bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanistic studies of a lipase unveil effect of pH on hydrolysis products of small PET modules
Authors: Świderek Katarzyna , Velasco-Lozano Susana , Galmés Miquel À. , Olazabal Ion , Sardon Haritz , López-Gallego Fernando , Moliner Vicent 
Published: June 2023

AbstractBiocatalysis is a key technology enabling plastic recycling. However, despite advances done in the development of plastic-degrading enzymes, the molecular mechanisms that govern their catalytic performance are poorly understood, hampering the engineering of more efficient enzyme-based technologies. In this work, we study the hydrolysis of PET-derived diesters and PET trimers catalyzed by the highly promiscuous lipase B from Candida antarctica (CALB) through QM/MM molecular dynamics simulations supported by experimental Michaelis–Menten kinetics. The computational studies reveal the role of the pH on the CALB regioselectivity toward the hydrolysis of bis-(hydroxyethyl) terephthalate (BHET). We exploit this insight to perform a pH-controlled biotransformation that selectively hydrolyzes BHET to either its corresponding diacid or monoesters using both soluble and immobilized CALB. The discoveries presented here can be exploited for the valorization of BHET resulting from the organocatalytic depolymerization of PET.
Gold-catalyzed four-component multifunctionalization of alkynes
Authors: Fang Shangwen , Han Jie , Zhu Chengjian , Li Weipeng , Xie Jin 
Published: June 2023

AbstractThe alkyne unit is a versatile building block in organic synthesis and the development of selective multifunctionalization of alkynes is an important object of research in this field. Herein, we report an interesting gold-catalyzed, four-component reaction that achieves the oxo-arylfluorination or oxo-arylalkenylation of internal aromatic or aliphatic alkynes, efficiently breaking a carbon-carbon triple bond and forming four new chemical bonds. The reaction divergence can be controlled by site-directing functional groups in the alkynes; the presence of a phosphonate unit favors the oxo-arylfluorination, while the carboxylate motif benefits oxo-arylalkenylation. This reaction is enabled by an Au(I)/Au(III) redox coupling process using Selectfluor as both an oxidant and a fluorinating reagent. A wide range of structurally diverse α,α-disubstituted ketones, and tri- or tetra-substituted unsaturated ketones have been prepared in synthetically valuable yields and with excellent chemo-, regio- and stereoselectivity. The gram-scale preparation and late-stage application of complex alkynes have further enhanced their synthetic value.
N-Acryloylindole-alkyne (NAIA) enables imaging and profiling new ligandable cysteines and oxidized thiols by chemoproteomics
Authors: Koo Tin-Yan , Lai Hinyuk , Nomura Daniel K. , Chung Clive Yik-Sham 
Published: June 2023

AbstractCysteine has been exploited as the binding site of covalent drugs. Its high sensitivity to oxidation is also important for regulating cellular processes. To identify new ligandable cysteines which can be hotspots for therapy and to better study cysteine oxidations, we develop cysteine-reactive probes,N-acryloylindole-alkynes (NAIAs), which have superior cysteine reactivity owing to delocalization of π electrons of the acrylamide warhead over the whole indole scaffold. This allows NAIAs to probe functional cysteines more effectively than conventional iodoacetamide-alkyne, and to image oxidized thiols by confocal fluorescence microscopy. In mass spectrometry experiments, NAIAs successfully capture new oxidized cysteines, as well as a new pool of ligandable cysteines and proteins. Competitive activity-based protein profiling experiments further demonstrate the ability of NAIA to discover lead compounds targeting these cysteines and proteins. We show the development of NAIAs with activated acrylamide for advancing proteome-wide profiling and imaging ligandable cysteines and oxidized thiols.
Reaction performance prediction with an extrapolative and interpretable graph model based on chemical knowledge
Authors: Li Shu-Wen , Xu Li-Cheng , Zhang Cheng , Zhang Shuo-Qing , Hong Xin 
Published: June 2023

AbstractAccurate prediction of reactivity and selectivity provides the desired guideline for synthetic development. Due to the high-dimensional relationship between molecular structure and synthetic function, it is challenging to achieve the predictive modelling of synthetic transformation with the required extrapolative ability and chemical interpretability. To meet the gap between the rich domain knowledge of chemistry and the advanced molecular graph model, herein we report a knowledge-based graph model that embeds the digitalized steric and electronic information. In addition, a molecular interaction module is developed to enable the learning of the synergistic influence of reaction components. In this study, we demonstrate that this knowledge-based graph model achieves excellent predictions of reaction yield and stereoselectivity, whose extrapolative ability is corroborated by additional scaffold-based data splittings and experimental verifications with new catalysts. Because of the embedding of local environment, the model allows the atomic level of interpretation of the steric and electronic influence on the overall synthetic performance, which serves as a useful guide for the molecular engineering towards the target synthetic function. This model offers an extrapolative and interpretable approach for reaction performance prediction, pointing out the importance of chemical knowledge-constrained reaction modelling for synthetic purpose.
Structural insight into the human SID1 transmembrane family member 2 reveals its lipid hydrolytic activity
Authors: Qian Dandan , Cong Ye , Wang Runhao , Chen Quan , Yan Chuangye , Gong Deshun 
Published: June 2023

AbstractThe systemic RNAi-defective (SID) transmembrane family member 2 (SIDT2) is a putative nucleic acid channel or transporter that plays essential roles in nucleic acid transport and lipid metabolism. Here, we report the cryo-electron microscopy (EM) structures of human SIDT2, which forms a tightly packed dimer with extensive interactions mediated by two previously uncharacterized extracellular/luminal β-strand-rich domains and the unique transmembrane domain (TMD). The TMD of each SIDT2 protomer contains eleven transmembrane helices (TMs), and no discernible nucleic acid conduction pathway has been identified within the TMD, suggesting that it may act as a transporter. Intriguingly, TM3-6 and TM9-11 form a large cavity with a putative catalytic zinc atom coordinated by three conserved histidine residues and one aspartate residue lying approximately 6 Å from the extracellular/luminal surface of the membrane. Notably, SIDT2 can hydrolyze C18 ceramide into sphingosine and fatty acid with a slow rate. The information presented advances the understanding of the structure-function relationships in the SID1 family proteins.
Dopamine and vesicular monoamine transport loss supports incidental Lewy body disease as preclinical idiopathic Parkinson
Authors: Pifl Christian , Reither Harald , Attems Johannes , Zecca Luigi 
Published: June 2023

AbstractIncidental Lewy body disease (ILBD) is a neuropathological diagnosis of brains with Lewy bodies without clinical neuropsychiatric symptoms. Dopaminergic deficits suggest a relationship to preclinical Parkinson’s disease (PD). We now report a subregional pattern of striatal dopamine loss in ILBD cases, with dopamine found significantly decreased in the putamen (−52%) and only to a lower extent in the caudate (−38%, not statistically significant); this is similar to the pattern in idiopathic PD in various neurochemical and in vivo imaging studies. We aimed to find out if our recently reported impaired storage of dopamine in striatal synaptic vesicles prepared from striatal tissue of cases with idiopathic PD might be an early or even causative event. We undertook parallel measurements of [3H]dopamine uptake and vesicular monoamine transporter (VMAT)2 binding sites by the specific label [3H]dihydrotetrabenazine on vesicular preparation from caudate and putamen in ILBD. Neither specific uptake of dopamine and binding of [3H]dihydrotetrabenazine, nor mean values of the calculated ratios of dopamine uptake and VMAT2 binding, a measure of uptake rate per transport site, were significantly different between ILBD and controls. ATP-dependence of [3H]dopamine uptake revealed significantly higher rates in putamen than in caudate at saturating concentrations of ATP in controls, a subregional difference lost in ILBD. Our findings support a loss of the normally higher VMAT2 activity in putamen as a contributing factor to the higher susceptibility of the putamen to dopamine depletion in idiopathic PD. Moreover, we suggest ILBD postmortem tissue as a valuable source for testing hypotheses on processes in idiopathic PD.
A locally activatable sensor for robust quantification of organellar glutathione
Authors: Emmert Sarah , Quargnali Gianluca , Thallmair Sebastian , Rivera-Fuentes Pablo 
Published: June 2023

AbstractGlutathione (GSH) is the main determinant of intracellular redox potential and participates in multiple cellular signalling pathways. Achieving a detailed understanding of intracellular GSH homeostasis depends on the development of tools to map GSH compartmentalization and intra-organelle fluctuations. Here we present a GSH-sensing platform for live-cell imaging, termed targetable ratiometric quantitative GSH (TRaQ-G). This chemogenetic sensor possesses a unique reactivity turn-on mechanism, ensuring that the small molecule is only sensitive to GSH in a desired location. Furthermore, TRaQ-G can be fused to a fluorescent protein to give a ratiometric response. Using TRaQ-G fused to a redox-insensitive fluorescent protein, we demonstrate that the nuclear and cytosolic GSH pools are independently regulated during cell proliferation. This sensor was used in combination with a redox-sensitive fluorescent protein to quantify redox potential and GSH concentration simultaneously in the endoplasmic reticulum. Finally, by exchanging the fluorescent protein, we created a near-infrared, targetable and quantitative GSH sensor.
Mechanistic basis for potent neutralization of Sin Nombre hantavirus by a human monoclonal antibody
Authors: Stass Robert , Engdahl Taylor B. , Chapman Nathaniel S. , Wolters Rachael M. , Handal Laura S. , Diaz Summer M. , Crowe James E. , Bowden Thomas A. 
Published: June 2023

AbstractRodent-borne hantaviruses are prevalent worldwide and upon spillover to human populations, cause severe disease for which no specific treatment is available. A potent antibody response is key for recovery from hantavirus infection. Here we study a highly neutralizing human monoclonal antibody, termed SNV-42, which was derived from a memory B cell isolated from an individual with previous Sin Nombre virus (SNV) infection. Crystallographic analysis demonstrates that SNV-42 targets the Gn subcomponent of the tetrameric (Gn−Gc)4 glycoprotein assembly that is relevant for viral entry. Integration of our 1.8 Å structure with the (Gn−Gc)4 ultrastructure arrangement indicates that SNV-42 targets the membrane-distal region of the virus envelope. Comparison of the SNV-42 paratope encoding variable genes with inferred germline gene segments reveals high sequence conservation, suggesting that germline-encoded antibodies inhibit SNV. Furthermore, mechanistic assays reveal that SNV-42 interferes with both receptor recognition and fusion during host-cell entry. This work provides a molecular-level blueprint for understanding the human neutralizing antibody response to hantavirus infection.
A dataset of micro biodiversity in benthic sediment at a global scale
Authors: Sun Xumei , Jiang Danni , Shao Yina , Zhang Siyuan 
Published: June 2023

AbstractMicroorganisms, occupying the largest biomass in deep sea, play essential roles in deep-sea ecosystem. It is believed that the microbes in deep-sea sediments are more representative of deep-sea microbial communities, the microbial composition of which is seldom affected by ocean currents. However, the community of benthic microbes on a global scale has not been adequately explored. Herein, we build a comprehensive global dataset determined by 16S rRNA gene sequencing to characterize the biodiversity of microorganisms in benthic sediment. The dataset comprised 212 records from 106 sites, included sequencing of bacteria and archaea for each site and yielded 4,766,502 and 1,562,989 reads, respectively. Through annotation, a total of 110,073 and 15,795 OTUs of bacteria and archaea were obtained, and 61 bacterial phyla and 15 archaeal phyla were identified, of which the dominant phyla were Proteobacteria and Thaumarchaeota in deep-sea sediment. Therefore, our findings provided a biodiversity data of microbial communities in deep-sea sediment at global-scale and laid a foundation to further reveal the structures of microorganism communities in deep sea.
A computational approach to design a polyvalent vaccine against human respiratory syncytial virus
Authors: Moin Abu Tayab , Ullah Md. Asad , Patil Rajesh B. , Faruqui Nairita Ahsan , Araf Yusha , Das Sowmen , Uddin Khaza Md. Kapil , Hossain Md. Shakhawat , Miah Md. Faruque , Moni Mohammad Ali , Chowdhury Dil Umme Salma , Islam Saiful 
Published: June 2023

AbstractHuman Respiratory Syncytial Virus (RSV) is one of the leading causes of lower respiratory tract infections (LRTI), responsible for infecting people from all age groups—a majority of which comprises infants and children. Primarily, severe RSV infections are accountable for multitudes of deaths worldwide, predominantly of children, every year. Despite several efforts to develop a vaccine against RSV as a potential countermeasure, there has been no approved or licensed vaccine available yet, to control the RSV infection effectively. Therefore, through the utilization of immunoinformatics tools, a computational approach was taken in this study, to design a multi-epitope polyvalent vaccine against two major antigenic subtypes of RSV, RSV-A and RSV-B. Potential predictions of the T-cell and B-cell epitopes were followed by extensive tests of antigenicity, allergenicity, toxicity, conservancy, homology to human proteome, transmembrane topology, and cytokine-inducing ability. The peptide vaccine was modeled, refined, and validated. Molecular docking analysis with specific Toll-like receptors (TLRs) revealed excellent interactions with suitable global binding energies. Additionally, molecular dynamics (MD) simulation ensured the stability of the docking interactions between the vaccine and TLRs. Mechanistic approaches to imitate and predict the potential immune response generated by the administration of vaccines were determined through immune simulations. Subsequent mass production of the vaccine peptide was evaluated; however, there remains a necessity for further in vitro and in vivo experiments to validate its efficacy against RSV infections.
Predicting the relationship between pesticide genotoxicity and breast cancer risk in South Indian women in in vitro and in vivo experiments
Authors: Sasikala S. , Minu Jenifer M. , Velavan K. , Sakthivel M. , Sivasamy R. , Fenwick Antony E. R. 
Published: June 2023

AbstractBreast cancer is the third most common cancer in women after skin and lung cancer. Pesticides are of interest in etiologic studies of breast cancer because many pesticides mimic estrogen, a known breast cancer risk factor. In this study, we discerned the toxic role of the pesticides atrazine, dichlorvos, and endosulfan in inducing breast cancer. Various experimental studies, such as biochemical profiling of pesticide-exposed blood samples, comet assays, karyotyping analysis, pesticide and DNA interaction analysis by molecular docking, DNA cleavage, and cell viability assays, have been carried out. Biochemical profiling showed an increased level of blood sugar, WBC, hemoglobin, and blood urea in the patient exposed to pesticides for more than 15 years. The comet assay for DNA damage performed on patients exposed to pesticides and pesticide-treated blood samples revealed more DNA damage at the 50 ng concentration of all three pesticides. Karyotyping analysis showed enlargements in the heterochromatin region and 14pstk+, and 15pstk+in the exposed groups. In molecular docking analysis, atrazine had the highest glide score (− 5.936) and glide energy (− 28.690), which reveals relatively high binding capability with the DNA duplex. The DNA cleavage activity results showed that atrazine caused higher DNA cleavage than the other two pesticides. Cell viability was the lowest at 50 ng/ml (72 h). Statistical analysis performed using SPSS software unveiled a positive correlation (< 0.05) between pesticide exposure and breast cancer. Our findings support attempts to minimize pesticide exposure.
Drug resistance related genes in lung adenocarcinoma predict patient prognosis and influence the tumor microenvironment
Authors: Yu Hui , Zhang Wenting , Xu Xian Rong , Chen Shengjie 
Published: June 2023

AbstractLung adenocarcinoma (LUAD) is the predominant type of non-small lung cancer (NSCLC) with strong invasive ability and poor prognosis. The drug resistance related genes are potentially associated with prognosis of LUAD. Our research aimed to identify the drug resistance related genes and explore their potential prognostic value in LUAD patients. The data used in this study were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Firstly, we screened drug resistance related genes in LUAD by differential gene analysis, univariate Cox regression and drug sensitivity analyses. Subsequently, we constructed a risk score model using LASSO Cox regression analysis, and verified whether the risk score can predict the survival of LUAD patients independent of other factors. Moreover, we explored the immune infiltration of 22 immune cells between high-risk and low-risk patients. Totally 10 drug-resistance positively related genes (PLEK2, TFAP2A, KIF20A, S100P, GDF15, HSPB8, SASH1, WASF3, LAMA3 and TCN1) were identified in LUAD. The risk score model of LUAD constructed with these 10 genes could reliably predict the prognosis of LUAD patients. 18 pathways were significantly activated in high-risk group compared with low-risk group. In addition, the infiltration proportion of multiple immune cells was significantly different between high-risk and low-risk groups, and the proportion of M1 phagocytes was significantly higher in the high-risk group compared with the low-risk group. The drug resistance related genes (PLEK2, TFAP2A, KIF20A, S100P, GDF15, HSPB8, SASH1, WASF3, LAMA3 and TCN1) could predict the prognosis of LUAD patients. Clarifying the roles and mechanisms of these 10 genes in regulating drug resistance in LUAD will help to improve individualized clinical treatment protocols and predict patient sensitivity to treatment.
The impact of small-scale green infrastructure on the affective wellbeing associated with urban sites
Authors: Navarrete-Hernandez Pablo , Laffan Kate 
Published: June 2023

AbstractThe largest public space in any city is its streets. Investments which incorporate small-scale green infrastructure into streetscapes can bring more nature into the lives of urban residents worldwide, including those living in even the most economically and spatially constraint places. However, little is known about the impact of such small-scale investments on urban residents’ affective perceptions of their local environments and how to design these investments to maximise their positive impacts. In the current study, we use photo simulation techniques and an adapted form of the Positive and Negative Affective Schedule to examine the impact of small-scale green infrastructure interventions on the affective perceptions of low, middle and high-income sites in Santiago Chile. Our results, based on 62,478 reports of affective perceptions from 3,472 people, indicate that green infrastructure investments can both promote positive affect and, to a lesser, but still substantial extent reduce negative affect. The magnitudes of these relationships vary across discrete affective measures and for many of these measures, both positive and negative, a minimum of 16% increase in green coverage is required to see an impact. Finally, we find people associated lower affect with low, compared to middle and high, income sites but that these affective inequalities can be addressed, at least in part, through green infrastructure interventions.
Remodeling of the focal adhesion complex by hydrogen-peroxide-induced senescence
Authors: Grandy Carolin , Port Fabian , Radzinski Meytal , Singh Karmveer , Erz Dorothee , Pfeil Jonas , Reichmann Dana , Gottschalk Kay-Eberhard 
Published: June 2023

AbstractCellular senescence is a phenotype characterized by cessation of cell division, which can be caused by exhaustive replication or environmental stress. It is involved in age-related pathophysiological conditions and affects both the cellular cytoskeleton and the prime cellular mechanosensors, focal adhesion complexes. While the size of focal adhesions increases during senescence, it is unknown if and how this is accompanied by a remodeling of the internal focal adhesion structure. Our study uses metal-induced energy transfer to study the axial dimension of focal adhesion proteins from oxidative-stress-induced senescent cells with nanometer precision, and compares these to unstressed cells. We influenced cytoskeletal tension and the functioning of mechanosensitive ion channels using drugs and studied the combined effect of senescence and drug intervention on the focal adhesion structure. We found that H2O2-induced restructuring of the focal adhesion complex indicates a loss of tension and altered talin complexation. Mass spectroscopy-based proteomics confirmed the differential regulation of several cytoskeletal proteins induced by H2O2 treatment.