bluuebunny/crossref_metadata_2025_split huggingface dataset:
FAM64A promotes HNSCC tumorigenesis by mediating transcriptional autoregulation of FOXM1
Authors: Zhao Xinyuan , Chen Huan , Qiu Yu , Cui Li 
Published: May 2022

AbstractHead and neck squamous cell carcinoma (HNSCC) still lacks effective targeted treatment. Therefore, exploring novel and robust molecular targets is critical for improving the clinical outcome of HNSCC. Here, we reported that the expression levels of family with sequence similarity 64, member A (FAM64A) were significantly higher in HNSCC tissues and cell lines. In addition, FAM64A overexpression was found to be strongly associated with an unfavorable prognosis of HNSCC. Both in vitro and in vivo evidence showed that FAM64A depletion suppressed the malignant activities of HNSCC cells, and vice versa. Moreover, we found that the FAM64A level was progressively increased from normal to dysplastic to cancerous tissues in a carcinogenic 4-nitroquinoline-1-oxide mouse model. Mechanistically, a physical interaction was found between FAM64A and forkhead box protein M1 (FOXM1) in HNSCC cells. FAM64A promoted HNSCC tumorigenesis not only by enhancing the transcriptional activity of FOXM1, but also, more importantly, by modulating FOXM1 expression via the autoregulation loop. Furthermore, a positive correlation between FAM64A and FOXM1 was found in multiple independent cohorts. Taken together, our findings reveal a previously unknown mechanism behind the activation of FOXM1 in HNSCC, and FAM64A might be a promising molecular therapeutic target for treating HNSCC.
The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites
Authors: Hedderich Janik B. , Persechino Margherita , Becker Katharina , Heydenreich Franziska M. , Gutermuth Torben , Bouvier Michel , Bünemann Moritz , Kolb Peter 
Published: May 2022

AbstractG-protein-coupled receptors do not only feature the orthosteric pockets, where most endogenous agonists bind, but also a multitude of other allosteric pockets that have come into the focus as potential binding sites for synthetic modulators. Here, to better characterise such pockets, we investigate 557 GPCR structures by exhaustively docking small molecular probes in silico and converting the ensemble of binding locations to pocket-defining volumes. Our analysis confirms all previously identified pockets and reveals nine previously untargeted sites. In order to test for the feasibility of functional modulation of receptors through binding of a ligand to such sites, we mutate residues in two sites, in two model receptors, the muscarinic acetylcholine receptor M3andβ2-adrenergic receptor. Moreover, we analyse the correlation of inter-residue contacts with the activation states of receptors and show that contact patterns closely correlating with activation indeed coincide with these sites.
EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
Authors: Zhang Lin , Qu Jingkun , Qi Yutao , Duan Yimin , Huang Yu-Wen , Zhou Zhifen , Li Ping , Yao Jun , Huang Beibei , Zhang Shuxing , Yu Dihua 
Published: May 2022

AbstractBone metastases occur in 50–70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2(EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn’t been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increasesITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer.
Cumulative SARS-CoV-2 mutations and corresponding changes in immunity in an immunocompromised patient indicate viral evolution within the host
Authors: Sonnleitner Sissy Therese , Prelog Martina , Sonnleitner Stefanie , Hinterbichler Eva , Halbfurter Hannah , Kopecky Dominik B. C. , Almanzar Giovanni , Koblmüller Stephan , Sturmbauer Christian , Feist Leonard , Horres Ralf , Posch Wilfried , Walder Gernot 
Published: May 2022

AbstractDifferent scenarios explaining the emergence of novel variants of concern (VOC) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported, including their evolution in scarcely monitored populations, in animals as alternative hosts, or in immunocompromised individuals. Here we report SARS-CoV-2 immune escape mutations over a period of seven months in an immunocompromised patient with prolonged viral shedding. Signs of infection, viral shedding and mutation events are periodically analyzed using RT-PCR and next-generation sequencing based on naso-pharyngeal swabs, with the results complemented by immunological diagnostics to determine humoral and T cell immune responses. Throughout the infection course, 17 non-synonymous intra-host mutations are noted, with 15 (88.2%) having been previously described as prominent immune escape mutations (S:E484K, S:D950N, S:P681H, S:N501Y, S:del(9), N:S235F and S:H655Y) in VOCs. The high frequency of these non-synonymous mutations is consistent with multiple events of convergent evolution. Thus, our results suggest that specific mutations in the SARS-CoV-2 genome may represent positions with a fitness advantage, and may serve as targets in future vaccine and therapeutics development for COVID-19.
Long-read sequencing unveils high-resolution HPV integration and its oncogenic progression in cervical cancer
Authors: Zhou Liyuan , Qiu Qiongzi , Zhou Qing , Li Jianwei , Yu Mengqian , Li Kezhen , Xu Lingling , Ke Xiaohui , Xu Haiming , Lu Bingjian , Wang Hui , Lu Weiguo , Liu Pengyuan , Lu Yan 
Published: May 2022

AbstractIntegration of human papillomavirus (HPV) DNA into the human genome is considered as a key event in cervical carcinogenesis. Here, we perform comprehensive characterization of large-range virus-human integration events in 16 HPV16-positive cervical tumors using the Nanopore long-read sequencing technology. Four distinct integration types characterized by the integrated HPV DNA segments are identified with Type B being particularly notable as lacking E6/E7 genes. We further demonstrate that multiple clonal integration events are involved in the use of shared breakpoints, the induction of inter-chromosomal translocations and the formation of extrachromosomal circular virus-human hybrid structures. Combined with the corresponding RNA-seq data, we highlight LINC00290, LINC02500 and LENG9 as potential driver genes in cervical cancer. Finally, we reveal the spatial relationship of HPV integration and its various structural variations as well as their functional consequences in cervical cancer. These findings provide insight into HPV integration and its oncogenic progression in cervical cancer.
Profiling of hMPV F-specific antibodies isolated from human memory B cells
Authors: Xiao Xiao , Fridman Arthur , Zhang Lu , Pristatsky Pavlo , Durr Eberhard , Minnier Michael , Tang Aimin , Cox Kara S. , Wen Zhiyun , Moore Renee , Tian Dongrui , Galli Jennifer D. , Cosmi Scott , Eddins Michael J. , Sullivan Nicole L. , Yan Xiaodong , Bett Andrew J. , Su Hua-Poo , Vora Kalpit A. , Chen Zhifeng , Zhang Lan 
Published: May 2022

AbstractHuman metapneumovirus (hMPV) belongs to thePneumoviridaefamily and is closely related to respiratory syncytial virus (RSV). The surface fusion (F) glycoprotein mediates viral fusion and is the primary target of neutralizing antibodies against hMPV. Here we report 113 hMPV-F specific monoclonal antibodies (mAbs) isolated from memory B cells of human donors. We characterize the antibodies’ germline usage, epitopes, neutralization potencies, and binding specificities. We find that unlike RSV-F specific mAbs, antibody responses to hMPV F are less dominant against the apex of the antigen, and the majority of the potent neutralizing mAbs recognize epitopes on the side of hMPV F. Furthermore, neutralizing epitopes that differ from previously defined antigenic sites on RSV F are identified, and multiple binding modes of site V and II mAbs are discovered. Interestingly, mAbs that bind preferentially to the unprocessed prefusion F show poor neutralization potency. These results elucidate the immune recognition of hMPV infection and provide novel insights for future hMPV antibody and vaccine development.
Mutual exclusivity of ESR1 and TP53 mutations in endocrine resistant metastatic breast cancer
Authors: Li Zheqi , Spoelstra Nicole S. , Sikora Matthew J. , Sams Sharon B. , Elias Anthony , Richer Jennifer K. , Lee Adrian V. , Oesterreich Steffi 
Published: May 2022

AbstractBothTP53andESR1mutations occur frequently in estrogen receptor positive (ER+) metastatic breast cancers (MBC) and their distinct roles in breast cancer tumorigenesis and progression are well appreciated. Recent clinical studies discovered mutual exclusivity betweenTP53andESR1mutations in metastatic breast cancers; however, mechanisms underlying this intriguing clinical observation remain largely understudied and unknown. Here, we explored the interplay betweenTP53andESR1mutations using publicly available clinical and experimental data sets. We first confirmed the robust mutational exclusivity using six independent cohorts with 1,056 ER+ MBC samples and found that the exclusivity broadly applies to all ER+ breast tumors regardless of their clinical and distinct mutational features.ESR1mutant tumors do not exhibit differential p53 pathway activity, whereas we identified attenuated ER activity and expression inTP53mutant tumors, driven by a p53-associated E2 response gene signature. Further, 81% of these p53-associated E2 response genes are either direct targets of wild-type (WT) p53-regulated transactivation or are mutant p53-associated microRNAs, representing bimodal mechanisms of ER suppression. Lastly, we analyzed the very rare cases with co-occurrences ofTP53andESR1mutations and found that their simultaneous presence was also associated with reduced ER activity. In addition, tumors with dual mutations showed higher levels of total and PD-L1 positive macrophages. In summary, our study utilized multiple publicly available sources to explore the mechanism underlying the mutual exclusivity betweenESR1andTP53mutations, providing further insights and testable hypotheses of the molecular interplay between these two pivotal genes in ER+ MBC.
Uncertainty about others’ trustworthiness increases during adolescence and guides social information sampling
Authors: Ma I. , Westhoff B. , van Duijvenvoorde A. C. K. 
Published: May 2022

AbstractAdolescence is a key life phase for developing well-adjusted social behaviour. An essential component of well-adjusted social behaviour is the ability to update our beliefs about the trustworthiness of others based on gathered information. Here, we examined how adolescents (n = 157, 10–24 years) sequentially sampled information about the trustworthiness of peers and how they used this information to update their beliefs about others’ trustworthiness. Our Bayesian computational modelling approach revealed an adolescence-emergent increase in uncertainty of prior beliefs about others’ trustworthiness. As a consequence, early to mid-adolescents (ages 10–16) gradually relied less on their prior beliefs and more on the gathered evidence when deciding to sample more information, and when deciding to trust. We propose that these age-related differences could be adaptive to the rapidly changing social environment of early and mid-adolescents. Together, these findings contribute to the understanding of adolescent social development by revealing adolescent-emergent flexibility in prior beliefs about others that drives adolescents’ information sampling and trust decisions.
Novel mobility index tracks COVID-19 transmission following stay-at-home orders
Authors: Her Peter Hyunwuk , Saeed Sahar , Tram Khai Hoan , Bhatnagar Sahir R 
Published: May 2022

AbstractConsidering the emergence of SARS-CoV-2 variants and low vaccine access and uptake, minimizing human interactions remains an effective strategy to mitigate the spread of SARS-CoV-2. Using a functional principal component analysis, we created a multidimensional mobility index (MI) using six metrics compiled by SafeGraph from all counties in Illinois, Ohio, Michigan and Indiana between January 1 to December 8, 2020. Changes in mobility were defined as a time-updated 7-day rolling average. Associations between our MI and COVID-19 cases were estimated using a quasi-Poisson hierarchical generalized additive model adjusted for population density and the COVID-19 Community Vulnerability Index. Individual mobility metrics varied significantly by counties and by calendar time. More than 50% of the variability in the data was explained by the first principal component by each state, indicating good dimension reduction. While an individual metric of mobility was not associated with surges of COVID-19, our MI was independently associated with COVID-19 cases in all four states given varying time-lags. Following the expiration of stay-at-home orders, a single metric of mobility was not sensitive enough to capture the complexity of human interactions. Monitoring mobility can be an important public health tool, however, it should be modelled as a multidimensional construct.
Memory-inspired spiking hyperdimensional network for robust online learning
Authors: Zou Zhuowen , Alimohamadi Haleh , Zakeri Ali , Imani Farhad , Kim Yeseong , Najafi M. Hassan , Imani Mohsen 
Published: May 2022

AbstractRecently, brain-inspired computing models have shown great potential to outperform today’s deep learning solutions in terms of robustness and energy efficiency. Particularly, Spiking Neural Networks (SNNs) and HyperDimensional Computing (HDC) have shown promising results in enabling efficient and robust cognitive learning. Despite the success, these two brain-inspired models have different strengths. While SNN mimics the physical properties of the human brain, HDC models the brain on a more abstract and functional level. Their design philosophies demonstrate complementary patterns that motivate their combination. With the help of the classical psychological model on memory, we propose SpikeHD, the first framework that fundamentally combines Spiking neural network and hyperdimensional computing. SpikeHD generates a scalable and strong cognitive learning system that better mimics brain functionality. SpikeHD exploits spiking neural networks to extract low-level features by preserving the spatial and temporal correlation of raw event-based spike data. Then, it utilizes HDC to operate over SNN output by mapping the signal into high-dimensional space, learning the abstract information, and classifying the data. Our extensive evaluation on a set of benchmark classification problems shows that SpikeHD provides the following benefit compared to SNN architecture: (1) significantly enhance learning capability by exploiting two-stage information processing, (2) enables substantial robustness to noise and failure, and (3) reduces the network size and required parameters to learn complex information.
Importance of vaccine action and availability and epidemic severity for delaying the second vaccine dose
Authors: Berec Luděk , Levínský René , Weiner Jakub , Šmíd Martin , Neruda Roman , Vidnerová Petra , Suchopárová Gabriela 
Published: May 2022

AbstractFollowing initial optimism regarding potentially rapid vaccination, delays and shortages in vaccine supplies occurred in many countries during spring 2021. Various strategies to counter this gloomy reality and speed up vaccination have been set forth, of which the most popular has been to delay the second vaccine dose for a longer period than originally recommended by the manufacturers. Controversy has surrounded this strategy, and overly simplistic models have been developed to shed light on this issue. Here we use three different epidemic models, all accounting for then actual COVID-19 epidemic in the Czech Republic, including the real vaccination rollout, to explore when delaying the second vaccine dose by another 3 weeks from 21 to 42 days is advantageous. Using COVID-19-related deaths as a quantity to compare various model scenarios, we find that the way of vaccine action at the beginning of the infection course (preventing infection and symptoms appearance), mild epidemic and sufficient vaccine supply rate call for the original inter-dose period of 21 days regardless of vaccine efficacy. On the contrary, for the vaccine action at the end of infection course (preventing severe symptoms and death), severe epidemic and low vaccine supply rate, the 42-day inter-dose period is preferable, at any plausible vaccine efficacy.
Exploring selective autophagy events in multiple biologic models using LC3-interacting regions (LIR)-based molecular traps
Authors: Quinet Grégoire , Génin Pierre , Ozturk Oznur , Belgareh-Touzé Naima , Courtot Lilas , Legouis Renaud , Weil Robert , Cohen Mickael M. , Rodriguez Manuel S. 
Published: May 2022

AbstractAutophagy is an essential cellular pathway that ensures degradation of a wide range of substrates including damaged organelles or large protein aggregates. Understanding how this proteolytic pathway is regulated would increase our comprehension on its role in cellular physiology and contribute to identify biomarkers or potential drug targets to develop more specific treatments for disease in which autophagy is dysregulated. Here, we report the development of molecular traps based in the tandem disposition of LC3-interacting regions (LIR). The estimated affinity of LC3-traps for distinct recombinant LC3/GABARAP proteins is in the low nanomolar range and allows the capture of these proteins from distinct mammalian cell lines, S. cerevisiae and C. elegans. LC3-traps show preferences for GABARAP/LGG1 or LC3/LGG2 and pull-down substrates targeted to proteaphagy and mitophagy. Therefore, LC3-traps are versatile tools that can be adapted to multiple applications to monitor selective autophagy events in distinct physiologic and pathologic circumstances.
Novel fabrication of hydrophobic/oleophilic human hair fiber for efficient oil/water separation through one-pot dip-coating synthesis route
Authors: Chenxi Yang , Jian Wang , Haiou Zhang , Tingting Cao , Hang Zhou , Jiawei Wang , Bo Bai 
Published: May 2022

AbstractFrequent oil spill accidents and industrial wastewater discharge has always been one of the most severe worldwide environmental problems. To cope with this problem, many fluorine-containing and high-cost materials with superwettability have been extensively applied for oil–water separation, which hinders its large-scale application. In this work, a novel human hair fiber (HHF)-polymerized octadecylsiloxane (PODS) fiber was fabricated with a facile one-pot dip-coating synthesis approach, inspired by the self-assembly performance and hydrophobicity of OTS modification. The benefits of prominent hydrophobic/lipophilic behavior lie in the low surface energy, and a rough PODS coating was rationally adhered on the surface of HHF. Driven solely by gravity and capillary force, the HHF-PODS showed excellent oil/water separation efficiency (> 99.0%) for a wide range of heavy and light oil/water mixtures. In addition, HHF-PODS demonstrated durability toward different harsh environments like alkaline, acid, and salty solutions.
Potential cosmeceutical lamellar liquid crystals containing black longan (Dimocarpus longan Lour.) seed extract for MMP-1 and hyaluronidase inhibition
Authors: Hong-in Preaploy , Chaiyana Wantida 
Published: May 2022

AbstractThe aims of this study were to evaluate the biological activities of black Dimocarpus longan Lour. seed extracts and develop a lamellar liquid crystal (LLC). Different solvents, including petroleum ether, ethyl acetate, and 95% v/v ethanol, were used in the maceration of black D. longan seeds. The inhibitory activities on matrix metalloproteinase-1 (MMP-1) and hyaluronidase were evaluated. The irritating potency of D. longan seed extracts was determined using the hen's egg chorioallantoic membrane test. The extract with the strongest anti-ageing activities and no irritant impact was examined for its chemical contents using high-performance liquid chromatography and incorporated into the LLC. Various factors affecting the LLC formulations, including surfactant types and amounts, thickening agent types and amounts, and various oil types, were investigated. The results demonstrated that the ethyl acetate extract (EtOAc) was the most potent inhibitor of MMP-1 (IC50 = 21.7 ± 5.4 µg/mL) and hyaluronidase (oleanolic acid equivalent = 0.44 ± 0.03 g per g extract). Interestingly, its MMP-1 inhibition was equivalent to that of oleanolic acid, corilagin, and gallic acid. Furthermore, its hyaluronidase inhibition was equivalent to that of gallic acid and ellagic acid. Gallic acid, which was the most abundant compound (15.6% ± 0.06% w/w) was suggested as the compound responsible for the biological activities of EtOAc extract. Considering its potential anti-skin ageing properties with no irritation of EtOAc extract, it was incorporated into the most suitable LLC, which was composed of 5% w/w Lexfeel® D5 oil, 0.5% w/w Carbopol® U21, 2% w/w Liquid Crystal Cream Maker, and 92.5% w/w DI water. The LLC containing EtOAc extract presented birefringence under a polarizing light microscope, indicating its crystallinity. The formulation had good stability after heating–cooling cycles in terms of external appearance, crystallinity, viscosity, and pH (5.5). As a result, it is recommended as a potential cosmeceutical formulation for anti-skin wrinkling. It is proposed that more research be conducted on the safety and efficacy of the treatment on human volunteers.
Photokinetics of Dacarbazine and Nifedipine under polychromatic light irradiation and their application as new reliable actinometers for the ultraviolet range
Authors: Maafi Mounir , Al-Qarni Mohammed Ahmed 
Published: May 2022

AbstractThe photokinetic behaviour of drugs driven by polychromatic light is an area of pharmaceutics that has not received a lot of attention. Most often, such photokinetic data is treated by thermal kinetic models (i.e., the classical 0th-, 1st- or 2nd-order equations). Such models were not analytically derived from the rate-laws of the photodegradation reactions. Polychromatic light kinetic modelling is hence of importance, as a means to providing adequate toolkits and metrics. This paper aims at proposing two reliable drug-actinometers useful for polychromatic UVA range. The general actinometric methodology offered here is also useful for any drugs/materials obeying a primary photoprocess where both reactant and photoproduct absorb the incident light, of the $$AB{(1\Phi )}_{{\varepsilon }_{B}\ne 0}$$

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type. The present method has been consolidated by the η-order kinetics. This framework further demonstrated the lamp-specificity of actinometers. Overall, Dacarbazine and Nifedipine photodegradations obeyed η-order kinetics, and stand as effective actinometers that can be recommended for the ICH Q1b photostability testing.