bluuebunny/crossref_metadata_2025 huggingface dataset:
Novel 1-hydroxy phenothiazinium-based derivative protects against bacterial sepsis by inhibiting AAK1-mediated LPS internalization and caspase-11 signaling
Authors: Yuan Chuang , Ai Kelong , Xiang Menghua , Xie Chengliang , Zhao Mingyi , Wu Ming , Li Hongli , Wu Yueren , Cao Yueqing , Li Can , Zhong Yanjun , Pei Xiaomeng , Law Helen Ka Wai , Gao Liqian , Xiao Qicai , Yang Xinyu
Published: August 2022

Sepsis is a life-threatening syndrome with disturbed host responses to severe infections, accounting for the majority of death in hospitalized patients. However, effective medicines are currently scant in clinics due to the poor understanding of the exact underlying mechanism. We previously found that blocking caspase-11 pathway (human orthologs caspase-4/5) is effective to rescue coagulation-induced organ dysfunction and lethality in sepsis models. Herein, we screened our existing chemical pools established in our lab using bacterial outer membrane vesicle (OMV)-challenged macrophages, and found 7-(diethylamino)-1-hydroxy-phenothiazin-3-ylidene-diethylazanium chloride (PHZ-OH), a novel phenothiazinium-based derivative, was capable of robustly dampening caspase-11-dependent pyroptosis. The in-vitro study both in physics and physiology showed that PHZ-OH targeted AP2-associated protein kinase 1 (AAK1) and thus prevented AAK1-mediated LPS internalization for caspase-11 activation. By using a series of gene-modified mice, our in-vivo study further demonstrated that administration of PHZ-OH significantly protected mice against sepsis-associated coagulation, multiple organ dysfunction, and death. Besides, PHZ-OH showed additional protection on Nlrp3−/− and Casp1−/− mice but not on Casp11−/−, Casp1/11−/−, Msr1−/−, and AAK1 inhibitor-treated mice. These results suggest the critical role of AAK1 on caspase-11 signaling and may provide a new avenue that targeting AAK1-mediated LPS internalization would be a promising therapeutic strategy for sepsis. In particular, PHZ-OH may serve as a favorable molecule and an attractive scaffold in future medicine development for efficient treatment of bacterial sepsis.
Oral administration of Blautia wexlerae ameliorates obesity and type 2 diabetes via metabolic remodeling of the gut microbiota
Authors: Hosomi Koji , Saito Mayu , Park Jonguk , Murakami Haruka , Shibata Naoko , Ando Masahiro , Nagatake Takahiro , Konishi Kana , Ohno Harumi , Tanisawa Kumpei , Mohsen Attayeb , Chen Yi-An , Kawashima Hitoshi , Natsume-Kitatani Yayoi , Oka Yoshimasa , Shimizu Hidenori , Furuta Mari , Tojima Yoko , Sawane Kento , Saika Azusa , Kondo Saki , Yonejima Yasunori , Takeyama Haruko , Matsutani Akira , Mizuguchi Kenji , Miyachi Motohiko , Kunisawa Jun
Published: August 2022

The gut microbiome is an important determinant in various diseases. Here we perform a cross-sectional study of Japanese adults and identify the Blautia genus, especially B. wexlerae, as a commensal bacterium that is inversely correlated with obesity and type 2 diabetes mellitus. Oral administration of B. wexlerae to mice induce metabolic changes and anti-inflammatory effects that decrease both high-fat diet–induced obesity and diabetes. The beneficial effects of B. wexlerae are correlated with unique amino-acid metabolism to produce S-adenosylmethionine, acetylcholine, and l-ornithine and carbohydrate metabolism resulting in the accumulation of amylopectin and production of succinate, lactate, and acetate, with simultaneous modification of the gut bacterial composition. These findings reveal unique regulatory pathways of host and microbial metabolism that may provide novel strategies in preventive and therapeutic approaches for metabolic disorders.
SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization
Authors: Mannar Dhiraj , Saville James W. , Sun Zehua , Zhu Xing , Marti Michelle M. , Srivastava Shanti S. , Berezuk Alison M. , Zhou Steven , Tuttle Katharine S. , Sobolewski Michele D. , Kim Andrew , Treat Benjamin R. , Da Silva Castanha Priscila Mayrelle , Jacobs Jana L. , Barratt-Boyes Simon M. , Mellors John W. , Dimitrov Dimiter S. , Li Wei , Subramaniam Sriram
Published: August 2022

Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (VH ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants.
SARS-CoV-2 antibodies and breakthrough infections in the Virus Watch cohort
Authors: Aldridge Robert W. , Yavlinsky Alexei , Nguyen Vincent , Eyre Max T. , Shrotri Madhumita , Navaratnam Annalan M. D. , Beale Sarah , Braithwaite Isobel , Byrne Thomas , Kovar Jana , Fragaszy Ellen , Fong Wing Lam Erica , Geismar Cyril , Patel Parth , Rodger Alison , Johnson Anne M. , Hayward Andrew
Published: August 2022

A range of studies globally demonstrate that the effectiveness of SARS-CoV-2 vaccines wane over time, but the total effect of anti-S antibody levels on risk of SARS-CoV-2 infection and whether this varies by vaccine type is not well understood. Here we show that anti-S levels peak three to four weeks following the second dose of vaccine and the geometric mean of the samples is nine fold higher for BNT162b2 than ChAdOx1. Increasing anti-S levels are associated with a reduced risk of SARS-CoV-2 infection (Hazard Ratio 0.85; 95%CIs: 0.79-0.92). We do not find evidence that this antibody relationship with risk of infection varies by second dose vaccine type (BNT162b2 vs. ChAdOx1). In keeping with our anti-S antibody data, we find that people vaccinated with ChAdOx1 had 1.64 times the odds (95% confidence interval 1.45-1.85) of a breakthrough infection compared to BNT162b2. We anticipate our findings to be useful in the estimation of the protective effect of anti-S levels on risk of infection due to Delta. Our findings provide evidence about the relationship between antibody levels and protection for different vaccines and will support decisions on optimising the timing of booster vaccinations and identifying individuals who should be prioritised for booster vaccination, including those who are older, clinically extremely vulnerable, or received ChAdOx1 as their primary course. Our finding that risk of infection by anti-S level does not interact with vaccine type, but that individuals vaccinated with ChAdOx1 were at higher risk of infection, provides additional support for the use of using anti-S levels for estimating vaccine efficacy.
Sustained and intensified lacustrine methane cycling during Early Permian climate warming
Authors: Sun Funing , Hu Wenxuan , Cao Jian , Wang Xiaolin , Zhang Zhirong , Ramezani Jahandar , Shen Shuzhong
Published: August 2022

Lakes are a major emitter of the atmospheric greenhouse gas methane (CH4); however, their roles in past climate warming episodes remain poorly understood owing to a scarcity of geological records. Here we report the occurrence of sustained and intensified microbial CH4 cycling in paleo-Lake Junggar in northwestern China, one of the largest known Phanerozoic lakes, during Early Permian climate warming. High-precision U-Pb geochronology refines the age of the upper Lucaogou Formation to the Artinskian, which marks a major glacial-to-postglacial climate transition. The 13C-enriched authigenic dolomites indicate active methanogenesis in the anoxic lake sediments, and 13C-depleted hopanes suggest vigorous methanotrophy in the water column. The intensification of CH4 cycling coincided with increasing global temperature, as evidenced from elevated continental chemical weathering. Our results suggest that the lacustrine CH4 emissions acted as a positive feedback to global warming and contributed to the demise of the Late Paleozoic Ice Age.
Multiscale light-sheet organoid imaging framework
Authors: de Medeiros Gustavo , Ortiz Raphael , Strnad Petr , Boni Andrea , Moos Franziska , Repina Nicole , Challet Meylan Ludivine , Maurer Francisca , Liberali Prisca
Published: August 2022

Organoids provide an accessible in vitro system to mimic the dynamics of tissue regeneration and development. However, long-term live-imaging of organoids remains challenging. Here we present an experimental and image-processing framework capable of turning long-term light-sheet imaging of intestinal organoids into digital organoids. The framework combines specific imaging optimization combined with data processing via deep learning techniques to segment single organoids, their lumen, cells and nuclei in 3D over long periods of time. By linking lineage trees with corresponding 3D segmentation meshes for each organoid, the extracted information is visualized using a web-based “Digital Organoid Viewer” tool allowing combined understanding of the multivariate and multiscale data. We also show backtracking of cells of interest, providing detailed information about their history within entire organoid contexts. Furthermore, we show cytokinesis failure of regenerative cells and that these cells never reside in the intestinal crypt, hinting at a tissue scale control on cellular fidelity.
Cross-tissue analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease
Authors: C. Silva Tiago , Young Juan I. , Zhang Lanyu , Gomez Lissette , Schmidt Michael A. , Varma Achintya , Chen X. Steven , Martin Eden R. , Wang Lily
Published: August 2022

To better understand DNA methylation in Alzheimer’s disease (AD) from both mechanistic and biomarker perspectives, we performed an epigenome-wide meta-analysis of blood DNA methylation in two large independent blood-based studies in AD, the ADNI and AIBL studies, and identified 5 CpGs, mapped to theSPIDR,CDH6genes, and intergenic regions, that are significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four brain methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model includes age, sex, immune cell type proportions, and methylation risk score based on prioritized CpGs in cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 − 0.770,P-value = 2.78 × 10−5). Our study offers new insights into epigenetics in AD and provides a valuable resource for future AD biomarker discovery.
Deep reaction network exploration at a heterogeneous catalytic interface
Authors: Zhao Qiyuan , Xu Yinan , Greeley Jeffrey , Savoie Brett M.
Published: August 2022

Characterizing the reaction energies and barriers of reaction networks is central to catalyst development. However, heterogeneous catalytic surfaces pose several unique challenges to automatic reaction network characterization, including large sizes and open-ended reactant sets, that make ad hoc network construction the current state-of-the-art. Here, we show how automated network exploration algorithms can be adapted to the constraints of heterogeneous systems using ethylene oligomerization on silica-supported single-site Ga3+ as a model system. Using only graph-based rules for exploring the network and elementary constraints based on activation energy and size for identifying network terminations, a comprehensive reaction network is generated and validated against standard methods. The algorithm (re)discovers the Ga-alkyl-centered Cossee-Arlman mechanism that is hypothesized to drive major product formation while also predicting several new pathways for producing alkanes and coke precursors. These results demonstrate that automated reaction exploration algorithms are rapidly maturing towards general purpose capability for exploratory catalytic applications.
Phase-locked constructing dynamic supramolecular ionic conductive elastomers with superior toughness, autonomous self-healing and recyclability
Authors: Chen Jing , Gao Yiyang , Shi Lei , Yu Wei , Sun Zongjie , Zhou Yifan , Liu Shuang , Mao Heng , Zhang Dongyang , Lu Tongqing , Chen Quan , Yu Demei , Ding Shujiang
Published: August 2022

Stretchable ionic conductors are considerable to be the most attractive candidate for next-generation flexible ionotronic devices. Nevertheless, high ionic conductivity, excellent mechanical properties, good self-healing capacity and recyclability are necessary but can be rarely satisfied in one material. Herein, we propose an ionic conductor design, dynamic supramolecular ionic conductive elastomers (DSICE), via phase-locked strategy, wherein locking soft phase polyether backbone conducts lithium-ion (Li+) transport and the combination of dynamic disulfide metathesis and stronger supramolecular quadruple hydrogen bonds in the hard domains contributes to the self-healing capacity and mechanical versatility. The dual-phase design performs its own functions and the conflict among ionic conductivity, self-healing capability, and mechanical compatibility can be thus defeated. The well-designed DSICE exhibits high ionic conductivity (3.77 × 10−3 S m−1 at 30 °C), high transparency (92.3%), superior stretchability (2615.17% elongation), strength (27.83 MPa) and toughness (164.36 MJ m−3), excellent self-healing capability (~99% at room temperature) and favorable recyclability. This work provides an interesting strategy for designing the advanced ionic conductors and offers promise for flexible ionotronic devices or solid-state batteries.
Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Authors: Chen Yang , Jia Keren , Sun Yu , Zhang Cheng , Li Yilin , Zhang Li , Chen Zifan , Zhang Jiangdong , Hu Yajie , Yuan Jiajia , Zhao Xingwang , Li Yanyan , Gong Jifang , Dong Bin , Zhang Xiaotian , Li Jian , Shen Lin
Published: August 2022

A single biomarker is not adequate to identify patients with gastric cancer (GC) who have the potential to benefit from anti-PD-1/PD-L1 therapy, presumably owing to the complexity of the tumour microenvironment. The predictive value of tumour-infiltrating immune cells (TIICs) has not been definitively established with regard to their density and spatial organisation. Here, multiplex immunohistochemistry is used to quantify in situ biomarkers at sub-cellular resolution in 80 patients with GC. To predict the response to immunotherapy, we establish a multi-dimensional TIIC signature by considering the density of CD4+FoxP3−PD-L1+, CD8+PD-1−LAG3−, and CD68+STING+ cells and the spatial organisation of CD8+PD-1+LAG3− T cells. The TIIC signature enables prediction of the response of patients with GC to anti-PD-1/PD-L1 immunotherapy and patient survival. Our findings demonstrate that a multi-dimensional TIIC signature may be relevant for the selection of patients who could benefit the most from anti-PD-1/PD-L1 immunotherapy.
Heterogenous humoral and cellular immune responses with distinct trajectories post-SARS-CoV-2 infection in a population-based cohort
Authors: Menges Dominik , Zens Kyra D. , Ballouz Tala , Caduff Nicole , Llanas-Cornejo Daniel , Aschmann Hélène E. , Domenghino Anja , Pellaton Céline , Perreau Matthieu , Fenwick Craig , Pantaleo Giuseppe , Kahlert Christian R. , Münz Christian , Puhan Milo A. , Fehr Jan S.
Published: August 2022

To better understand the development of SARS-CoV-2-specific immunity over time, a detailed evaluation of humoral and cellular responses is required. Here, we characterize anti-Spike (S) IgA and IgG in a representative population-based cohort of 431 SARS-CoV-2-infected individuals up to 217 days after diagnosis, demonstrating that 85% develop and maintain anti-S responses. In a subsample of 64 participants, we further assess anti-Nucleocapsid (N) IgG, neutralizing antibody activity, and T cell responses to Membrane (M), N, and S proteins. In contrast to S-specific antibody responses, anti-N IgG levels decline substantially over time and neutralizing activity toward Delta and Omicron variants is low to non-existent within just weeks of Wildtype SARS-CoV-2 infection. Virus-specific T cells are detectable in most participants, albeit more variable than antibody responses. Cluster analyses of the co-evolution of antibody and T cell responses within individuals identify five distinct trajectories characterized by specific immune patterns and clinical factors. These findings demonstrate the relevant heterogeneity in humoral and cellular immunity to SARS-CoV-2 while also identifying consistent patterns where antibody and T cell responses may work in a compensatory manner to provide protection.
Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs
Authors: Kumar Arvind , Kindig Kayla , Rao Shanlin , Zaki Afroditi-Maria , Basak Sandip , Sansom Mark S. P. , Biggin Philip C. , Chakrapani Sudha
Published: August 2022

Nociception and motor coordination are critically governed by glycine receptor (GlyR) function at inhibitory synapses. Consequentially, GlyRs are attractive targets in the management of chronic pain and in the treatment of several neurological disorders. High-resolution mechanistic details of GlyR function and its modulation are just emerging. While it has been known that cannabinoids such as Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent in marijuana, potentiate GlyR in the therapeutically relevant concentration range, the molecular mechanism underlying this effect is still not understood. Here, we present Cryo-EM structures of full-length GlyR reconstituted into lipid nanodisc in complex with THC under varying concentrations of glycine. The GlyR-THC complexes are captured in multiple conformational states that reveal the basis for THC-mediated potentiation, manifested as different extents of opening at the level of the channel pore. Taken together, these structural findings, combined with molecular dynamics simulations and functional analysis, provide insights into the potential THC binding site and the allosteric coupling to the channel pore.
Achieving thermally stable nanoparticles in chemically complex alloys via controllable sluggish lattice diffusion
Authors: Xiao Bo , Luan Junhua , Zhao Shijun , Zhang Lijun , Chen Shiyao , Zhao Yilu , Xu Lianyong , Liu C. T. , Kai Ji-Jung , Yang Tao
Published: August 2022

Nanoparticle strengthening provides a crucial basis for developing high-performance structural materials with potentially superb mechanical properties for structural applications. However, the general wisdom often fails to work well due to the poor thermal stability of nanoparticles, and the rapid coarsening of these particles will lead to the accelerated failures of these materials especially at elevated temperatures. Here, we demonstrate a strategy to achieve ultra-stable nanoparticles at 800~1000 °C in a Ni59.9-xCoxFe13Cr15Al6Ti6B0.1 (at.%) chemically complex alloy, resulting from the controllable sluggish lattice diffusion (SLD) effect. Our diffusion kinetic simulations reveal that the Co element leads to a significant reduction in the interdiffusion coefficients of all the main elements, especially for the Al element, with a maximum of up to 5 orders of magnitude. Utilizing first-principles calculations, we further unveil the incompressibility of Al induced by the increased concentration of Co plays a critical role in controlling the SLD effect. These findings are useful for providing advances in the design of novel structural alloys with extraordinary property-microstructure stability combinations for structural applications.
Ano5 modulates calcium signaling during bone homeostasis in gnathodiaphyseal dysplasia
Authors: Li Xin , Wang Lei , Wang Hongwei , Qin An , Qin Xingjun
Published: August 2022

ANO5 encodes transmembrane protein 16E (TMEM16E), an intracellular calcium-activated chloride channel in the endoplasmic reticulum. Mutations in ANO5 are associated with gnathodiaphyseal dysplasia (GDD), a skeletal disorder causing the jaw deformity and long bone fractures. However, the coordinated mechanism by which ANO5 mediates bone homeostasis in GDD remains poorly defined. Here, we show that ablation of Ano5 reduced intracellular calcium transients, leading to defects in osteogenesis and osteoclastogenesis and thus bone dysplasia. We found a causative de novo ANO5 frameshift insertion mutation (p.L370_A371insDYWRLNSTCL) in a GDD family with osteopenia, accompanied by a decrease in TMEM16E expression and impaired RANKL-induced intracellular calcium ([Ca2+]i) oscillations in osteoclasts. Moreover, using Ano5 knockout (KO) mice, we found that they exhibited low bone volume, abnormal calcium deposits, and defective osteoblast and osteoclast differentiation. We also showed that Ano5 deletion in mice significantly diminished [Ca2+]i oscillations in both osteoblasts and osteoclasts, which resulted in reduced WNT/β-Catenin and RANKL-NFATc1 signaling, respectively. Osteoanabolic treatment of parathyroid hormone was effective in enhancing bone strength in Ano5 KO mice. Consequently, these data demonstrate that Ano5 positively modulates bone homeostasis via calcium signaling in GDD.
Characterization of interactions of dietary cholesterol with the murine and human gut microbiome
Authors: Le Henry H. , Lee Min-Ting , Besler Kevin R. , Comrie Janine M. C. , Johnson Elizabeth L.
Published: August 2022

Consumption of dietary lipids, such as cholesterol, modulates the gut microbiome with consequences for host health through the production of microbiome-derived metabolites. Despite the implications for host metabolism, a limited number of specific interactions of the gut microbiome with diet-derived lipids have been characterized. This is partially because obtaining species-level resolution of the responsible taxa can be challenging and additional approaches are needed to identify health-relevant metabolites produced from cholesterol–microbiome interactions. Here we performed bio-orthogonal labelling sort sequence spectrometry, a click chemistry based workflow, to profile cholesterol-specific host–microbe interactions. Mice were exposed to an alkyne-functionalized variant of cholesterol and 16S ribosomal RNA gene amplicon sequencing of faecal samples identified diet-derived cholesterol-interacting microbes from the genera Bacteroides, Bifidobacterium, Enterococcus and Parabacteroides. Shotgun metagenomic analysis provided species-level resolution of diet-derived cholesterol-interacting microbes with enrichment of bile acid-like and sulfotransferase-like activities. Using untargeted metabolomics, we identify that cholesterol is converted to cholesterol sulfate in a Bacteroides-specific manner via the enzyme BT_0416. Mice monocolonized with Bacteroides thetaiotaomicron lacking Bt_0416 showed altered host cholesterol and cholesterol sulfate compared with wild-type mice, identifying a previously uncharacterized microbiome-transformation of cholesterol and a mechanism for microbiome-dependent contributions to host phenotype. Moreover, identification of a cholesterol-responsive sulfotransferase in Bacteroides suggests diet-dependent mechanisms for altering microbiome-specific cholesterol metabolism. Overall, our work identifies numerous cholesterol-interacting microbes with implications for more precise microbiome-conscious regulation of host cholesterol homeostasis.
Percutaneous transluminal angioplasty for symptomatic hepatic vein-type Budd-Chiari syndrome: feasibility and long-term outcomes
Authors: Elkilany Aboelyazid , Alwarraky Mohamed , Denecke Timm , Geisel Dominik
Published: August 2022

For management of Budd-Chiari syndrome (BCS), a step-wise therapeutic approach starting with medical treatment, followed by endovascular recanalization, transjugular intrahepatic portosystemic shunt, and finally liver transplantation has been adopted. We retrospectively analyzed 51 patients with symptomatic short segment (≤ 30 mm) hepatic vein (HV)-type BCS who underwent percutaneous transluminal balloon angioplasty (PTBA) with/without stenting to determine the feasibility, clinical effectiveness, and long-term outcomes. The intervention was technically successful in 94.1% of cases (48/51)—32 patients underwent PTBA and 16 patients underwent HV stenting. Procedure-related complications occurred in 14 patients (29.1%). The clinical success rate at 4 weeks was 91.7% (44/48). Nine patients underwent reintervention, six patients due to restenosis/occlusion and three patients with clinical failure. The mean primary patency duration was 64.6 ± 19.9 months (CI, 58.5–70.8; range, 1.2–81.7 months). The cumulative 1-, 2-, and 5-year primary patency rates were 85.4, 74.5, and 58.3%, respectively. The cumulative 1-, 2-, and 5-year secondary patency rates were 93.8, 87.2, and 75%, respectively. The cumulative 1-, 2-, and 5-year survival rates were 97.9, 91.5, and 50%, respectively. Percutaneous transluminal angioplasty with and without stenting is effective and achieves excellent long-term patency and survival rates in patients with symptomatic HV-type BCS. With its lower incidence of re-occlusion and higher clinical success rate, HV angioplasty combined with stenting should be the preferred option especially in patients with segmental HV-type BCS.
Novel covalent and non-covalent complex-based pharmacophore models of SARS-CoV-2 main protease (Mpro) elucidated by microsecond MD simulations
Authors: Hayek-Orduz Yasser , Vásquez Andrés Felipe , Villegas-Torres María Francisca , Caicedo Paola A. , Achenie Luke E. K. , González Barrios Andrés Fernando
Published: August 2022

As the world enters its second year of the pandemic caused by SARS-CoV-2, intense efforts have been directed to develop an effective diagnosis, prevention, and treatment strategies. One promising drug target to design COVID-19 treatments is the SARS-CoV-2 Mpro. To date, a comparative understanding of Mprodynamic stereoelectronic interactions with either covalent or non-covalent inhibitors (depending on their interaction with a pocket called S1’ or oxyanion hole) has not been still achieved. In this study, we seek to fill this knowledge gap using a cascade in silico protocol of docking, molecular dynamics simulations, and MM/PBSA in order to elucidate pharmacophore models for both types of inhibitors. After docking and MD analysis, a set of complex-based pharmacophore models was elucidated for covalent and non-covalent categories making use of the residue bonding point feature. The highest ranked models exhibited ROC-AUC values of 0.93 and 0.73, respectively for each category. Interestingly, we observed that the active site region of Mproprotein–ligand complex undergoes large conformational changes, especially within the S2 and S4 subsites. The results reported in this article may be helpful in virtual screening (VS) campaigns to guide the design and discovery of novel small-molecule therapeutic agents against SARS-CoV-2 Mproprotein.
Feeding ecology of the endangered Asiatic wild dogs (Cuon alpinus) across tropical forests of the Central Indian Landscape
Authors: Ghaskadbi Pallavi , Bathla Neetu , Bhandari Aishwarya , Modi Shrushti , Nigam Parag , Habib Bilal
Published: August 2022

Studies on resource utilisation by carnivores are essential as they aid in assessing their role in a community, by unravelling predator–prey relationships. Globally, prey depletion is one of the primary causes of declining Asiatic wild dog (dhole) populations. Therefore, it is essential to examine their diet across their range. Our study presents insights into dhole feeding ecology across multiple sites from the central Indian landscape of Maharashtra, India, for the first time. We conducted scat analysis using a subset of genetically identified scats and collected additional data from kills observed while tracking radio-collared dholes and other known packs from 2 study sites. We analysed 861 scats, and 191 dhole kills to identify species and age class of prey. We estimated the relative contribution of various prey, utilising non-linear biomass models of prey consumption. Overall, wild ungulates like sambar and chital were the principal prey in terms of biomass (sambar 61.08%; chital 19.08%) and number of prey consumed (sambar 39.28%; chital 13.83%). An analysis of kill data also suggested that dholes strongly preferred the two deer species; and differential selection of age classes was observed at the 2 study sites. Our study can potentially help manage and conserve this important population of an endangered carnivore.
Structural characterization and antibacterial activity of silver nanoparticles synthesized using a low-molecular-weight Royal Jelly extract
Authors: Gevorgyan Susanna , Schubert Robin , Falke Sven , Lorenzen Kristina , Trchounian Karen , Betzel Christian
Published: August 2022

In recent years silver nanoparticles (Ag NPs) gained increased and widespread applications in various fields of industry, technology, and medicine. This study describes the green synthesis of silver nanoparticles (Ag NPs) applying a low-molecular-weight fraction (LMF) of Royal Jelly, the nanoparticle characterization, and particularly their antibacterial activity. The optical properties of NPs, characterized by UV–Vis absorption spectroscopy, showed a peak at ~ 430 nm. The hydrodynamic radius and concentration were determined by complementary dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The particle morphology was investigated using transmission electron microscopy (TEM), and the crystallinity of the silver was confirmed by X-ray diffraction (XRD). The antibacterial activities were evaluated utilizing Gram-negative and Gram-positive bacteria and colony counting assays. The growth inhibition curve method was applied to obtain information about the corresponding minimum inhibitory concentrations (MIC) and the minimum bactericidal concentrations (MBC) required. Obtained results showed that (i) the sizes of Ag NPs are increasing within the increase of silver ion precursor concentration, (ii) DLS, in agreement with NTA, showed that most particles have dimensions in the range of 50–100 nm; (iii) E. coli was more susceptible to all Ag NP samples compared to B. subtilis.
Association of extracellular vesicle inflammatory proteins and mortality
Authors: Noren Hooten Nicole , Torres Stephanie , Mode Nicolle A. , Zonderman Alan B. , Ghosh Paritosh , Ezike Ngozi , Evans Michele K.
Published: August 2022

Even before the COVID-19 pandemic declines in life expectancy in the United States were attributed to increased mortality rates in midlife adults across racial and ethnic groups, indicating a need for markers to identify individuals at risk for early mortality. Extracellular vesicles (EVs) are small, lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids. Given their role as intercellular communicators and potential biomarkers of disease, we explored whether circulating EVs may be markers of mortality in a prospective, racially, and socioeconomically diverse middle-aged cohort. We isolated plasma EVs from 76 individuals (mean age = 59.6 years) who died within a 5 year period and 76 surviving individuals matched by age, race, and poverty status. There were no significant differences in EV concentration, size, or EV-associated mitochondrial DNA levels associated with mortality. We found that several EV-associated inflammatory proteins including CCL23, CSF-1, CXCL9, GDNF, MCP-1, STAMBP, and 4E-BP1 were significantly associated with mortality. IL-10RB and CDCP1 were more likely to be present in plasma EVs from deceased individuals than in their alive counterparts. We also report differences in EV-associated inflammatory proteins with poverty status, race, and sex. Our results suggest that plasma EV-associated inflammatory proteins are promising potential clinical biomarkers of mortality.
Real-time single-pixel imaging using a system on a chip field-programmable gate array
Authors: Hoshi Ikuo , Shimobaba Tomoyoshi , Kakue Takashi , Ito Tomoyoshi
Published: August 2022

Unlike conventional imaging, the single-pixel imaging technique uses a single-element detector, which enables high sensitivity, broad wavelength, and noise robustness imaging. However, it has several challenges, particularly requiring extensive computations for image reconstruction with high image quality. Therefore, high-performance computers are required for real-time reconstruction with higher image quality. In this study, we developed a compact dedicated computer for single-pixel imaging using a system on a chip field-programmable gate array (FPGA), which enables real-time reconstruction at 40 frames per second with an image size of 128 × 128 pixels. An FPGA circuit was implemented with the proposed reconstruction algorithm to obtain higher image quality by introducing encoding mask pattern optimization. The dedicated computer can accelerate the reconstruction 10 times faster than a recent CPU. Because it is very compact compared with typical computers, it can expand the application of single-pixel imaging to the Internet of Things and outdoor applications.
Cognitive flexibility supports the development of cumulative cultural learning in children
Authors: Davis Sarah , Rawlings Bruce , Clegg Jennifer M. , Ikejimba Daniel , Watson-Jones Rachel E. , Whiten Andrew , Legare Cristine H.
Published: August 2022

The scale of cumulative cultural evolution (CCE) is a defining characteristic of humans. Despite marked scientific interest in CCE, the cognitive underpinnings supporting its development remain understudied. We examined the role cognitive flexibility plays in CCE by studying U.S. children’s (N = 167, 3–5-year-olds) propensity to relinquish an inefficient solution to a problem in favor of a more efficient alternative, and whether they would resist reverting to earlier versions. In contrast to previous work with chimpanzees, most children who first learned to solve a puzzlebox in an inefficient way switched to an observed, more efficient alternative. However, over multiple task interactions, 85% of children who switched reverted to the inefficient method. Moreover, almost all children in a control condition (who first learned the efficient method) switched to the inefficient method. Thus, children were keen to explore an alternative solution but, like chimpanzees, are overall conservative in reverting to their first-learned one.
Transcriptome-guided annotation and functional classification of long non-coding RNAs in Arabidopsis thaliana
Authors: Corona-Gomez Jose Antonio , Coss-Navarrete Evelia Lorena , Garcia-Lopez Irving Jair , Klapproth Christopher , Pérez-Patiño Jaime Alejandro , Fernandez-Valverde Selene L.
Published: August 2022

Long non-coding RNAs (lncRNAs) are a prominent class of eukaryotic regulatory genes. Despite the numerous available transcriptomic datasets, the annotation of plant lncRNAs remains based on dated annotations that have been historically carried over. We present a substantially improved annotation of Arabidopsis thaliana lncRNAs, generated by integrating 224 transcriptomes in multiple tissues, conditions, and developmental stages. We annotate 6764 lncRNA genes, including 3772 that are novel. We characterize their tissue expression patterns and find 1425 lncRNAs are co-expressed with coding genes, with enriched functional categories such as chloroplast organization, photosynthesis, RNA regulation, transcription, and root development. This improved transcription-guided annotation constitutes a valuable resource for studying lncRNAs and the biological processes they may regulate.
Large-scale vivid metasurface color printing using advanced 12-in. immersion photolithography
Authors: Khaidarov Egor , Eschimese Damien , Lai Keng Heng , Huang Aihong , Fu Yuan Hsing , Lin Qunying , Paniagua-Dominguez Ramon , Kuznetsov Arseniy I.
Published: August 2022

Nanostructures exhibiting optical resonances (so-called nanoantennas) have strong potential for applications in color printing and filtering with sub-wavelength resolution. While small scale demonstrations of these systems are interesting as a proof-of-concept, their large scale and volume fabrication requires deeper analysis and further development for industrial adoption. Here, we evaluate the color quality produced by large size nanoantenna arrays fabricated on a 12-in. wafer using deep UV immersion photolithography and dry etching processes. The color reproduction and quality are analyzed in context of the CIE color diagram, showing that a vivid and vibrant color palette, almost fully covering the sRGB color space, can be obtained with this mass-manufacturing-ready fabrication process. The obtained results, thus, provide a solid foundation for the potential industrial adoption of this emerging technology and expose the limits and challenges of the process.
Rapid evolution of a novel protective symbiont into keystone taxon in Caenorhabditis elegans microbiota
Authors: Wu-Chuang Alejandra , Bates Kieran A. , Obregon Dasiel , Estrada-Peña Agustín , King Kayla C. , Cabezas-Cruz Alejandro
Published: August 2022

Protective microbes have a major role in shaping host–pathogen interactions, but their relative importance in the structure of the host microbiota remains unclear. Here, we used a network approach to characterize the impact of a novel, experimentally evolved ‘protective microbial symbiont’ (Enterococcus faecalis) on the structure and predicted function of the natural microbiota of the model organism Caenorhabditis elegans. We used microbial network analysis to identify keystone taxa and describe the hierarchical placement of protective and non-protective symbionts in the microbiota. We found that early colonization with symbionts produce statistically significant changes in the structure of the community. Notably, only the protective E. faecalis became a keystone taxon in the nematode microbiota. Non-protective lineages of the same bacterial species remained comparatively unimportant to the community. Prediction of functional profiles in bacterial communities using PICRUSt2 showed that the presence of highly protective E. faecalis decreased the abundance of ergothioneine (EGT) biosynthesis pathway involved in the synthesis of the antioxidant molecule EGT, a potential public good. These data show that in addition to direct antagonism with virulent pathogens, keystone protective symbionts are linked to modified bacterial community structure and possible reductions in public goods, potentially driving decreased antioxidant defense. We suggest that this response could suppress infection via wholesale microbial community changes to further benefit the host. These findings extend the concept of protective symbionts beyond bodyguards to ecosystem engineers.
Effects of online parietal transcranial electric stimulation on associative memory: a direct comparison between tDCS, theta tACS, and theta-oscillatory tDCS
Authors: Živanović Marko , Bjekić Jovana , Konstantinović Uroš , Filipović Saša R.
Published: August 2022

Associative memory (AM) is the ability to remember and retrieve multiple items bound together. Previous studies aiming to modulate AM by various transcranial electric stimulation (tES) techniques were inconclusive, although overall suggestive that tES could be a tool for AM enhancement. However, evidence from a direct comparison between different tES techniques is lacking. Here, in a sham-controlled cross-over experiment, we comparatively assessed the effects of three types of tES—anodal tDCS, theta-band transcranial alternating current stimulation (tACS), and theta-oscillatory tDCS (otDCS), delivered over the left posterior parietal cortex, during a short-term digit-color AM task with cued-recall. The effects were tested in 40 healthy young participants while both oscillatory tES were delivered at a previously determined individual theta frequency (4–8 Hz). All three active stimulations facilitated the overall AM performance, and no differences could be detected between them on direct comparison. However, unlike tDCS, the effects of which appeared to stem mainly from the facilitation of low-memory demand trials, both theta-modulated tACS and otDCS primarily promoted AM in high memory demand trials. Comparable yet differential effects of tDCS, theta tACS, and otDCS could be attributed to differences in their presumed modes of action.
Occupations and their impact on the spreading of COVID-19 in urban communities
Authors: Hâncean Marian-Gabriel , Lerner Jürgen , Perc Matjaž , Oană Iulian , Bunaciu David-Andrei , Stoica Adelina Alexandra , Ghiţă Maria-Cristina
Published: August 2022

The current pandemic has disproportionally affected the workforce. To improve our understanding of the role that occupations play in the transmission of COVID-19, we analyse real-world network data that were collected in Bucharest between August 1st and October 31st 2020. The data record sex, age, and occupation of 6895 patients and the 13,272 people they have interacted with, thus providing a social network from an urban setting through which COVID-19 has spread. Quite remarkably, we find that medical occupations have no significant effect on the spread of the virus. Instead, we find common transmission chains to start with infected individuals who hold jobs in the private sector and are connected with non-active alters, such as spouses, siblings, or elderly relatives. We use relational hyperevent models to assess the most likely homophily and network effects in the community transmission. We detect homophily with respect to age and anti-homophily with respect to sex and employability. We note that, although additional data would be welcomed to perform more in-depth network analyses, our findings may help public authorities better target under-performing vaccination campaigns.
Study on the water-richness law and zoning assessment of mine water-bearing aquifers based on sedimentary characteristics
Authors: Wang Yang , Pu Zhiguo , Ge Qin , Liu Jinhui
Published: August 2022

To study and prevent the water hazards of deep coal mines roof in the Inner Mongolia–Shaanxi (IM–S) mining area, it is essential to correctly evaluate the water-richness distributions of water-bearing aquifers in roof. This paper puts forward a sediment control method for water-richness law and zoning in the roof aquifers of deep Jurassic coals. To determine the vertical distance of direct water-bearing aquifers, the height of fractured water-conducting zone was detected by an underground network parallel electrical method. The plane and lateral spatial distribution patterns of the water-bearing aquifers and the control of the water-richness distribution was analyzed with the sediment control method. An evaluation system that consisted of four indicators, i.e., sedimentary environmental impact index, interlayer ratio of sandstone and mudstone, sandstone thickness, geophysical water-richness anomaly index was constructed. Furthermore, an Analytic Hierarchy Process (AHP) was introduced to establish the comprehensive zoning map. Finally, through the example analysis of Muduchaideng coal mine, the zoning evaluation results of water-richness were verified by the mine inflow. The findings of this study provide scientific guidance for prevention and control of mine water hazards in the IM–S mining area.
STUB1 is an intracellular checkpoint for interferon gamma sensing
Authors: Ng Simon , Lim Shuhui , Sim Adrian Chong Nyi , Mangadu Ruban , Lau Ally , Zhang Chunsheng , Martinez Sarah Bollinger , Chandramohan Arun , Lim U-Ming , Ho Samantha Shu Wen , Chang Shih Chieh , Gopal Pooja , Hong Lewis Z. , Schwaid Adam , Fernandis Aaron Zefrin , Loboda Andrey , Li Cai , Phan Uyen , Henry Brian , Partridge Anthony W.
Published: August 2022

Immune checkpoint blockade (ICB) leads to durable and complete tumour regression in some patients but in others gives temporary, partial or no response. Accordingly, significant efforts are underway to identify tumour-intrinsic mechanisms underlying ICB resistance. Results from a published CRISPR screen in a mouse model suggested that targeting STUB1, an E3 ligase involved in protein homeostasis, may overcome ICB resistance but the molecular basis of this effect remains unclear. Herein, we report an under-appreciated role of STUB1 to dampen the interferon gamma (IFNγ) response. Genetic deletion of STUB1 increased IFNGR1 abundance on the cell surface and thus enhanced the downstream IFNγ response as showed by multiple approaches including Western blotting, flow cytometry, qPCR, phospho-STAT1 assay, immunopeptidomics, proteomics, and gene expression profiling. Human prostate and breast cancer cells with STUB1 deletion were also susceptible to cytokine-induced growth inhibition. Furthermore, blockade of STUB1 protein function recapitulated the STUB1-null phenotypes. Despite these encouraging in vitro data and positive implications from clinical datasets, we did not observe in vivo benefits of inactivating Stub1 in mouse syngeneic tumour models—with or without combination with anti-PD-1 therapy. However, our findings elucidate STUB1 as a barrier to IFNγ sensing, prompting further investigations to assess if broader inactivation of human STUB1 in both tumors and immune cells could overcome ICB resistance.
Characteristics of major and macular branch retinal vein occlusion
Authors: Choi Yu-Jin , Jee Donghyun , Kwon Jin-woo
Published: August 2022

We compared the aqueous profiles, baseline characteristics, and clinical outcomes of 54 eyes with macular edema secondary to major branch retinal vein occlusion (BRVO) and macular BRVO. We also identified the characteristics of poor responders to anti-vascular endothelial growth factor (VEGF) injections. Aqueous inflammatory cytokine and VEGF concentrations were significantly higher in major BRVO. In optical coherence tomography, major BRVO had a higher proportion with subretinal fluid, disorganization of retinal inner layers, and ellipsoid zone disruption. Comparing the clinical outcomes, major BRVO required more intravitreal anti-VEGF injections and had a poorer visual prognosis in the first 12 months. A significantly higher proportion of patients with major BRVO required additional treatments after 6 months compared to macular BRVO. Patients who responded poorly to anti-VEGF had higher aqueous VEGF levels and central subfield thickness (CST) at baseline. In conclusion, major BRVO patients required more and longer treatments, and had worse visual prognoses. BRVO that responds poorly to anti-VEGF had greater CST and higher aqueous VEGF levels at baseline.