bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction
Authors: Lin Xiangfeng , Mu Xia , Cui Hongqiang , Li Qian , Feng Zhaochi , Liu Yan , Li Guohui , Li Can 
Published: May 2024

AbstractHindered ethers are ubiquitous in natural products and bioactive molecules. However, developing an efficient method for the stereocontrolled synthesis of all stereoisomers of chiral hindered ethers is highly desirable but challenging. Here we show a strategy that utilizes in situ-generated water as a nucleophile in an asymmetric cascade reaction involving two highly reactive intermediates, 3-furyl methyl cations and ortho-quinone methides (o-QMs), to synthesize chiral hindered ethers. The Ca(II)/Au(I) synergistic catalytic system enables the control of diastereoselectivity and enantioselectivity by selecting suitable chiral phosphine ligands in this cascade hydration/1,4-addition reaction, affording all four stereoisomers of a diverse range of chiral tetra-aryl substituted ethers with high diastereoselectivities (up to >20/1) and enantioselectivities (up to 95% ee). This work provides an example of chiral Ca(II)/Au(I) bimetallic catalytic system controlling two stereogenic centers via a cascade reaction in a single operation.
Isostructural doping for organic persistent mechanoluminescence
Authors: Xie Zongliang , Xue Yufeng , Zhang Xianhe , Chen Junru , Lin Zesen , Liu Bin 
Published: May 2024

AbstractMechanoluminescence, featuring light emission triggered by mechanical stimuli, holds immense promise for diverse applications. However, most organic Mechanoluminescence materials suffer from short-lived luminescence, limiting their practical applications. Herein, we report isostructural doping as a valuable strategy to address this challenge. By strategically modifying the host matrices with specific functional groups and simultaneously engineering guest molecules with structurally analogous features for isostructural doping, we have successfully achieved diverse multicolor and high-efficiency persistent mechanoluminescence materials with ultralong lifetimes. The underlying persistent mechanoluminescence mechanism and the universality of the isostructural doping strategy are also clearly elucidated and verified. Moreover, stress sensing devices are fabricated to show their promising prospects in high-resolution optical storage, pressure-sensitive displays, and stress monitoring. This work may facilitate the development of highly efficient organic persistent mechanoluminescence materials, expanding the horizons of next-generation smart luminescent technologies.
Optochemical control of slow-wave sleep in the nucleus accumbens of male mice by a photoactivatable allosteric modulator of adenosine A2A receptors
Authors: Roy Koustav , Zhou Xuzhao , Otani Rintaro , Yuan Ping-Chuan , Ioka Shuji , Vogt Kaspar E. , Kondo Tamae , Farag Nouran H. T. , Ijiri Haruto , Wu Zhaofa , Chitose Youhei , Amezawa Mao , Uygun David S. , Cherasse Yoan , Nagase Hiroshi , Li Yulong , Yanagisawa Masashi , Abe Manabu , Basheer Radhika , Wang Yi-Qun , Saitoh Tsuyoshi , Lazarus Michael 
Published: May 2024

AbstractOptochemistry, an emerging pharmacologic approach in which light is used to selectively activate or deactivate molecules, has the potential to alleviate symptoms, cure diseases, and improve quality of life while preventing uncontrolled drug effects. The development of in-vivo applications for optochemistry to render brain cells photoresponsive without relying on genetic engineering has been progressing slowly. The nucleus accumbens (NAc) is a region for the regulation of slow-wave sleep (SWS) through the integration of motivational stimuli. Adenosine emerges as a promising candidate molecule for activating indirect pathway neurons of the NAc expressing adenosine A2A receptors (A2ARs) to induce SWS. Here, we developed a brain-permeable positive allosteric modulator of A2ARs (A2AR PAM) that can be rapidly photoactivated with visible light (λ > 400 nm) and used it optoallosterically to induce SWS in the NAc of freely behaving male mice by increasing the activity of extracellular adenosine derived from astrocytic and neuronal activity.
Primary prophylaxis with mTOR inhibitor enhances T cell effector function and prevents heart transplant rejection during talimogene laherparepvec therapy of squamous cell carcinoma
Authors: Joo Victor , Abdelhamid Karim , Noto Alessandra , Latifyan Sofiya , Martina Federica , Daoudlarian Douglas , De Micheli Rita , Pruijm Menno , Peters Solange , Hullin Roger , Gaide Olivier , Pantaleo Giuseppe , Obeid Michel 
Published: May 2024

AbstractThe application of mammalian target of rapamycin inhibition (mTORi) as primary prophylactic therapy to optimize T cell effector function while preserving allograft tolerance remains challenging. Here, we present a comprehensive two-step therapeutic approach in a male patient with metastatic cutaneous squamous cell carcinoma and heart transplantation followed with concomitant longitudinal analysis of systemic immunologic changes. In the first step, calcineurin inhibitor/ mycophenolic acid is replaced by the mTORi everolimus to achieve an improved effector T cell status with increased cytotoxic activity (perforin, granzyme), enhanced proliferation (Ki67) and upregulated activation markers (CD38, CD69). In the second step, talimogene laherparepvec (T-VEC) injection further enhances effector function by switching CD4 and CD8 cells from central memory to effector memory profiles, enhancing Th1 responses, and boosting cytotoxic and proliferative activities. In addition, cytokine release (IL-6, IL-18, sCD25, CCL-2, CCL-4) is enhanced and the frequency of circulating regulatory T cells is increased. Notably, no histologic signs of allograft rejection are observed in consecutive end-myocardial biopsies. These findings provide valuable insights into the dynamics of T cell activation and differentiation and suggest that timely initiation of mTORi-based primary prophylaxis may provide a dual benefit of revitalizing T cell function while maintaining allograft tolerance.
Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases
Authors: Karlsson Linda , Vogel Jacob , Arvidsson Ida , Åström Kalle , Janelidze Shorena , Blennow Kaj , Palmqvist Sebastian , Stomrud Erik , Mattsson-Carlgren Niklas , Hansson Oskar 
Published: May 2024

AbstractCerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer’s disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.
Glis2 is an early effector of polycystin signaling and a target for therapy in polycystic kidney disease
Authors: Zhang Chao , Rehman Michael , Tian Xin , Pei Steven Lim Cho , Gu Jianlei , Bell Thomas A. , Dong Ke , Tham Ming Shen , Cai Yiqiang , Wei Zemeng , Behrens Felix , Jetten Anton M. , Zhao Hongyu , Lek Monkol , Somlo Stefan 
Published: May 2024

AbstractMouse models of autosomal dominant polycystic kidney disease (ADPKD) show that intact primary cilia are required for cyst growth following the inactivation of polycystin-1. The signaling pathways underlying this process, termed cilia-dependent cyst activation (CDCA), remain unknown. Using translating ribosome affinity purification RNASeq on mouse kidneys with polycystin-1 and cilia inactivation before cyst formation, we identify the differential ‘CDCA pattern’ translatome specifically dysregulated in kidney tubule cells destined to form cysts. From this, Glis2 emerges as a candidate functional effector of polycystin signaling and CDCA. In vitro changes in Glis2 expression mirror the polycystin- and cilia-dependent changes observed in kidney tissue, validating Glis2 as a cell culture-based indicator of polycystin function related to cyst formation. Inactivation of Glis2 suppresses polycystic kidney disease in mouse models of ADPKD, and pharmacological targeting of Glis2 with antisense oligonucleotides slows disease progression. Glis2 transcript and protein is a functional target of CDCA and a potential therapeutic target for treating ADPKD.
An artificial visual neuron with multiplexed rate and time-to-first-spike coding
Authors: Li Fanfan , Li Dingwei , Wang Chuanqing , Liu Guolei , Wang Rui , Ren Huihui , Tang Yingjie , Wang Yan , Chen Yitong , Liang Kun , Huang Qi , Sawan Mohamad , Qiu Min , Wang Hong , Zhu Bowen 
Published: May 2024

AbstractHuman visual neurons rely on event-driven, energy-efficient spikes for communication, while silicon image sensors do not. The energy-budget mismatch between biological systems and machine vision technology has inspired the development of artificial visual neurons for use in spiking neural network (SNN). However, the lack of multiplexed data coding schemes reduces the ability of artificial visual neurons in SNN to emulate the visual perception ability of biological systems. Here, we present an artificial visual spiking neuron that enables rate and temporal fusion (RTF) coding of external visual information. The artificial neuron can code visual information at different spiking frequencies (rate coding) and enables precise and energy-efficient time-to-first-spike (TTFS) coding. This multiplexed sensory coding scheme could improve the computing capability and efficacy of artificial visual neurons. A hardware-based SNN with the RTF coding scheme exhibits good consistency with real-world ground truth data and achieves highly accurate steering and speed predictions for self-driving vehicles in complex conditions. The multiplexed RTF coding scheme demonstrates the feasibility of developing highly efficient spike-based neuromorphic hardware.
Optofluidic crystallithography for directed growth of single-crystalline halide perovskites
Authors: Chen Xue-Guang , Lin Linhan , Huang Guan-Yao , Chen Xiao-Mei , Li Xiao-Ze , Zhou Yun-Ke , Zou Yixuan , Fu Tairan , Li Peng , Li Zhengcao , Sun Hong-Bo 
Published: May 2024

AbstractCrystallization is a fundamental phenomenon which describes how the atomic building blocks such as atoms and molecules are arranged into ordered or quasi-ordered structure and form solid-state materials. While numerous studies have focused on the nucleation behavior, the precise and spatiotemporal control of growth kinetics, which dictates the defect density, the micromorphology, as well as the properties of the grown materials, remains elusive so far. Herein, we propose an optical strategy, termed optofluidic crystallithography (OCL), to solve this fundamental problem. Taking halide perovskites as an example, we use a laser beam to manipulate the molecular motion in the native precursor environment and create inhomogeneous spatial distribution of the molecular species. Harnessing the coordinated effect of laser-controlled local supersaturation and interfacial energy, we precisely steer the ionic reaction at the growth interface and directly print arbitrary single crystals of halide perovskites of high surface quality, crystallinity, and uniformity at a high printing speed of 102 μm s−1. The OCL technique can be potentially extended to the fabrication of single-crystal structures beyond halide perovskites, once crystallization can be triggered under the laser-directed local supersaturation.
Investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment
Authors: Bhattarai Kashi Raj , Mobley Robert J. , Barnett Kelly R. , Ferguson Daniel C. , Hansen Baranda S. , Diedrich Jonathan D. , Bergeron Brennan P. , Yoshimura Satoshi , Yang Wenjian , Crews Kristine R. , Manring Christopher S. , Jabbour Elias , Paietta Elisabeth , Litzow Mark R. , Kornblau Steven M. , Stock Wendy , Inaba Hiroto , Jeha Sima , Pui Ching-Hon , Cheng Cheng , Pruett-Miller Shondra M. , Relling Mary V. , Yang Jun J. , Evans William E. , Savic Daniel 
Published: May 2024

AbstractDefining genetic factors impacting chemotherapy failure can help to better predict response and identify drug resistance mechanisms. However, there is limited understanding of the contribution of inherited noncoding genetic variation on inter-individual differences in chemotherapy response in childhood acute lymphoblastic leukemia (ALL). Here we map inherited noncoding variants associated with treatment outcome and/or chemotherapeutic drug resistance to ALL cis-regulatory elements and investigate their gene regulatory potential and target gene connectivity using massively parallel reporter assays and three-dimensional chromatin looping assays, respectively. We identify 54 variants with transcriptional effects and high-confidence gene connectivity. Additionally, functional interrogation of the top variant, rs1247117, reveals changes in chromatin accessibility, PU.1 binding affinity and gene expression, and deletion of the genomic interval containing rs1247117 sensitizes cells to vincristine. Together, these data demonstrate that noncoding regulatory variants associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to antileukemic agents.
Structural mechanism of voltage-gated sodium channel slow inactivation
Authors: Chen Huiwen , Xia Zhanyi , Dong Jie , Huang Bo , Zhang Jiangtao , Zhou Feng , Yan Rui , Shi Yiqiang , Gong Jianke , Jiang Juquan , Huang Zhuo , Jiang Daohua 
Published: May 2024

AbstractVoltage-gated sodium (NaV) channels mediate a plethora of electrical activities. NaV channels govern cellular excitability in response to depolarizing stimuli. Inactivation is an intrinsic property of NaV channels that regulates cellular excitability by controlling the channel availability. The fast inactivation, mediated by the Ile-Phe-Met (IFM) motif and the N-terminal helix (N-helix), has been well-characterized. However, the molecular mechanism underlying NaV channel slow inactivation remains elusive. Here, we demonstrate that the removal of the N-helix of NaVEh (NaVEhΔN) results in a slow-inactivated channel, and present cryo-EM structure of NaVEhΔN in a potential slow-inactivated state. The structure features a closed activation gate and a dilated selectivity filter (SF), indicating that the upper SF and the inner gate could serve as a gate for slow inactivation. In comparison to the NaVEh structure, NaVEhΔN undergoes marked conformational shifts on the intracellular side. Together, our results provide important mechanistic insights into NaV channel slow inactivation.
Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy
Authors: Yan Jiaqi , Bhadane Rajendra , Ran Meixin , Ma Xiaodong , Li Yuanqiang , Zheng Dongdong , Salo-Ahen Outi M. H. , Zhang Hongbo 
Published: May 2024

AbstractThe metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.
Edible mycelium as proliferation and differentiation support for anchorage-dependent animal cells in cultivated meat production
Authors: Ogawa Minami , Kermani Alex S. , Huynh Mayrene J. , Baar Keith , Leach J. Kent , Block David E. 
Published: May 2024

AbstractCultivated meat production requires bioprocess optimization to achieve cell densities that are multiple orders of magnitude higher compared to conventional cell culture techniques. These processes must maximize resource efficiency and cost-effectiveness by attaining high cell growth productivity per unit of medium. Microcarriers, or carriers, are compatible with large-scale bioreactor use, and offer a large surface-area-to-volume ratio for the adhesion and proliferation of anchorage-dependent animal cells. An ongoing challenge persists in the efficient retrieval of cells from the carriers, with conflicting reports on the effectiveness of trypsinization and the need for additional optimization measures such as carrier sieving. To surmount this issue, edible carriers have been proposed, offering the advantage of integration into the final food product while providing opportunities for texture, flavor, and nutritional incorporation. Recently, a proof of concept (POC) utilizing inactivated mycelium biomass derived from edible filamentous fungus demonstrated its potential as a support structure for myoblasts. However, this POC relied on a model mammalian cell line combination with a single mycelium species, limiting realistic applicability to cultivated meat production. This study aims to advance the POC. We found that the species of fungi composing the carriers impacts C2C12 myoblast cell attachment—with carriers derived from Aspergillus oryzae promoting the best proliferation. C2C12 myoblasts effectively differentiated on mycelium carriers when induced in myogenic differentiation media. Mycelium carriers also supported proliferation and differentiation of bovine satellite cells. These findings demonstrate the potential of edible mycelium carrier technology to be readily adapted in product development within the cultivated meat industry.
Chromatin accessibility during human first-trimester neurodevelopment
Authors: Mannens Camiel C. A. , Hu Lijuan , Lönnerberg Peter , Schipper Marijn , Reagor Caleb C. , Li Xiaofei , He Xiaoling , Barker Roger A. , Sundström Erik , Posthuma Danielle , Linnarsson Sten 
Published: May 2024

Abstract
The human brain develops through a tightly organized cascade of patterning events, induced by transcription factor expression and changes in chromatin accessibility. Although gene expression across the developing brain has been described at single-cell resolution1, similar atlases of chromatin accessibility have been primarily focused on the forebrain2–4. Here we describe chromatin accessibility and paired gene expression across the entire developing human brain during the first trimester (6–13 weeks after conception). We defined 135 clusters and used multiomic measurements to link candidate cis-regulatory elements to gene expression. The number of accessible regions increased both with age and along neuronal differentiation. Using a convolutional neural network, we identified putative functional transcription factor-binding sites in enhancers characterizing neuronal subtypes. We applied this model to cis-regulatory elements linked to ESRRB to elucidate its activation mechanism in the Purkinje cell lineage. Finally, by linking disease-associated single nucleotide polymorphisms to cis-regulatory elements, we validated putative pathogenic mechanisms in several diseases and identified midbrain-derived GABAergic neurons as being the most vulnerable to major depressive disorder-related mutations. Our findings provide a more detailed view of key gene regulatory mechanisms underlying the emergence of brain cell types during the first trimester and a comprehensive reference for future studies related to human neurodevelopment.
Sleep pressure modulates single-neuron synapse number in zebrafish
Authors: Suppermpool Anya , Lyons Declan G. , Broom Elizabeth , Rihel Jason 
Published: May 2024

AbstractSleep is a nearly universal behaviour with unclear functions1. The synaptic homeostasis hypothesis proposes that sleep is required to renormalize the increases in synaptic number and strength that occur during wakefulness2. Some studies examining either large neuronal populations3 or small patches of dendrites4 have found evidence consistent with the synaptic homeostasis hypothesis, but whether sleep merely functions as a permissive state or actively promotes synaptic downregulation at the scale of whole neurons is unclear. Here, by repeatedly imaging all excitatory synapses on single neurons across sleep–wake states of zebrafish larvae, we show that synapses are gained during periods of wake (either spontaneous or forced) and lost during sleep in a neuron-subtype-dependent manner. However, synapse loss is greatest during sleep associated with high sleep pressure after prolonged wakefulness, and lowest in the latter half of an undisrupted night. Conversely, sleep induced pharmacologically during periods of low sleep pressure is insufficient to trigger synapse loss unless adenosine levels are boosted while noradrenergic tone is inhibited. We conclude that sleep-dependent synapse loss is regulated by sleep pressure at the level of the single neuron and that not all sleep periods are equally capable of fulfilling the functions of synaptic homeostasis.
Phylogenomics and genetic analysis of solvent-producing Clostridium species
Authors: Jensen Rasmus O. , Schulz Frederik , Roux Simon , Klingeman Dawn M. , Mitchell Wayne P. , Udwary Daniel , Moraïs Sarah , Reynoso Vinicio , Winkler James , Nagaraju Shilpa , De Tissera Sashini , Shapiro Nicole , Ivanova Natalia , Reddy T. B. K. , Mizrahi Itzhak , Utturkar Sagar M. , Bayer Edward A. , Woyke Tanja , Mouncey Nigel J. , Jewett Michael C. , Simpson Séan D. , Köpke Michael , Jones David T. , Brown Steven D. 
Published: May 2024

AbstractThe genus Clostridium is a large and diverse group within the Bacillota (formerly Firmicutes), whose members can encode useful complex traits such as solvent production, gas-fermentation, and lignocellulose breakdown. We describe 270 genome sequences of solventogenic clostridia from a comprehensive industrial strain collection assembled by Professor David Jones that includes 194 C. beijerinckii, 57 C. saccharobutylicum, 4 C. saccharoperbutylacetonicum, 5 C. butyricum, 7 C. acetobutylicum, and 3 C. tetanomorphum genomes. We report methods, analyses and characterization for phylogeny, key attributes, core biosynthetic genes, secondary metabolites, plasmids, prophage/CRISPR diversity, cellulosomes and quorum sensing for the 6 species. The expanded genomic data described here will facilitate engineering of solvent-producing clostridia as well as non-model microorganisms with innately desirable traits. Sequences could be applied in conventional platform biocatalysts such as yeast or Escherichia coli for enhanced chemical production. Recently, gene sequences from this collection were used to engineer Clostridium autoethanogenum, a gas-fermenting autotrophic acetogen, for continuous acetone or isopropanol production, as well as butanol, butanoic acid, hexanol and hexanoic acid production.