bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stem cell microencapsulation maintains stemness in inflammatory microenvironment
Authors: Zhao Yajun , Shi Yilin , Yang Huiqi , Liu Mengmeng , Shen Lanbo , Zhang Shengben , Liu Yue , Zhu Jie , Lan Jing , Li Jianhua , Ge Shaohua 
Published: October 2022

AbstractMaintaining the stemness of the transplanted stem cell spheroids in an inflammatory microenvironment is challenging but important in regenerative medicine. Direct delivery of stem cells to repair periodontal defects may yield suboptimal effects due to the complexity of the periodontal inflammatory environment. Herein, stem cell spheroid is encapsulated by interfacial assembly of metal-phenolic network (MPN) nanofilm to form a stem cell microsphere capsule. Specifically, periodontal ligament stem cells (PDLSCs) spheroid was coated with FeIII/tannic acid coordination network to obtain spheroid@[FeIII-TA] microcapsules. The formed biodegradable MPN biointerface acted as a cytoprotective barrier and exhibited antioxidative, antibacterial and anti-inflammatory activities, effectively remodeling the inflammatory microenvironment and maintaining the stemness of PDLSCs. The stem cell microencapsulation proposed in this study can be applied to multiple stem cells with various functional metal ion/polyphenol coordination, providing a simple yet efficient delivery strategy for stem cell stemness maintenance in an inflammatory environment toward a better therapeutic outcome.
The breast milk and childhood gastrointestinal microbiotas and disease outcomes: a longitudinal study
Authors: Lif Holgerson Pernilla , Esberg Anders , West Christina E. , Johansson Ingegerd 
Published: October 2022

Abstract
Background
We aimed to characterize breast milk microbiota and define associations with saliva and fecal microbiota and selected diseases in preschool children.

Methods
In a longitudinal cohort study, the microbiotas from breast milk, mouth, and fecal samples were characterized by 16S rRNA gene sequencing. Questionnaires and medical records provided information on demographics, medical, and dental data.

Results
The phylogeny in breast milk, saliva swabs, and feces differed at all levels (p < 0.0003), though all harbored species in Streptococcus, Veillonella, and Haemophilus. Species richness was highest in breast milk with increasing resemblance with the oral swab microbiota by increasing age. Caries-affected children at age 5 had been fed breast milk with tenfold higher abundance of caries-associated bacteria, e.g., Streptococcus mutans, than caries-free children (p < 0.002). At that age, taxa, e.g., Neisseria sicca were overrepresented in saliva swabs of children with otitis media (LDA score >2, p < 0.05). Gut symbionts, e.g., Bacteroides, were underrepresented in 3-month fecal samples in children later diagnosed with allergic disease (LDA score >2, p < 0.05).

Conclusions
Distinct microbiotas for the three sources were confirmed, though resemblance between milk and oral swab microbiota increased by age. Future studies should evaluate if the observed associations with disease outcomes are causal.

Impact

Few studies have studied the association between breast milk microbiota and gastrointestinal microbiota beyond early infancy.

The present study confirms distinct microbiota profiles in breast milk, saliva swabs, and feces in infancy and indicates increasing resemblance between breast milk and the oral microbiota by increasing age.

The fecal microbiota at 3 months was associated with later allergic disease; the saliva microbiota by age 5 differed between children with and without otitis media at the same age; and children with caries by age 5 had been fed breast milk with a higher abundance of caries-associated bacteria.
Unique H2-utilizing lithotrophy in serpentinite-hosted systems
Authors: Nobu Masaru Konishi , Nakai Ryosuke , Tamazawa Satoshi , Mori Hiroshi , Toyoda Atsushi , Ijiri Akira , Suzuki Shino , Kurokawa Ken , Kamagata Yoichi , Tamaki Hideyuki 
Published: October 2022

Abstract
Serpentinization of ultramafic rocks provides molecular hydrogen (H2) that can support lithotrophic metabolism of microorganisms, but also poses extremely challenging conditions, including hyperalkalinity and limited electron acceptor availability. Investigation of two serpentinization-active systems reveals that conventional H2-/CO2-dependent homoacetogenesis is thermodynamically unfavorable in situ due to picomolar CO2 levels. Through metagenomics and thermodynamics, we discover unique taxa capable of metabolism adapted to the habitat. This included a novel deep-branching phylum, “Ca. Lithacetigenota”, that exclusively inhabits serpentinite-hosted systems and harbors genes encoding alternative modes of H2-utilizing lithotrophy. Rather than CO2, these putative metabolisms utilize reduced carbon compounds detected in situ presumably serpentinization-derived: formate and glycine. The former employs a partial homoacetogenesis pathway and the latter a distinct pathway mediated by a rare selenoprotein—the glycine reductase. A survey of microbiomes shows that glycine reductases are diverse and nearly ubiquitous in serpentinite-hosted environments. “Ca. Lithacetigenota” glycine reductases represent a basal lineage, suggesting that catabolic glycine reduction is an ancient bacterial innovation by Terrabacteria for gaining energy from geogenic H2 even under hyperalkaline, CO2-poor conditions. Unique non-CO2-reducing metabolisms presented here shed light on potential strategies that extremophiles may employ for overcoming a crucial obstacle in serpentinization-associated environments, features potentially relevant to primordial lithotrophy in early Earth.
Integrin-KCNB1 potassium channel complexes regulate neocortical neuronal development and are implicated in epilepsy
Authors: Bortolami Alessandro , Yu Wei , Forzisi Elena , Ercan Koray , Kadakia Ritik , Murugan Madhuvika , Fedele Denise , Estevez Irving , Boison Detlev , Rasin Mladen-Roko , Sesti Federico 
Published: October 2022

AbstractPotassium (K+) channels are robustly expressed during prenatal brain development, including in progenitor cells and migrating neurons, but their function is poorly understood. Here, we investigate the role of voltage-gated K+channel KCNB1 (Kv2.1) in neocortical development. Neuronal migration of glutamatergic neurons was impaired in the neocortices of KCNB1 null mice. Migratory defects persisted into the adult brains, along with disrupted morphology and synaptic connectivity. Mice developed seizure phenotype, anxiety, and compulsive behavior. To determine whether defective KCNB1 can give rise to developmental channelopathy, we constructed Knock In (KI) mice, harboring the gene variantKcnb1R312H(R312H mice) found in children with developmental and epileptic encephalopathies (DEEs). The R312H mice exhibited a similar phenotype to the null mice. Wild type (WT) and R312H KCNB1 channels made complexes with integrins α5β5 (Integrin_K+channel_Complexes, IKCs), whose biochemical signaling was impaired in R312H brains. Treatment with Angiotensin II in vitro, an agonist of Focal Adhesion kinase, a key component of IKC signaling machinery, corrected the neuronal abnormalities. Thus, a genetic mutation in a K+channel induces severe neuromorphological abnormalities through non-conducting mechanisms, that can be rescued by pharmacological intervention. This underscores a previously unknown role of IKCs as key players in neuronal development, and implicate developmental channelopathies in the etiology of DEEs.
Choroidal vascularity index and choroidal thickness: potential biomarkers in retinitis pigmentosa
Authors: Abdolrahimzadeh Solmaz , Di Pippo Mariachiara , Ciancimino Chiara , Di Staso Federico , Lotery Andrew John 
Published: October 2022

AbstractRetinitis pigmentosa (RP) is the commonest inherited retinal dystrophy. It is characterized by progressive photoreceptor degeneration and cell death and ongoing neuronal and vascular impairment. In recent years, pathophysiological alterations of the choroid have begun to be appreciated in RP. Thus, representing a potential diagnostic and therapeutic biomarker. In particular, choroidal thickness and the choroidal vascularity index can be used to understand the pathogenesis of disease and evaluate new therapeutic possibilities. Photoreceptor changes seen in eyes with RP are directly correlated to a decrease of choroidal flow, leading to a strong association between relative choroidal ischemia and visual impairment. In this review we analyse the literature on choroidal thickness and choroidal vascularity index in patients with RP and assess whether these markers may reflect progression of disease from an anatomical and functional point of view.
The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis
Authors: Zhang Qi , Abdo Rober , Iosef Cristiana , Kaneko Tomonori , Cecchini Matthew , Han Victor K. , Li Shawn Shun-Cheng 
Published: October 2022

AbstractBrain metastases (BrMs) are a common occurrence in lung cancer with a dismal outcome. To understand the mechanism of metastasis to inform prognosis and treatment, here we analyze primary and metastasized tumor specimens from 44 non-small cell lung cancer patients by spatial RNA sequencing, affording a whole transcriptome map of metastasis resolved with morphological markers for the tumor core, tumor immune microenvironment (TIME), and tumor brain microenvironment (TBME). Our data indicate that the tumor microenvironment (TME) in the brain, including the TIME and TBME, undergoes extensive remodeling to create an immunosuppressive and fibrogenic niche for the BrMs. Specifically, the brain TME is characterized with reduced antigen presentation and B/T cell function, increased neutrophils and M2-type macrophages, immature microglia, and reactive astrocytes. Differential gene expression and network analysis identify fibrosis and immune regulation as the major functional modules disrupted in both the lung and brain TME. Besides providing systems-level insights into the mechanism of lung cancer brain metastasis, our study uncovers potential prognostic biomarkers and suggests that therapeutic strategies should be tailored to the immune and fibrosis status of the BrMs.
A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Authors: Kofink Christiane , Trainor Nicole , Mair Barbara , Wöhrle Simon , Wurm Melanie , Mischerikow Nikolai , Roy Michael J. , Bader Gerd , Greb Peter , Garavel Géraldine , Diers Emelyne , McLennan Ross , Whitworth Claire , Vetma Vesna , Rumpel Klaus , Scharnweber Maximilian , Fuchs Julian E. , Gerstberger Thomas , Cui Yunhai , Gremel Gabriela , Chetta Paolo , Hopf Stefan , Budano Nicole , Rinnenthal Joerg , Gmaschitz Gerhard , Mayer Moriz , Koegl Manfred , Ciulli Alessio , Weinstabl Harald , Farnaby William 
Published: October 2022

AbstractTargeted protein degradation offers an alternative modality to classical inhibition and holds the promise of addressing previously undruggable targets to provide novel therapeutic options for patients. Heterobifunctional molecules co-recruit a target protein and an E3 ligase, resulting in ubiquitylation and proteosome-dependent degradation of the target. In the clinic, the oral route of administration is the option of choice but has only been achieved so far by CRBN- recruiting bifunctional degrader molecules. We aimed to achieve orally bioavailable molecules that selectively degrade the BAF Chromatin Remodelling complex ATPase SMARCA2 over its closely related paralogue SMARCA4, to allow in vivo evaluation of the synthetic lethality concept of SMARCA2 dependency in SMARCA4-deficient cancers. Here we outline structure- and property-guided approaches that led to orally bioavailable VHL-recruiting degraders. Our tool compound, ACBI2, shows selective degradation of SMARCA2 over SMARCA4 in ex vivo human whole blood assays and in vivo efficacy in SMARCA4-deficient cancer models. This study demonstrates the feasibility for broadening the E3 ligase and physicochemical space that can be utilised for achieving oral efficacy with bifunctional molecules.
A neural theory for counting memories
Authors: Dasgupta Sanjoy , Hattori Daisuke , Navlakha Saket 
Published: October 2022

AbstractKeeping track of the number of times different stimuli have been experienced is a critical computation for behavior. Here, we propose a theoretical two-layer neural circuit that stores counts of stimulus occurrence frequencies. This circuit implements a data structure, called acount sketch, that is commonly used in computer science to maintain item frequencies in streaming data. Our first model implements a count sketch using Hebbian synapses and outputs stimulus-specific frequencies. Our second model uses anti-Hebbian plasticity and only tracks frequencies within four count categories (“1-2-3-many”), which trades-off the number of categories that need to be distinguished with the potential ethological value of those categories. We show how both models can robustly track stimulus occurrence frequencies, thus expanding the traditional novelty-familiarity memory axis from binary to discrete with more than two possible values. Finally, we show that an implementation of the “1-2-3-many” count sketch exists in the insect mushroom body.
Scleral PERK and ATF6 as targets of myopic axial elongation of mouse eyes
Authors: Ikeda Shin-ichi , Kurihara Toshihide , Jiang Xiaoyan , Miwa Yukihiro , Lee Deokho , Serizawa Naho , Jeong Heonuk , Mori Kiwako , Katada Yusaku , Kunimi Hiromitsu , Ozawa Nobuhiro , Shoda Chiho , Ibuki Mari , Negishi Kazuno , Torii Hidemasa , Tsubota Kazuo 
Published: October 2022

AbstractAxial length is the primary determinant of eye size, and it is elongated in myopia. However, the underlying mechanism of the onset and progression of axial elongation remain unclear. Here, we show that endoplasmic reticulum (ER) stress in sclera is an essential regulator of axial elongation in myopia development through activation of both PERK and ATF6 axis followed by scleral collagen remodeling. Mice with lens-induced myopia (LIM) showed ER stress in sclera. Pharmacological interventions for ER stress could induce or inhibit myopia progression. LIM activated all IRE1, PERK and ATF6 axis, and pharmacological inhibition of both PERK and ATF6 suppressed myopia progression, which was confirmed by knocking down above two genes via CRISPR/Cas9 system. LIM dramatically changed the expression of scleral collagen genes responsible for ER stress. Furthermore, collagen fiber thinning and expression of dysregulated collagens in LIM were ameliorated by 4-PBA administration. We demonstrate that scleral ER stress and PERK/ATF6 pathway controls axial elongation during the myopia development in vivo model and 4-PBA eye drop is promising drug for myopia suppression/treatment.
Charge self-regulation in 1T'''-MoS2 structure with rich S vacancies for enhanced hydrogen evolution activity
Authors: Guo Xiaowei , Song Erhong , Zhao Wei , Xu Shumao , Zhao Wenli , Lei Yongjiu , Fang Yuqiang , Liu Jianjun , Huang Fuqiang 
Published: October 2022

AbstractActive electronic states in transition metal dichalcogenides are able to prompt hydrogen evolution by improving hydrogen absorption. However, the development of thermodynamically stable hexagonal 2H-MoS2 as hydrogen evolution catalyst is likely to be shadowed by its limited active electronic state. Herein, the charge self-regulation effect mediated by tuning Mo−Mo bonds and S vacancies is revealed in metastable trigonal MoS2 (1T'''-MoS2) structure, which is favarable for the generation of active electronic states to boost the hydrogen evolution reaction activity. The optimal 1T'''-MoS2 sample exhibits a low overpotential of 158 mV at 10 mA cm−2 and a Tafel slope of 74.5 mV dec−1 in acidic conditions, which are far exceeding the 2H-MoS2 counterpart (369 mV and 137 mV dec−1). Theoretical modeling indicates that the boosted performance is attributed to the formation of massive active electronic states induced by the charge self-regulation effect of Mo−Mo bonds in defective 1T'''-MoS2 with rich S vacancies.
Atomic model of vesicular stomatitis virus and mechanism of assembly
Authors: Zhou Kang , Si Zhu , Ge Peng , Tsao Jun , Luo Ming , Zhou Z. Hong 
Published: October 2022

AbstractLike other negative-strand RNA viruses (NSVs) such as influenza and rabies, vesicular stomatitis virus (VSV) has a three-layered organization: a layer of matrix protein (M) resides between the glycoprotein (G)-studded membrane envelope and the nucleocapsid, which is composed of the nucleocapsid protein (N) and the encapsidated genomic RNA. Lack of in situ atomic structures of these viral components has limited mechanistic understanding of assembling the bullet-shaped virion. Here, by cryoEM and sub-particle reconstruction, we have determined the in situ structures of M and N inside VSV at 3.47 Å resolution. In the virion, N and M sites have a stoichiometry of 1:2. The in situ structures of both N and M differ from their crystal structures in their N-terminal segments and oligomerization loops. N-RNA, N-N, and N-M-M interactions govern the formation of the capsid. A double layer of M contributes to packaging of the helical nucleocapsid: the inner M (IM) joins neighboring turns of the N helix, while the outer M (OM) contacts G and the membrane envelope. The pseudo-crystalline organization of G is further mapped by cryoET. The mechanism of VSV assembly is delineated by the network interactions of these viral components.
Rapid and efficient hydrogen clathrate hydrate formation in confined nanospace
Authors: Farrando-Perez Judit , Balderas-Xicohtencatl Rafael , Cheng Yongqiang , Daemen Luke , Cuadrado-Collados Carlos , Martinez-Escandell Manuel , Ramirez-Cuesta Anibal J. , Silvestre-Albero Joaquin 
Published: October 2022

AbstractClathrate hydrates are crystalline solids characterized by their ability to accommodate large quantities of guest molecules. Although CH4 and CO2 are the traditional guests found in natural systems, incorporating smaller molecules (e.g., H2) is challenging due to the need to apply higher pressures to stabilize the hydrogen-bonded network. Another critical limitation of hydrates is the slow nucleation and growth kinetics. Here, we show that specially designed activated carbon materials can surpass these obstacles by acting as nanoreactors promoting the nucleation and growth of H2 hydrates. The confinement effects in the inner cavities promote the massive growth of hydrogen hydrates at moderate temperatures, using pure water, with extremely fast kinetics and much lower pressures than the bulk system.
Structural insights into PA3488-mediated inactivation of Pseudomonas aeruginosa PldA
Authors: Yang Xiaoyun , Li Zongqiang , Zhao Liang , She Zhun , Gao Zengqiang , Sui Sen-Fang , Dong Yuhui , Li Yanhua 
Published: October 2022

AbstractPldA, a phospholipase D (PLD) effector, catalyzes hydrolysis of the phosphodiester bonds of glycerophospholipids—the main component of cell membranes—and assists the invasion of the opportunistic pathogen Pseudomonas aeruginosa. As a cognate immunity protein, PA3488 can inhibit the activity of PldA to avoid self-toxicity. However, the precise inhibitory mechanism remains elusive. We determine the crystal structures of full-length and truncated PldA and the cryogenic electron microscopy structure of the PldA–PA3488 complex. Structural analysis reveals that there are different intermediates of PldA between the “open” and “closed” states of the catalytic pocket, accompanied by significant conformational changes in the “lid” region and the peripheral helical domain. Through structure-based mutational analysis, we identify the key residues responsible for the enzymatic activity of PldA. Together, these data provide an insight into the molecular mechanisms of PldA invasion and its neutralization by PA3488, aiding future design of PLD-targeted inhibitors and drugs.
Giant enhancement of superconducting critical temperature in substitutional alloy (La,Ce)H9
Authors: Bi Jingkai , Nakamoto Yuki , Zhang Peiyu , Shimizu Katsuya , Zou Bo , Liu Hanyu , Zhou Mi , Liu Guangtao , Wang Hongbo , Ma Yanming 
Published: October 2022

AbstractA sharp focus of current research on superconducting superhydrides is to raise their critical temperature Tc at moderate pressures. Here, we report a discovery of giant enhancement of Tc in CeH9 obtained via random substitution of half Ce by La, leading to equal-atomic (La,Ce)H9 alloy stabilized by maximum configurational entropy, containing the LaH9 unit that is unstable in pure compound form. The synthesized (La,Ce)H9 alloy exhibits Tc of 148–178 K in the pressure range of 97–172 GPa, representing up to 80% enhancement of Tc compared to pure CeH9 and showcasing the highest Tc at sub-megabar pressure among the known superhydrides. This work demonstrates substitutional alloying as a highly effective enabling tool for substantially enhancing Tc via atypical compositional modulation inside suitably selected host crystal. This optimal substitutional alloying approach opens a promising avenue for synthesis of high-entropy multinary superhydrides that may exhibit further increased Tc at even lower pressures.
Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing
Authors: Gonzalez Trevor J. , Simon Katherine E. , Blondel Leo O. , Fanous Marco M. , Roger Angela L. , Maysonet Maribel Santiago , Devlin Garth W. , Smith Timothy J. , Oh Daniel K. , Havlik L. Patrick , Castellanos Rivera Ruth M. , Piedrahita Jorge A. , ElMallah Mai K. , Gersbach Charles A. , Asokan Aravind 
Published: October 2022

AbstractRecombinant adeno-associated viral (AAV) vectors are a promising gene delivery platform, but ongoing clinical trials continue to highlight a relatively narrow therapeutic window. Effective clinical translation is confounded, at least in part, by differences in AAV biology across animal species. Here, we tackle this challenge by sequentially evolving AAV capsid libraries in mice, pigs and macaques. We discover a highly potent, cross-species compatible variant (AAV.cc47) that shows improved attributes benchmarked against AAV serotype 9 as evidenced by robust reporter and therapeutic gene expression, Cre recombination and CRISPR genome editing in normal and diseased mouse models. Enhanced transduction efficiency of AAV.cc47 vectors is further corroborated in macaques and pigs, providing a strong rationale for potential clinical translation into human gene therapies. We envision that ccAAV vectors may not only improve predictive modeling in preclinical studies, but also clinical translatability by broadening the therapeutic window of AAV based gene therapies.