathway to the study of ecosystem-wide marine shifts and paleo-productivity phases throughout multiple glacial-interglacial cycles.
Structure of the TnsB transposase-DNA complex of type V-K CRISPR-associated transposon
Authors: Tenjo-Castaño Francisco , Sofos Nicholas , López-Méndez Blanca , Stutzke Luisa S. , Fuglsang Anders , Stella Stefano , Montoya Guillermo 
Published: October 2022

AbstractCRISPR-associated transposons (CASTs) are mobile genetic elements that co-opted CRISPR-Cas systems for RNA-guided transposition. Here we present the 2.4 Å cryo-EM structure of the Scytonema hofmannii (sh) TnsB transposase from Type V-K CAST, bound to the strand transfer DNA. The strand transfer complex displays an intertwined pseudo-symmetrical architecture. Two protomers involved in strand transfer display a catalytically competent active site composed by DDE residues, while other two, which play a key structural role, show active sites where the catalytic residues are not properly positioned for phosphodiester hydrolysis. Transposon end recognition is accomplished by the NTD1/2 helical domains. A singular in trans association of NTD1 domains of the catalytically competent subunits with the inactive DDE domains reinforces the assembly. Collectively, the structural features suggest that catalysis is coupled to protein-DNA assembly to secure proper DNA integration. DNA binding residue mutants reveal that lack of specificity decreases activity, but it could increase transposition in some cases. Our structure sheds light on the strand transfer reaction of DDE transposases and offers new insights into CAST transposition.
Schemas provide a scaffold for neocortical integration of new memories over time
Authors: Audrain Sam , McAndrews Mary Pat 
Published: October 2022

AbstractMemory transformation is increasingly acknowledged in theoretical accounts of systems consolidation, yet how memory quality and neural representation change over time and how schemas influence this process remains unclear. We examined the behavioral quality and neural representation of schema-congruent and incongruent object-scene pairs retrieved across 10-minutes and 72-hours using fMRI. When a congruent schema was available, memory became coarser over time, aided by post-encoding coupling between the anterior hippocampus and medial prefrontal cortex (mPFC). Only schema-congruent representations were integrated in the mPFC over time, and were organized according to schematic context. In the hippocampus, pattern similarity changed across 72-hours such that the posterior hippocampus represented specific details and the anterior hippocampus represented the general context of specific memories, irrespective of congruency. Our findings suggest schemas are used as a scaffold to facilitate neocortical integration of congruent information, and illustrate evolution in hippocampal organization of detailed contextual memory over time.
Farey tree and devil’s staircase of frequency-locked breathers in ultrafast lasers
Authors: Wu Xiuqi , Zhang Ying , Peng Junsong , Boscolo Sonia , Finot Christophe , Zeng Heping 
Published: October 2022

AbstractNonlinear systems with two competing frequencies show locking or resonances. In lasers, the two interacting frequencies can be the cavity repetition rate and a frequency externally applied to the system. Conversely, the excitation of breather oscillations in lasers naturally triggers a second characteristic frequency in the system, therefore showing competition between the cavity repetition rate and the breathing frequency. Yet, the link between breathing solitons and frequency locking is missing. Here we demonstrate frequency locking at Farey fractions of a breather laser. The winding numbers exhibit the hierarchy of the Farey tree and the structure of a devil’s staircase. Numerical simulations of a discrete laser model confirm the experimental findings. The breather laser may therefore serve as a simple test bed to explore ubiquitous synchronization dynamics of nonlinear systems. The locked breathing frequencies feature a high signal-to-noise ratio and can give rise to dense radio-frequency combs, which are attractive for applications.