bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional control of motor pool formation and motor circuit connectivity by the LIM-HD protein Isl2
Authors: Lee Yunjeong , Yeo In Seo , Kim Namhee , Lee Dong-Keun , Kim Kyung-Tai , Yoon Jiyoung , Yi Jawoon , Hong Young Bin , Choi Byung-Ok , Kosodo Yoichi , Kim Daesoo , Park Jihwan , Song Mi-Ryoung
Published: October 2023

The fidelity of motor control requires the precise positional arrangement of motor pools and the establishment of synaptic connections between them. During neural development in the spinal cord, motor nerves project to specific target muscles and receive proprioceptive input from these muscles via the sensorimotor circuit. LIM-homeodomain transcription factors are known to play a crucial role in successively restricting specific motor neuronal fates. However, their exact contribution to limb-based motor pools and locomotor circuits has not been fully understood. To address this, we conducted an investigation into the role of Isl2, a LIM-homeodomain transcription factor, in motor pool organization. We found that deletion of Isl2 led to the dispersion of motor pools, primarily affecting the median motor column (MMC) and lateral motor column (LMC) populations. Additionally, hindlimb motor pools lacked Etv4 expression, and we observed reduced terminal axon branching and disorganized neuromuscular junctions in Isl2-deficient mice. Furthermore, we performed transcriptomic analysis on the spinal cords of Isl2-deficient mice and identified a variety of downregulated genes associated with motor neuron (MN) differentiation, axon development, and synapse organization in hindlimb motor pools. As a consequence of these disruptions, sensorimotor connectivity and hindlimb locomotion were impaired in Isl2-deficient mice. Taken together, our findings highlight the critical role of Isl2 in organizing motor pool position and sensorimotor circuits in hindlimb motor pools. This research provides valuable insights into the molecular mechanisms governing motor control and its potential implications for understanding motor-related disorders in humans.
Quantitative analyses of T cell motion in tissue reveals factors driving T cell search in tissues
Authors: Torres David J , Mrass Paulus , Byrum Janie , Gonzales Arrick , Martinez Dominick N , Juarez Evelyn , Thompson Emily , Vezys Vaiva , Moses Melanie E , Cannon Judy L
Published: October 2023

T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within the villi of small intestine and lung under different activation conditions. Our motility analysis found that while the speeds and the overall displacement of T cells vary within all tissues analyzed, T cells in all tissues tended to persist at the same speed. Interestingly, we found that T cells in the lung show a marked population of T cells turning at close to 180o, while T cells in lymph nodes and villi do not exhibit this “reversing” movement. T cells in the lung also showed significantly decreased meandering ratios and increased confinement compared to T cells in lymph nodes and villi. These differences in motility patterns led to a decrease in the total volume scanned by T cells in lung compared to T cells in lymph node and villi. These results suggest that the tissue environment in which T cells move can impact the type of motility and ultimately, the efficiency of T cell search for target cells within specialized tissues such as the lung.
Water and chloride as allosteric inhibitors in WNK kinase osmosensing
Authors: Teixeira Liliana R , Akella Radha , Humphreys John M , He Haixia , Goldsmith Elizabeth J
Published: October 2023

Osmotic stress and chloride regulate the autophosphorylation and activity of the WNK1 and WNK3 kinase domains. The kinase domain of unphosphorylated WNK1 (uWNK1) is an asymmetric dimer possessing water molecules conserved in multiple uWNK1 crystal structures. Conserved waters are present in two networks, referred to here as conserved water networks 1 and 2 (CWN1 and CWN2). Here, we show that PEG400 applied to crystals of dimeric uWNK1 induces de-dimerization. Both the WNK1 the water networks and the chloride-binding site are disrupted by PEG400. CWN1 is surrounded by a cluster of pan-WNK-conserved charged residues. Here, we mutagenized these charges in WNK3, a highly active WNK isoform kinase domain, and WNK1, the isoform best studied crystallographically. Mutation of E314 in the Activation Loop of WNK3 (WNK3/E314Q and WNK3/E314A, and the homologous WNK1/E388A) enhanced the rate of autophosphorylation, and reduced chloride sensitivity. Other WNK3 mutants reduced the rate of autophosphorylation activity coupled with greater chloride sensitivity than wild-type. The water and chloride regulation thus appear linked. The lower activity of some mutants may reflect effects on catalysis. Crystallography showed that activating mutants introduced conformational changes in similar parts of the structure to those induced by PEG400. WNK activating mutations and crystallography support a role for CWN1 in WNK inhibition consistent with water functioning as an allosteric ligand.
Characterization of Tryptophan Oxidation Affecting D1 Degradation by FtsH in the Photosystem II Quality Control of Chloroplasts
Authors: Kato Yusuke , Kuroda Hiroshi , Ozawa Shin-Ichiro , Saito Keisuke , Dogra Vivek , Scholz Martin , Zhang Guoxian , de Vitry Catherine , Ishikita Hiroshi , Kim Chanhong , Hippler Michael , Takahashi Yuichiro , Sakamoto Wataru
Published: October 2023

Photosynthesis is one of the most important reactions for sustaining our environment. Photosystem II (PSII) is the initial site of photosynthetic electron transfer by water oxidation. Light in excess, however, causes the simultaneous production of reactive oxygen species (ROS), leading to photo-oxidative damage in PSII. To maintain photosynthetic activity, the PSII reaction center protein D1, which is the primary target of unavoidable photo-oxidative damage, is efficiently degraded by FtsH protease. In PSII subunits, photo-oxidative modifications of several amino acids such as Trp have been indeed documented, whereas the linkage between such modifications and D1 degradation remains elusive. Here, we show that an oxidative post-translational modification of Trp residue at the N-terminal tail of D1 is correlated with D1 degradation by FtsH during high-light stress. We revealed that
Arabidopsis
mutant lacking FtsH2 had increased levels of oxidative Trp residues in D1, among which an N-terminal Trp-14 was distinctively localized in the stromal side. Further characterization of Trp-14 using chloroplast transformation in
Chlamydomonas
indicated that substitution of D1 Trp-14 to Phe, mimicking Trp oxidation enhanced FtsH-mediated D1 degradation under high light, although the substitution did not affect protein stability and PSII activity. Molecular dynamics simulation of PSII implies that both Trp-14 oxidation and Phe substitution cause fluctuation of D1 N-terminal tail. Furthermore, Trp-14 to Phe modification appeared to have an additive effect in the interaction between FtsH and PSII core in vivo. Together, our results suggest that the Trp oxidation at its N-terminus of D1 may be one of the key oxidations in the PSII repair, leading to processive degradation by FtsH.In photosynthetic organisms, maintenance of photosynthetic light reaction is manifested by so called Photosystem II (PSII) repair system, where the reaction center protein D1 is targeted to photo-oxidative damage and rapidly degraded by the processive protease FtsH. While this system is well known to cope with photoinhibition, the actual oxidation within the D1 polypeptide and its association to degradation remained elusive. Here, we characterized oxidative modification of tryptophan (Trp) residues in the PSII core, and hypothesize that the oxidation of N-terminal Trp is one of the key oxidations in the PSII repair, likely enhancing D1’s accessibility to FtsH.
A Chemical Reaction Similarity-Based Prediction Algorithm Identifies the Multiple Taxa Required to Catalyze an Entire Metabolic Pathway of Dietary Flavonoids
Authors: Gulsan Ebru Ece , Nowshad Farrhin , Yamaguchi Pomaikaimaikalani , Dong Xiaokun , Jayaraman Arul , Lee Kyongbum
Published: October 2023

Flavonoids are polyphenolic phytochemicals abundant in plant-based, health-promoting foods. They are only partially absorbed in the small intestine, and gut microbiota plays a significant role in their metabolism. As flavonoids are not natural substrates of gut bacterial enzymes, reactions of flavonoid metabolism have been attributed to the ability of general classes of enzymes to metabolize non-natural substrates. To systematically characterize this promiscuous enzyme activity, we developed a prediction tool that is based on chemical reaction similarity. The tool takes a list of enzymes or organisms to match microbial enzymes with their non-native flavonoid substrates and orphan reactions. We successfully predicted the promiscuous activity of known flavonoid-metabolizing bacterial and plant enzymes.Next, we used this tool to identify the multiple taxa required to catalyze an entire metabolic pathway of dietary flavonoids. Tilianin is a flavonoid-O-glycoside having biological and pharmacological activities, including neuroprotection. Using our prediction tool, we defined a novel bacterial pathway of tilianin metabolism that includes O-deglycosylation to acacetin, demethylation of acacetin to apigenin, and hydrogenation of apigenin to naringenin. We predicted and confirmed using in vitro experiments and LC-MS techniques that Bifidobacterium longum subsp.
animalis
,
Blautia coccoides
and
Flavonifractor plautii
can catalyze this pathway. Prospectively, the prediction-validation methodology developed in this work could be used to systematically characterize gut microbial metabolism of dietary flavonoids and other phytochemicals.The bioactivities of flavonoids and their metabolic products can vary widely. We used an in vitro rat neuronal model to show that tilianin metabolites exhibit protective effect against H
2
O
2
through reactive oxygen species (Delepine et al.) scavenging activity and thus, improve cell viability, while the parent compound, tilianin, was ineffective. These results are important to understand the gut microbiota-dependent physiological effects of dietary flavonoids.
Mecp2 fine-tunes quiescence exit by targeting nuclear receptors
Authors: Yang Jun , Zou Shitian , Qiu Zeyou , Lai Mingqiang , Long Qing , Chen Huan , Lai Ping lin , Zhang Sheng , Rao Zhi , Xie Xiaoling , Gong Yan , Liu Anling , Li Mangmang , Bai Xiaochun
Published: October 2023

Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.
Mecp2 Fine-tunes Quiescence Exit by Targeting Nuclear Receptors
Authors: Yang Jun , Zou Shitian , Qiu Zeyou , Lai Mingqiang , Long Qing , Chen Huan , Zhang Sheng , Xie Xiaoling , Gong Yan , Liu Anling , Li Mangmang , Bai Xiaochun
Published: October 2023

Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit, as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. Genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly, disruption of two nuclear receptors (NRs),
Rara
or
Nr1h3,
accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.
H2-O deficiency promotes regulatory T cell differentiation and CD4 hyperactivity
Authors: Welsh Robin A. , Song Nianbin , Park Chan-su , Peske J. David , Sadegh-Nasseri Scheherazade
Published: October 2023

Regulatory T cells (Treg) are crucial immune modulators, yet the exact mechanism of thymic Treg development remains controversial. Here, we present the first direct evidence for H-2O, a peptide editing molecular chaperon for MHC class II antigen processing, on selection of thymic Tregs. We demonstrate that lack of H2-O in the thymic medulla promotes thymic Treg development and leads to an increased peripheral Treg frequency. Single-cell RNA-sequencing (scRNA-seq) analysis of splenic CD4 T cells revealed an enrichment of both effector-like Tregs and activated CD4 T cells in the absence of H2-O. H2-O has been shown to increase the presentation of high-affinity class II epitopes, thus leading to proper negative selection in the medullary thymus. In spite of this notion, our data support two concepts; a) lack of expression of H2-O in thymic medulla creates an environment permissive to Treg development and, b) that loss of H2-O drives increased basal auto-stimulation of CD4 T cells. These findings can help in better understanding of autoimmunity and design of therapeutics for treatment of autoimmune diseases.
Experience shapes chandelier cell function and structure in the visual cortex
Authors: Seignette Koen , Jamann Nora , Papale Paolo , Terra Huub , Porneso Ralph O , de Kraker Leander , van der Togt Chris , van der Aa Maaike , Neering Paul , Ruimschotel Emma , Roelfsema Pieter R , Montijn Jorrit S , Self Matthew W , Kole Maarten HP , Levelt Christiaan N
Published: October 2023

Detailed characterization of interneuron types in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells (ChCs) in visual processing remains poorly characterized. Using viral tracing we found that V1 ChCs predominantly receive monosynaptic input from local layer 5 pyramidal cells and higher-order cortical regions. Two-photon calcium imaging and convolutional neural network modeling revealed that ChCs are visually responsive but weakly selective for stimulus content. In mice running in a virtual tunnel, ChCs respond strongly to events known to elicit arousal, including locomotion and visuomotor mismatch. Repeated exposure of the mice to the virtual tunnel was accompanied by reduced visual responses of ChCs and structural plasticity of ChC boutons and axon initial segment length. Finally, ChCs only weakly inhibited pyramidal cells. These findings suggest that ChCs provide an arousal-related signal to layer 2/3 pyramidal cells that may modulate their activity and/or gate plasticity of their axon initial segments during behaviorally relevant events.
Visuomotor experience induces functional and structural plasticity of chandelier cells
Authors: Seignette Koen , Jamann Nora , Papale Paolo , Terra Huub , Porneso Ralph P. O. , de Kraker Leander , van der Togt Chris , van der Aa Maaike , Neering Paul , Ruimschotel Emma , Roelfsema Pieter R. , Montijn Jorrit S. , Self Matthew W. , Kole Maarten H. P. , Levelt Christiaan N.
Published: October 2023

Detailed characterization of interneuron subtypes in primary visual cortex (V1) has greatly contributed to understanding visual perception, yet the role of chandelier cells (ChCs) in visual processing remains poorly characterized. Using viral tracing we found that V1 ChCs predominantly receive monosynaptic input from local layer 5 pyramidal cells and higher-order cortical regions. Two-photon calcium imaging and convolutional neural network modelling revealed that ChCs are visually responsive but weakly selective for stimulus content. In mice running in a virtual tunnel, ChCs respond strongly to locomotion and halting visual flow, suggesting arousal-related activity. Visuomotor experience in the tunnel diminished visual responses of ChCs and induced structural plasticity of ChC boutons and axon initial segment length. Finally, ChCs only weakly inhibited pyramidal cells. These findings suggest that ChCs provide an arousal-related signal to layer 2/3 pyramidal cells that may modulate their activity and/or gate plasticity of their axon initial segments during behaviorally relevant events.
Analysis of foothold selection during locomotion using terrain reconstruction
Authors: Muller Karl S , Bonnen Kathryn , Shields Stephanie M , Panfili Daniel P , Matthis Jonathan , Hayhoe Mary M
Published: October 2023

Relatively little is known about the way vision is used to guide locomotion in the natural world. What visual features are used to choose paths in natural complex terrain? To answer this question, we measured eye and body movements while participants walked in natural outdoor environments. We incorporated measurements of the three-dimensional (3D) terrain structure into our analyses and reconstructed the terrain along the walker’s path, applying photogrammetry techniques to the eye tracker’s scene camera videos. Combining these reconstructions with the walker’s body movements, we demonstrate that walkers take terrain structure into account when selecting paths through an environment. We find that they change direction to avoid taking steeper steps that involve large height changes, instead of choosing more circuitous, relatively flat paths. Our data suggest walkers plan the location of individual footholds and plan ahead to select flatter paths. These results provide evidence that locomotor behavior in natural environments is controlled by decision mechanisms that account for multiple factors, including sensory and motor information, costs, and path planning.
Integrating Gaze, image analysis, and body tracking: Foothold selection during locomotion
Authors: Muller Karl , Panfili Dan , Matthis Jonathan S. , Bonnen Kathryn , Hayhoe Mary
Published: October 2023

Relatively little is known about the way vision is use to guide locomo-tion in the natural world. What visual features are used to choose paths in natural complex terrain? How do walkers trade off different costs such as getting to the goal, minimizing energy, and satisfying stability constraints? To answer these questions, it is necessary to monitor not only the eyes and the body, but also to represent the three dimensional structure of the terrain. We used photogrammetry techniques to do this, and found substantial regularities in the choice of paths. Walkers avoid paths that involve changes in height and choose more circuitous and flatter paths. This stable tradeoff is related to the walker’s leg length and reflects both energetic and stability constraints. Gaze data and path choices suggest that subjects take into account the terrain approximately 5 steps ahead, and so are planning routes as well as particular footplants. Such planning ahead allows the minimization of energetic costs. Thus locomotor behavior in natural environments is controlled by decision mechanisms that attempt to optimize for multiple factors in the context of well-calibrated sensory and motor internal models.
Eye-specific synaptic clustering through activity-dependent stabilization and punishment mechanisms in the developing visual system
Authors: Zhang Chenghang , Speer Colenso M.
Published: October 2023

Co-active synaptic connections are often spatially clustered to enable local dendritic computations underlying learning, memory, and basic sensory processing. In the mammalian visual system, retinal ganglion cell (RGC) axons converge to form clustered synaptic inputs for local signal integration in the dorsal lateral geniculate nucleus (dLGN) of the thalamus. Retinogeniculate synapse clustering is promoted by visual experience after eye-opening, but the earliest events in cluster formation and potential regulation by spontaneous retinal wave activity prior to visual experience are unknown. Here, using volumetric super-resolution single-molecule localization microscopy together with eye-specific labeling of developing retinogeniculate synapses in the mouse, we show that synaptic clustering is eye-specific and activity-dependent during the first postnatal week. We identified a subset of complex retinogeniculate synapses with larger presynaptic vesicle pools and multiple active zones that simultaneously promote the clustering of like-eye synapses (synaptic stabilization) and prohibit synapse clustering from the opposite eye (synaptic punishment). In mutant mice with disrupted spontaneous retinal wave activity, complex synapses form, but fail to drive eye-specific synaptic clustering and punishment seen in controls. These results highlight a role for spontaneous retinal activity in regulating eye-specific stabilization and punishment signals contributing to synaptic clustering in circuits essential for visual perception and behavior.
Disordered regions and folded modules in CAF-1 promote histone deposition in Schizosaccharomyces pombe
Authors: Ouasti Fouad , Audin Maxime , Fréon Karine , Quivy Jean-Pierre , Tachekort Mehdi , Cesard Elizabeth , Thureau Aurélien , Ropars Virginie , Fernández Varela Paloma , Moal Gwenaelle , Soumana-Amadou Ibrahim , Uryga Aleksandra , Legrand Pierre , Andreani Jessica , Guerois Raphaël , Almouzni Geneviève , Lambert Sarah , Ochsenbein Francoise
Published: October 2023

Genome and epigenome integrity in eukaryotes depends on the proper coupling of histone deposition with DNA synthesis. This process relies on the evolutionary conserved histone chaperone CAF-1 for which the links between structure and functions are still a puzzle. While studies of the Saccharomyces cerevisiae CAF-1 complex enabled to propose a model for the histone deposition mechanism, we still lack a framework to demonstrate its generality and in particular, how its interaction with the polymerase accessory factor PCNA is operating. Here, we reconstituted a complete SpCAF-1 from fission yeast. We characterized its dynamic structure using NMR, SAXS and molecular modeling together with in vitro and in vivo functional studies on rationally designed interaction mutants. Importantly, we identify the unfolded nature of the acidic domain which folds up when binding to histones. We also show how the long KER helix mediates DNA binding and stimulates SpCAF-1 association with PCNA. Our study highlights how the organization of CAF-1 comprising both disordered regions and folded modules enables the dynamics of multiple interactions to promote synthesis-coupled histone deposition essential for its DNA replication, heterochromatin maintenance, and genome stability functions.
Disordered regions and folded modules in CAF-1 promote histone deposition in S. pombe
Authors: Ouasti Fouad , Audin Maxime , Freon Karine , Quivy Jean-Pierre , Tachekort Mehdi , Cesard Elizabeth , Thureau Aurélien , Ropars Virginie , Varela Paloma F. , Moal Gwenaelle , Amadou Ibrahim Soumana , Uryga Aleksandra , Legrand Pierre , Andreani Jessica , Guerois Raphael , Almouzni Geneviève , Lambert Sarah , Ochsenbein Francoise
Published: October 2023

Genome and epigenome integrity in eukaryotes depends on the proper coupling of histone deposition with DNA synthesis. This process relies on the evolutionary conserved histone chaperone CAF-1, for which the links between structure and function are still a puzzle. While studies of the
S. cerevisiae
CAF-1 complex enabled to propose a model for the histone deposition mechanism, we still lack a framework to demonstrate its generality and in particular, how its interaction with the polymerase accessory factor PCNA is operating. Here, we reconstituted a complete
Sp
CAF-1 from fission yeast. We characterized its dynamic structure using NMR, SAXS and molecular modeling together with
in vitro
and
in vivo
functional studies on rationally designed interaction mutants. Importantly, we identify the unfolded nature of the acidic domain which folds up when binding to histones. We also show how the long KER helix mediates DNA binding and stimulates
Sp
CAF-1 association with PCNA. Our study highlights how the organization of CAF-1 comprising both disordered regions and folded modules enables the dynamics of multiple interactions to promote histone deposition coupled to DNA synthesis, and is essential for CAF-1 functions in DNA replication, heterochromatin maintenance, and genome stability.
Dieciséis es a uno: cómo reconstruir la unidad de la serie Carceri d’invenzione
Authors:   , Campo Pedro del
Published: October 2023

En este trabajo se presenta un mecanismo para la reconstrucción de la serie Carceri d’invenzione de Giovanni Battista Piranesi como una única unidad. Aunque tradicionalmente se ha interpretado como dieciséis representaciones independientes de cárceles, esta nueva perspectiva sugiere que son fragmentos de un mismo espacio único descompuesto, desafiando la idea convencional de unidad. La investigación busca restaurar esta unidad a través de una metodología que convierte las representaciones en objetos tangibles sin imponer una respuesta definitiva. Esto implica prácticas como reinterpretar, traducir, traicionar, desmembrar y recomponer. El enfoque es promover la exploración constante de su potencial unidad en lugar de establecer respuestas definitivas.
La voz endriaga: monstruosidad, subalternidad e identidad en la novela sicaresca
Authors:   , Parejas Fierro Héctor
Published: October 2023

Las nociones de subalternidad, marginalidad y monstruosidad parecen orbitar en torno a dos subjetividades que, pese a originarse en diferentes campos del saber, están vinculadas en razón de sus contextos de producción, estas son: el sujeto endriago –concepto propuesto por la filósofa transfeminista Dra. Sayak Valencia– y el sicario –personaje que oscila entre la realidad social que lo produce y el discurso literario que lo reproduce ficcionalmente. Sin perjuicio de que el concepto de Valencia es potencialmente extensible a otros personajes de las narrativas de la violencia –como es el caso del narco y las narconarrativas–, la presente investigación se centrará exclusivamente en el sicario, personaje que embona orgánicamente con el sujeto endriago en la medida que ambos se erigen como una subjetividad monstruosa y subalternizada en un contexto de marginalidad socioeconómica y violencia social. La aparición del sicario en la literatura latinoamericana nos remite necesariamente a la sicaresca antioqueña, género novelesco que comenzó a gestarse desde la década del ’90 en la región de Antioquía (Colombia). Si bien, los estudios crítico-literarios realizados por la Dra. Margarita Jácome (2009) y el Dr. Oscar Osorio (2015) –entre otros académicos– han abordado esta producción literaria a cabalidad, poco o nada se ha escrito acerca del sicario fuera de Colombia. Es por este motivo que la siguiente investigación tomará como principal dispositivo de estudio la novela Cachorro (2020) del escritor peruano Charlie Becerra (Lima, Perú, 1989), puesto que esta obra posee una serie de puntos de convergencia o continuidades, así como puntos de divergencia o discontinuidades, con respecto a la sicaresca antioqueña. Siendo la discontinuidad más importante la ausencia un narrador/personaje letrado que haga las veces de interprete o amanuense del personaje subalterno (el sicario). Proponemos que, a través de Cachorro, es posible analizar al personaje sicario desde su propio discurso, con una voz y enunciación autónoma, sin que ello signifique verlo con benevolencia ni tolerancia.
Cancer‐associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7
Authors: Baxter Joseph S. , Brough Rachel , Krastev Dragomir B. , Song Feifei , Sridhar Sandhya , Gulati Aditi , Alexander John , Roumeliotis Theodoros I. , Kozik Zuza , Choudhary Jyoti S. , Haider Syed , Pettitt Stephen J. , Tutt Andrew N. J. , Lord Christopher J.
Published: October 2023

The F‐box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate‐recognition subunit of Skp, cullin, F‐box (SCF)‐containing complexes. The tumour‐suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome‐wide clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9 screens, focussed RNA‐interference screens and whole and phospho‐proteome mass spectrometry profiling in multiple FBXW7 wild‐type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7‐related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small‐molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere‐associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7‐selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.
Water Harvesting MOF Enables Stable Cycling of Nickel‐Rich Batteries
Authors: Yang Kai , Sheng Li , Zhu Da , Hu Yang , Tang Zhuozhuo , Chen Jia , Liang Hongmei , Song Youzhi , Wang Xiaoling , Xu Hong , He Xiangming
Published: October 2023

Nickel (Ni)‐rich cathode materials use a high abundance of Ni instead of Cobalt (Co) while increasing battery voltage, making them the representative materials for developing high‐energy‐density batteries. However, Ni‐rich batteries are prone to Ni leaching and performance deterioration; stable cycling thus requires strict control of the H2O/HF content in the electrolyte. Here, the use of an emerging H2O capture metal–organic framework (MOF) is reported to realize stable cycling of Ni‐rich batteries with H2O‐containing electrolytes. The MOF‐801 separator enables NCM622 and even NCM811 batteries containing electrolyte solutions with a 300 ppm H2O content to maintain 91.4% and 81% of the initial capacities after 200 cycles at 0.2 C. Moreover, MOF‐801 is found to significantly suppress fragmentation of the cathode, Li–Ni intermixing, and Ni dissolution. Additionally, the MOF‐801@PP based separator can largely inhibit the lithium dendrite. The results reveal the pivotal role of MOF‐801 in high‐energy‐density batteries, inspiring in‐depth exploration of MOF's indispensable application in lithium batteries.
Single‐Atom Catalysts Originated from Metal–Organic Frameworks for Sulfate Radical‐Based Advanced Oxidation Processes: Critical Insights into Mechanisms
Authors: Chen Yaoning , Kang Huayue , Cheng Min , Zhang Gaoxia , Wang Guangfu , Liu Hongda , Xiao Wenjun , Liu Yihuan , Jiang Hongjuan
Published: October 2023

The widely discussed single‐atom catalysts (SACs) are regarded as a kind of attractive material for sulfate radical‐based advanced oxidation processes (SR‐AOPs) owing to their maximum atomic utilization efficiency and outstanding stability. Currently, metal–organic frameworks (MOFs) have appeared as prospective precursors for building SACs due to extensive chelating sites, functional adjustability, and structural tunability. However, there are few critical and systematic reviews about the application of MOF‐derived SACs in SR‐AOPs, especially in‐depth analysis of the mechanisms. Therefore, this review seeks to offer a thorough summary of the development of MOF‐derived SACs in SR‐AOPs. First, the unique advantages of MOFs as derivative precursors for SACs are discussed thoroughly. Afterward, the current synthesis strategies are elaborated categorically to unveil the formation process of single atoms and their coordination environments. Notably, the roles of different reaction sites including the generation of reactive species and mediating electron transfer are further analyzed to explain mechanisms comprehensively. Thereafter, the characterization techniques and theoretical calculations for mechanisms studies are also highlighted. Eventually, critical insights into present challenges and future developments are proposed, which are expected to enhance the catalytic efficiency of MOF‐derived SACs in SR‐AOPs.
Targeting USP8 Inhibits O‐GlcNAcylation of SLC7A11 to Promote Ferroptosis of Hepatocellular Carcinoma via Stabilization of OGT
Authors: Tang Jianing , Long Guo , Hu Kuan , Xiao Desheng , Liu Shuang , Xiao Liang , Zhou Ledu , Tao Yongguang
Published: October 2023

Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti‐tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB‐IN‐3 shows the most effective anti‐cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB‐IN‐3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O‐GlcNAc transferase (OGT) via inhibiting K48‐specific poly‐ubiquitination process on OGT protein at K117 site, and STE20‐like kinase (SLK)‐mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O‐GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment.
Manganese Mineralization of Pathogenic Viruses as a Universal Vaccine Platform
Authors: Shi Pan‐Deng , Xu Yan‐Peng , Zhu Zhu , Zhou Chao , Wu Mei , He Yangzhige , Zhao Hui , Liu Liying , Zhao Linqing , Li Xiao‐Feng , Qin Cheng‐Feng
Published: October 2023

Biomimetic viral mineralization improves viral vaccine stability and immunogenicity using inorganic metals such as Ca, Al, or Fe. Mn is a metal found in high concentrations in mammalian tissues; however, under natural or laboratory conditions, Mn mineralization by medical viruses has yet to be established. Herein, a single IAV particle is successfully encapsulated with manganese phosphate (MnP) under specific conditions using the human influenza A virus (IAV). MnP‐mineralized IAVs (IAV@Mn) exhibited physiochemical and in vitro properties similar to Ca‐mineralized IAVs. In animal models, IAV@Mn shows limited replication in immune‐competent cells and a significant attenuation compared to naïve cells. Moreover, a single‐dose vaccination with IAV@Mn induced robust humoral and cellular immune responses and conferred significant protection against a wild‐type IAV challenge in mice. Thus, Mn mineralization in pathogenic viruses provides a rapid and universal strategy for generating an emergency vaccine in response to emerging viruses.
Efficient Solar‐Driven CO2 Methanation and Hydrogen Storage Over Nickel Catalyst Derived from Metal–Organic Frameworks with Rich Oxygen Vacancies
Authors: Wang Huiling , Li Qiang , Chen Jin , Chen Jing , Jia Hongpeng
Published: October 2023

Solar‐driven photothermal conversion of carbon dioxide (CO2) to methane (CH4) is a promising approach to remedy energy shortage and climate changes, where highly efficient photothermal catalysts for CO2 methanation urgently need to be designed. Herein, nickel‐based catalysts (Ni/ZrO2) derived from metal–organic frameworks (MOFs) are fabricated and studied for photothermal CO2 methanation. The optimized catalyst 50Ni/ZrO2 achieves a stable CH4 production rate of 583.3 mmol g−1 h−1 in a continuous stability test, which is almost tenfold higher than that of 50Ni/C‐ZrO2 synthesized via commercial ZrO2. Physicochemical properties indicate that 50Ni/ZrO2 generates more tetragonal ZrO2 and possesses more oxygen vacancies (OVs) as well as enhanced nickel‐ZrO2 interaction. As a result, 50Ni/ZrO2 exhibits the strong abilities of light absorption and light‐to‐heat conversion, superior adsorption capacities of reactants (H2, CO2), and an intermediate product (CO), which finally boosts CH4 formation. This work provides an efficient strategy to design a photothermocatalyst of CO2 methanation through utilizing MOFs‐derived support.
A Bacterial Quorum Sensing Regulated Protease Inhibits Host Immune Responses by Cleaving Death Domains of Innate Immune Adaptors
Authors: Duan Xiangke , Boo Zhao Zhi , Chua Song Lin , Chong Kelvin Han Chung , Long Ziqi , Yang Renliang , Zhou Yachun , Janela Baptiste , Chotirmall Sanjay Haresh , Ginhoux Florent , Hu Qinghua , Wu Bin , Yang Liang
Published: October 2023

Innate immune adaptor proteins are critical components of the innate immune system that propagate pro‐inflammatory responses from their upstream receptors, and lead to pathogen clearance from the host. Bacterial pathogens have developed strategies to survive inside host cells without triggering the innate immune surveillance in ways that are still not fully understood. Here, it is reported that Pseudomonas aeruginosa induces its quorum sensing mechanism after macrophage engulfment. Further investigation of its secretome identified a quorum sensing regulated product, LasB, is responsible for innate immune suppression depending on the MyD88‐mediated signaling. Moreover, it is showed that this specific type of pathogen‐mediated innate immune suppression is due to the enzymatic digestion of the death domains of the innate immune adaptors, mainly MyD88, and attributed to LasB's large substrate binding groove. Lastly, it is demonstrated that the secretion of LasB from P. aeruginosa directly contributed to MyD88 degradation within macrophages. Hence, it is discovered an example of bacterial quorum sensing‐regulated cellular innate immune suppression by direct cleavage of immune adaptors.
Promoting Homogeneous Zinc‐Ion Transfer Through Preferential Ion Coordination Effect in Gel Electrolyte for Stable Zinc Metal Batteries
Authors: Lee Sangyeop , Han Im Kyung , Jeon Na Gyeong , Lee Yubin , Son Hye Bin , Han Dong‐Yeob , Nam Seoha , Chung Taehun , Kwak Myung‐Jun , Kim Youn Soo , Park Soojin
Published: October 2023

Aqueous zinc metal batteries (AZMBs) are emerging energy storage systems that are poised to replace conventional lithium‐ion batteries owing to their intrinsic safety, facile manufacturing process, economic benefits, and superior ionic conductivity. However, the issues of inferior anode reversibility and dendritic plating during operation remain challenging for the practical use of AZMBs. Herein, a gel electrolyte based on zwitterionic poly(sulfobetaine methacrylate) (poly(SBMA)) dissolved with different concentrations of ZnSO4 is proposed. Two‐dimensional correlation spectroscopy based on Raman analysis reveals an enhanced interaction priority between the polar groups in SBMA and the dissolved ions as electrolyte concentration increases, which establishes a robust interaction and renders homogeneous ion distribution. Attributable to the modified coordination, zwitterionic gel polymer electrolyte with 5 mol kg−1 of ZnSO4 (ZGPE‐5) facilitates stable zinc deposition and improves anode reversibility. By taking advantage of preferential coordination, a symmetrical cell evaluation employing ZGPE‐5 demonstrates a cycle life over 3600 h, where ZGPE‐5 also exerts a beneficial effect on the full cell cycling when assembled with Zn0.25V2O5 cathode. This study elucidates changes in the internal ion behavior that are dependent on electrolyte concentrations and pave the way for durable AZMBs.
Single‐Cell RNA‐Sequencing Provides Insight into Skeletal Muscle Evolution during the Selection of Muscle Characteristics
Authors: Xu Doudou , Wan Boyang , Qiu Kai , Wang Yubo , Zhang Xin , Jiao Ning , Yan Enfa , Wu Jiangwei , Yu Run , Gao Shuai , Du Min , Liu Chousheng , Li Mingzhou , Fan Guoping , Yin Jingdong
Published: October 2023

Skeletal muscle comprises a large, heterogeneous assortment of cell populations that interact to maintain muscle homeostasis, but little is known about the mechanism that controls myogenic development in response to artificial selection. Different pig (Sus scrofa) breeds exhibit distinct muscle phenotypes resulting from domestication and selective breeding. Using unbiased single‐cell transcriptomic sequencing analysis (scRNA‐seq), the impact of artificial selection on cell profiles is investigated in neonatal skeletal muscle of pigs. This work provides panoramic muscle‐resident cell profiles and identifies novel and breed‐specific cells, mapping them on pseudotime trajectories. Artificial selection has elicited significant changes in muscle‐resident cell profiles, while conserving signs of generational environmental challenges. These results suggest that fibro‐adipogenic progenitors serve as a cellular interaction hub and that specific transcription factors identified here may serve as candidate target regulons for the pursuit of a specific muscle phenotype. Furthermore, a cross‐species comparison of humans, mice, and pigs illustrates the conservation and divergence of mammalian muscle ontology. The findings of this study reveal shifts in cellular heterogeneity, novel cell subpopulations, and their interactions that may greatly facilitate the understanding of the mechanism underlying divergent muscle phenotypes arising from artificial selection.
Free Radical‐Mediated Photocyclization of Triphenylphosphindole Oxides for Photoactivated and Self‐Reported Lipid Peroxidation
Authors: Li Jianqing , Zhuang Zeyan , Guo Jingjing , Dong Xiaobin , Gong Junyi , Tang Ben Zhong , Zhao Zujin
Published: October 2023

Photocyclization is demonstrated as a powerful tool for building complicated polycyclic molecules. And efficient photocyclization is competent as an artful strategy to develop photo‐responsive smart materials. Herein, an efficient free radical‐mediated photocyclization for triphenylphosphindole oxide (TPPIO) derivatives to generate tribenzophosphindole oxide (TBPIO) derivatives at ambient condition is reported. The reaction mechanism and substituent effect on photocyclization efficiency are thoroughly investigated. Additionally, photophysical and photochemical properties of TPPIO and TBPIO derivatives are measured for comparison and deeply deciphered by theoretical calculation. TPPIO derivatives own typical aggregation‐induced emission feature but barely generate reactive oxygen species (ROS), while TBPIO derivatives experience aggregation‐caused quenching but show efficient Type I ROS generation capacity. Further, in vitro experiments demonstrate that this photo‐conversion can efficiently occur in situ in living cells to activate photodynamic therapy (PDT) effect to trigger lipid peroxidation with selective fluorescence “light up” in lipid droplet area under continuous irradiation. This work extends the optoelectronically and biologically interesting phosphindole oxide‐containing π‐conjugated systems through an efficient synthetic strategy, provides in‐depth mechanistic descriptions in the aspects of reaction and property, and further presents their great potentials for photoactivated and self‐reported PDT.
Using extracorporeal membrane oxygenation in donations after cardiac death or brain death: A single‐center experience and long‐term outcome
Authors: Hsieh Chia‐En , Hsu Ya‐Lan , Chen Yao‐Li , Liang Hsin‐Rou , Lin Kuo‐Hua , Chen Wen‐Yuan , Wu Hsiu‐Man , Hunang Sin‐Bao , Hung Yu‐Ju
Published: October 2023

Aims

The use of extended criteria donors is a routine practice that sometimes involves extracorporeal membrane oxygenation (ECMO) in donations after cardiac death or brain death.

Methods

We performed a retrospective study in a single center from January 2006 to December 2019. The study included 90 deceased donor liver transplants. The patients were divided into three groups: the donation after brain death (DBD) group (n = 58, 64.4%), the DBD with ECMO group (n = 11, 12.2%) and the donation after cardiac death (DCD) with ECMO group (n = 21, 23.3%).

Results

There were no significant differences between the DBD with ECMO group and the DBD group. When comparing the DCD with ECMO group and the DBD group, there were statistically significant differences for total warm ischemia time (p < 0.001), total cold ischemia time (p = 0.023), and split liver transplantation (p < 0.001), and there was significantly poor recovery in regard to total bilirubin level (p = 0.027) for the DCD with ECMO group by repeated measures ANOVA. The 5‐year survival rates of the DBD, DBD with ECMO, and DCD with ECMO groups were 78.1%, 90.9%, and 75.6%, respectively. The survival rate was not significantly different when comparing the DBD group to either the DBD with ECMO group (p = 0.435) or the DCD with ECMO group (p = 0.310).

Conclusions

Using ECMO in donations after cardiac death or brain death is a good technology, and it contributed to 35.6% of the liver graft pool.