bluuebunny/crossref_metadata_2025_split huggingface dataset:
Central nervous system effects of TAK-653, an investigational alpha-amino-3-hydroxy-5-methyl-4-isoxazole receptor (AMPAR) positive allosteric modulator in healthy volunteers
Authors: Dijkstra Francis , O’Donnell Patricio , Klaassen Erica , Buhl Derek , Asgharnejad Mahnaz , Rosen Laura , Zuiker Rob , van Gerven Joop , Jacobs Gabriël 
Published: September 2022

AbstractTAK-653 is a novel AMPA receptor positive allosteric modulator in clinical development for the treatment of major depressive disorder (MDD). This study aimed to measure the functional pharmacodynamic central nervous system (CNS) effects of TAK-653. A randomised, double-blind, placebo-controlled, three-way crossover (placebo, TAK-653 0.5 mg and 6 mg) study with 24 healthy volunteers was performed. NeuroCart tests consisting of body sway (BS), saccadic peak velocity (SPV), smooth pursuit eye movements (SP), adaptive tracking (AT), Bowdle and Bond and Lader Visual Analogue Scales (B-VAS and BL-VAS) and Stroop test were performed pre-dose and 3.5 and 4 h post-dose. Data were analysed using a mixed model analysis of covariance with baseline as covariate. It was found that TAK-653 did not affect BS and subjective drug effects as measured by B-VAS and BL-VAS at either dose level. TAK-653 0.5 mg increased SPV (degrees/second) (19.49 [5.98, 32.99],P = 0.02) and affected Stroop difference in reaction time between correct congruent and correct incongruent answers and number of correct responses in incongruent trials (22.0 [4.0, 40.0],P = 0.05 and −0.3 [−0.5, −0.1],P = 0.02, respectively). TAK-653 6 mg improved AT (%) (1.68 [0.51, 2.84],P = 0.02) and increased SPV (degrees/s) (15.40 [1.91, 28.90],P = 0.06) and SP (%) (2.32 [0.37, 4.27],P = 0.05). Based on these findings it can be concluded that TAK-653 demonstrated a psychostimulant-like pharmacodynamic profile on the NeuroCart consistent with previously reported increase of cortical excitability following Transcranial Magnetic Stimulation (TMS) of the human motor cortex.
Quantitative trait locus analysis for endophenotypes reveals genetic substrates of core symptom domains and neurocognitive function in autism spectrum disorder
Authors: Lee In-Hee , Koelliker Ekaterina , Kong Sek Won 
Published: September 2022

AbstractAutism spectrum disorder (ASD) represents a heterogeneous group of neurodevelopmental disorders and is largely attributable to genetic risk factors. Phenotypic and genetic heterogeneity of ASD have been well-recognized; however, genetic substrates for endophenotypes that constitute phenotypic heterogeneity are not yet known. In the present study, we compiled data from the Autism Genetic Resource Exchange, which contains the demographic and detailed phenotype information of 11,961 individuals. Notably, the whole-genome sequencing data available from MSSNG and iHART for 3833 individuals in this dataset was used to perform an endophenotype-wide association study. Using a linear mixed model, genome-wide association analyses were performed for 29 endophenotype scores and 0.58 million common variants with variant allele frequency ≥ 5%. We discovered significant associations between 9 genetic variants and 6 endophenotype scores comprising neurocognitive development and severity scores for core symptoms of ASD at a significance threshold of p < 5 × 10–7. Of note, the Stereotyped Behaviors and Restricted Interests total score in Autism Diagnostic Observation Schedule Module 3 was significantly associated with multiple variants in the VPS13B gene, a causal gene for Cohen syndrome and a candidate gene for syndromic ASD. Our findings yielded loci with small effect sizes due to the moderate sample size and, thus, require validation in another cohort. Nonetheless, our endophenotype-wide association analysis extends previous candidate gene discovery in the context of genotype and endophenotype association. As a result, these candidate genes may be responsible for specific traits that constitute core symptoms and neurocognitive function of ASD rather than the disorder itself.
A calpain-6/YAP axis in sarcoma stem cells that drives the outgrowth of tumors and metastases
Authors: Tchicaya-Bouanga Joëlle , Hung Yu-Jen , Schwartz Jean-Marc , Yoon Diane Ji Yun , Chotard Emilie , Marty Clarice , Odri Guillaume Anthony , de Pinieux Gonzague , Cohen-Solal Martine , Modrowski Dominique 
Published: September 2022

AbstractSarcomas include cancer stem cells, but how these cells contribute to local and metastatic relapse is largely unknown. We previously showed the pro-tumor functions of calpain-6 in sarcoma stem cells. Here, we use an osteosarcoma cell model, osteosarcoma tissues and transcriptomic data from human tumors to study gene patterns associated with calpain-6 expression or suppression. Calpain-6 modulates the expression of Hippo pathway genes and stabilizes the hippo effector YAP. It also modulates the vesicular trafficking of β-catenin degradation complexes. Calpain-6 expression is associated with genes of the G2M phase of the cell cycle, supports G2M-related YAP activities and up-regulated genes controlling mitosis in sarcoma stem cells and tissues. In mouse models of bone sarcoma, most tumor cells expressed calpain-6 during the early steps of tumor out-growth. YAP inhibition prevented the neoformation of primary tumors and metastases but had no effect on already developed tumors. It could even accelerate lung metastasis associated with large bone tumors by affecting tumor-associated inflammation in the host tissues. Our results highlight a specific mechanism involving YAP transcriptional activity in cancer stem cells that is crucial during the early steps of tumor and metastasis outgrowth and that could be targeted to prevent sarcoma relapse.
Recruitment of LEF1 by Pontin chromatin modifier amplifies TGFBR2 transcription and activates TGFβ/SMAD signalling during gliomagenesis
Authors: Zhou Xuexia , Li Xuebing , Wang Run , Hua Dan , Sun Cuiyun , Yu Lin , Shi Cuijuan , Luo Wenjun , Jiang Zhendong , An Wenzhe , Wang Qian , Yu Shizhu 
Published: September 2022

AbstractSynergies of transcription factors, chromatin modifiers and their target genes are vital for cell fate determination in human cancer. Although the importance of numerous epigenetic machinery for regulating gliomagenesis has been previously recognized, how chromatin modifiers collaborate with specific transcription factors remains largely elusive. Herein we report that Pontin chromatin remodelling factor acts as a coactivator for LEF1 to activate TGFβ/SMAD signalling, thereby contributing to gliomagenesis. Pontin is highly expressed in gliomas, and its overexpression paralleled the grade elevation and poor prognosis of patients. Functional studies verified its oncogenic roles in GBM cells by facilitating cell proliferation, survival and invasion both in vitro and in vivo. RNA sequencing results revealed that Pontin regulated multiple target genes involved in TGFβ/SMAD signalling. Intriguingly, we found that Pontin amplified TGFβR2 gene transcription by recruiting LEF1, thereby activating TGFβ/SMAD signalling and facilitating gliomagenesis. Furthermore, higher TGFβR2 expression conferred worse patient outcomes in glioma. To conclude, our study revealed that the Pontin-LEF1 module plays a crucial role in driving TGFβR2 gene transcription, which could be exploited to target TGFβ/SMAD signalling for anti-glioma therapy.
Inhibition of USP1 enhances anticancer drugs-induced cancer cell death through downregulation of survivin and miR-216a-5p-mediated upregulation of DR5
Authors: Woo Seon Min , Kim Seok , Seo Seung Un , Kim Shin , Park Jong-Wook , Kim Gyeonghwa , Choi Yu-Ra , Hur Keun , Kwon Taeg Kyu 
Published: September 2022

AbstractUbiquitin-specific protease 1 (USP1) is a deubiquitinase involved in DNA damage repair by modulating the ubiquitination of major regulators, such as PCNA and FANCD2. Because USP1 is highly expressed in many cancers, dysregulation of USP1 contributes to cancer therapy. However, the role of USP1 and the mechanisms underlying chemotherapy remain unclear. In this study, we found high USP1 expression in tumor tissues and that it correlated with poor prognosis in RCC. Mechanistically, USP1 enhanced survivin stabilization by removing ubiquitin. Pharmacological inhibitors (ML23 and pimozide) and siRNA targeting USP1 induced downregulation of survivin expression. In addition, ML323 upregulated DR5 expression by decreasing miR-216a-5p expression at the post-transcriptional level, and miR-216a-5p mimics suppressed the upregulation of DR5 by ML323. Inhibition of USP1 sensitized cancer cells. Overexpression of survivin or knockdown of DR5 markedly prevented the co-treatment with ML323 and TRAIL-induced apoptosis. These results of in vitro were proved in a mouse xenograft model, in which combined treatment significantly reduced tumor size and induced survivin downregulation and DR5 upregulation. Furthermore, USP1 and survivin protein expression showed a positive correlation, whereas miR-216a-5p and DR5 were inversely correlated in RCC tumor tissues. Taken together, our results suggest two target substrates of USP1 and demonstrate the involvement of survivin and DR5 in USP1-targeted chemotherapy.
Interferon gamma mediates the reduction of adipose tissue regulatory T cells in human obesity
Authors: Bradley David , Smith Alan J. , Blaszczak Alecia , Shantaram Dharti , Bergin Stephen M. , Jalilvand Anahita , Wright Valerie , Wyne Kathleen L. , Dewal Revati S. , Baer Lisa A. , Wright Katherine R. , Stanford Kristin I. , Needleman Bradley , Brethauer Stacy , Noria Sabrena , Renton David , Joseph Joshua J. , Lovett-Racke Amy , Liu Joey , Hsueh Willa A. 
Published: September 2022

AbstractDecreased adipose tissue regulatory T cells contribute to insulin resistance in obese mice, however, little is known about the mechanisms regulating adipose tissue regulatory T cells numbers in humans. Here we obtain adipose tissue from obese and lean volunteers. Regulatory T cell abundance is lower in obese vs. lean visceral and subcutaneous adipose tissue and associates with reduced insulin sensitivity and altered adipocyte metabolic gene expression. Regulatory T cells numbers decline following high-fat diet induction in lean volunteers. We see alteration in major histocompatibility complex II pathway in adipocytes from obese patients and after high fat ingestion, which increases T helper 1 cell numbers and decreases regulatory T cell differentiation. We also observe increased expression of inhibitory co-receptors including programmed cell death protein 1 and OX40 in visceral adipose tissue regulatory T cells from patients with obesity. In human obesity, these global effects of interferon gamma to reduce regulatory T cells and diminish their function appear to instigate adipose inflammation and suppress adipocyte metabolism, leading to insulin resistance.
Synthetic neuromorphic computing in living cells
Authors: Rizik Luna , Danial Loai , Habib Mouna , Weiss Ron , Daniel Ramez 
Published: September 2022

AbstractComputational properties of neuronal networks have been applied to computing systems using simplified models comprising repeated connected nodes, e.g., perceptrons, with decision-making capabilities and flexible weighted links. Analogously to their revolutionary impact on computing, neuro-inspired models can transform synthetic gene circuit design in a manner that is reliable, efficient in resource utilization, and readily reconfigurable for different tasks. To this end, we introduce the perceptgene, a perceptron that computes in the logarithmic domain, which enables efficient implementation of artificial neural networks in Escherichia coli cells. We successfully modify perceptgene parameters to create devices that encode a minimum, maximum, and average of analog inputs. With these devices, we create multi-layer perceptgene circuits that compute a soft majority function, perform an analog-to-digital conversion, and implement a ternary switch. We also create a programmable perceptgene circuit whose computation can be modified from OR to AND logic using small molecule induction. Finally, we show that our approach enables circuit optimization via artificial intelligence algorithms.
Tail proteins of phage SU10 reorganize into the nozzle for genome delivery
Authors: Šiborová Marta , Füzik Tibor , Procházková Michaela , Nováček Jiří , Benešík Martin , Nilsson Anders S. , Plevka Pavel 
Published: September 2022

AbstractEscherichia coliphage SU10 belongs to the genusKuravirusfrom the classCaudoviricetesof phages with short non-contractile tails. In contrast to other short-tailed phages, the tails of Kuraviruses elongate upon cell attachment. Here we show that the virion of SU10 has a prolate head, containing genome and ejection proteins, and a tail, which is formed of portal, adaptor, nozzle, and tail needle proteins and decorated with long and short fibers. The binding of the long tail fibers to the receptors in the outer bacterial membrane induces the straightening of nozzle proteins and rotation of short tail fibers. After the re-arrangement, the nozzle proteins and short tail fibers alternate to form a nozzle that extends the tail by 28 nm. Subsequently, the tail needle detaches from the nozzle proteins and five types of ejection proteins are released from the SU10 head. The nozzle with the putative extension formed by the ejection proteins enables the delivery of the SU10 genome into the bacterial cytoplasm. It is likely that this mechanism of genome delivery, involving the formation of the tail nozzle, is employed by all Kuraviruses.
Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant Enterobacteriaceae
Authors: Djukovic Ana , Garzón María José , Canlet Cécile , Cabral Vitor , Lalaoui Rym , García-Garcerá Marc , Rechenberger Julia , Tremblay-Franco Marie , Peñaranda Iván , Puchades-Carrasco Leonor , Pineda-Lucena Antonio , González-Barberá Eva María , Salavert Miguel , López-Hontangas José Luis , Sanz Miguel Á. , Sanz Jaime , Kuster Bernhard , Rolain Jean-Marc , Debrauwer Laurent , Xavier Karina B. , Xavier Joao B. , Ubeda Carles 
Published: September 2022

AbstractInfections by multidrug-resistantEnterobacteriaceae(MRE) are life-threatening to patients. The intestinal microbiome protects against MRE colonization, but antibiotics cause collateral damage to commensals and open the way to colonization and subsequent infection. Despite the significance of this problem, the specific commensals and mechanisms that restrict MRE colonization remain largely unknown. Here, by performing a multi-omic prospective study of hospitalized patients combined with mice experiments, we find thatLactobacillusis key, though not sufficient, to restrict MRE gut colonization.Lactobacillus rhamnosusandmurinusincrease the levels of Clostridiales bacteria, which induces a hostile environment for MRE growth through increased butyrate levels and reduced nutrient sources. This mechanism of colonization resistance, an interaction betweenLactobacillusspp. and Clostridiales involving cooperation between microbiota members, is conserved in mice and patients. These results stress the importance of exploiting microbiome interactions for developing effective probiotics that prevent infections in hospitalized patients.
Bond engineering of molecular ferroelectrics renders soft and high-performance piezoelectric energy harvesting materials
Authors: Hu Yuzhong , Parida Kaushik , Zhang Hao , Wang Xin , Li Yongxin , Zhou Xinran , Morris Samuel Alexander , Liew Weng Heng , Wang Haomin , Li Tao , Jiang Feng , Yang Mingmin , Alexe Marin , Du Zehui , Gan Chee Lip , Yao Kui , Xu Bin , Lee Pooi See , Fan Hong Jin 
Published: September 2022

AbstractPiezoelectric materials convert mechanical stress to electrical energy and thus are widely used in energy harvesting and wearable devices. However, in the piezoelectric family, there are two pairs of properties that improving one of them will generally compromises the other, which limits their applications. The first pair is piezoelectric strain and voltage constant, and the second is piezoelectric performance and mechanical softness. Here, we report a molecular bond weakening strategy to mitigate these issues in organic-inorganic hybrid piezoelectrics. By introduction of large-size halide elements, the metal-halide bonds can be effectively weakened, leading to a softening effect on bond strength and reduction in polarization switching barrier. The obtained solid solution C6H5N(CH3)3CdBr2Cl0.75I0.25exhibits excellent piezoelectric constants (d33 = 367 pm/V,g33 = 3595 × 10−3 Vm/N), energy harvesting property (power density is 11 W/m2), and superior mechanical softness (0.8 GPa), promising this hybrid as high-performance soft piezoelectrics.
Tunable quantum gaps to decouple carrier and phonon transport leading to high-performance thermoelectrics
Authors: Yu Yong , Xu Xiao , Wang Yan , Jia Baohai , Huang Shan , Qiang Xiaobin , Zhu Bin , Lin Peijian , Jiang Binbin , Liu Shixuan , Qi Xia , Pan Kefan , Wu Di , Lu Haizhou , Bosman Michel , Pennycook Stephen J. , Xie Lin , He Jiaqing 
Published: September 2022

AbstractThermoelectrics enable direct heat-to-electricity transformation, but their performance has so far been restricted by the closely coupled carrier and phonon transport. Here, we demonstrate that the quantum gaps, a class of planar defects characterized by nano-sized potential wells, can decouple carrier and phonon transport by selectively scattering phonons while allowing carriers to pass effectively. We choose the van der Waals gap in GeTe-based materials as a representative example of the quantum gap to illustrate the decoupling mechanism. The nano-sized potential well of the quantum gap in GeTe-based materials is directly visualized by in situ electron holography. Moreover, a more diffused distribution of quantum gaps results in further reduction of lattice thermal conductivity, which leads to a peak ZT of 2.6 at 673 K and an average ZT of 1.6 (323–723 K) in a GeTe system. The quantum gap can also be engineered into other thermoelectrics, which provides a general method for boosting their thermoelectric performance.
Phosphorylcholine-conjugated gold-molecular clusters improve signal for Lymph Node NIR-II fluorescence imaging in preclinical cancer models
Authors: Baghdasaryan Ani , Wang Feifei , Ren Fuqiang , Ma Zhuoran , Li Jiachen , Zhou Xueting , Grigoryan Lilit , Xu Chun , Dai Hongjie 
Published: September 2022

AbstractSentinel lymph node imaging and biopsy is important to clinical assessment of cancer metastasis, and novel non-radioactive lymphographic tracers have been actively pursued over the years. Here, we develop gold molecular clusters (Au25) functionalized by phosphorylcholine (PC) ligands for NIR-II (1000–3000 nm) fluorescence imaging of draining lymph nodes in 4T1 murine breast cancer and CT26 colon cancer tumor mouse models. The Au-phosphorylcholine (Au-PC) probes exhibit ‘super-stealth’ behavior with little interactions with serum proteins, cells and tissues in vivo, which differs from the indocyanine green (ICG) dye. Subcutaneous injection of Au-PC allows lymph node mapping by NIR-II fluorescence imaging at an optimal time of ~ 0.5 − 1 hour postinjection followed by rapid renal clearance. Preclinical NIR-II fluorescence LN imaging with Au-PC affords high signal to background ratios and high safety and biocompatibility, promising for future clinical translation.
Comprehensive assessment of miniature CRISPR-Cas12f nucleases for gene disruption
Authors: Xin Changchang , Yin Jianhang , Yuan Shaopeng , Ou Liqiong , Liu Mengzhu , Zhang Weiwei , Hu Jiazhi 
Published: September 2022

AbstractBecause of their small size, the recently developed CRISPR-Cas12f nucleases can be effectively packaged into adeno-associated viruses for gene therapy. However, a systematic evaluation of the editing outcomes of CRISPR-Cas12f is lacking. In this study, we apply a high-throughput sequencing method to comprehensively assess the editing efficiency, specificity, and safety of four Cas12f proteins in parallel with that of Cas9 and two Cas12a proteins at multiple genomic sites. Cas12f nucleases achieve robust cleavage at most of the tested sites and mainly produce deletional fragments. In contrast, Cas9 and Cas12a show relatively higher editing efficiency at the vast majority of the tested sites. However, the off-target hotspots identified in the Cas9- and Cas12a-edited cells are negligibly detected in the Cas12f-edited cells. Moreover, compared to Cas9 and Cas12a nucleases, Cas12f nucleases reduce the levels of chromosomal translocations, large deletions, and integrated vectors by 2- to 3-fold. Therefore, our findings confirm the editing capacity of Cas12f and reveal the ability of this nuclease family to preserve genome integrity during genome editing.
Experimental evidence for core-Merge in the vocal communication system of a wild passerine
Authors: Suzuki Toshitaka N. , Matsumoto Yui K. 
Published: September 2022

AbstractOne of the cognitive capacities underlying language is core-Merge, which allows senders to combine two words into a sequence and receivers to recognize it as a single unit. Recent field studies suggest intriguing parallels in non-human animals, e.g., Japanese tits (Parus minor) combine two meaning-bearing calls into a sequence when prompting antipredator displays in other individuals. However, whether such examples represent core-Merge remains unclear; receivers may perceive a two-call sequence as two individual calls that are arbitrarily produced in close time proximity, not as a single unit. If an animal species has evolved core-Merge, its receivers should treat a two-call sequence produced by a single individual differently from the same two calls produced by two individuals with the same timing. Here, we show that Japanese tit receivers exhibit antipredator displays when perceiving two-call sequences broadcast from a single source, but not from two sources, providing evidence for core-Merge in animals.
High-resolution silkworm pan-genome provides genetic insights into artificial selection and ecological adaptation
Authors: Tong Xiaoling , Han Min-Jin , Lu Kunpeng , Tai Shuaishuai , Liang Shubo , Liu Yucheng , Hu Hai , Shen Jianghong , Long Anxing , Zhan Chengyu , Ding Xin , Liu Shuo , Gao Qiang , Zhang Bili , Zhou Linli , Tan Duan , Yuan Yajie , Guo Nangkuo , Li Yan-Hong , Wu Zhangyan , Liu Lulu , Li Chunlin , Lu Yaru , Gai Tingting , Zhang Yahui , Yang Renkui , Qian Heying , Liu Yanqun , Luo Jiangwen , Zheng Lu , Lou Jinghou , Peng Yunwu , Zuo Weidong , Song Jiangbo , He Songzhen , Wu Songyuan , Zou Yunlong , Zhou Lei , Cheng Lan , Tang Yuxia , Cheng Guotao , Yuan Lianwei , He Weiming , Xu Jiabao , Fu Tao , Xiao Yang , Lei Ting , Xu Anying , Yin Ye , Wang Jian , Monteiro Antónia , Westhof Eric , Lu Cheng , Tian Zhixi , Wang Wen , Xiang Zhonghuai , Dai Fangyin 
Published: September 2022

AbstractThe silkwormBombyx moriis an important economic insect for producing silk, the “queen of fabrics”. The currently available genomes limit the understanding of its genetic diversity and the discovery of valuable alleles for breeding. Here, we deeply re-sequence 1,078 silkworms and assemble long-read genomes for 545 representatives. We construct a high-resolution pan-genome dataset representing almost the entire genomic content in the silkworm. We find that the silkworm population harbors a high density of genomic variants and identify 7308 new genes, 4260 (22%) core genes, and 3,432,266 non-redundant structure variations (SVs). We reveal hundreds of genes and SVs that may contribute to the artificial selection (domestication and breeding) of silkworm. Further, we focus on four genes responsible, respectively, for two economic (silk yield and silk fineness) and two ecologically adaptive traits (egg diapause and aposematic coloration). Taken together, our population-scale genomic resources will promote functional genomics studies and breeding improvement for silkworm.