bluuebunny/crossref_metadata_2025 huggingface dataset:
Language models can learn complex molecular distributions
Authors: Flam-Shepherd Daniel , Zhu Kevin , Aspuru-Guzik Alán
Published: June 2022

Deep generative models of molecules have grown immensely in popularity, trained on relevant datasets, these models are used to search through chemical space. The downstream utility of generative models for the inverse design of novel functional compounds, depends on their ability to learn a training distribution of molecules. The most simple example is a language model that takes the form of a recurrent neural network and generates molecules using a string representation. Since their initial use, subsequent work has shown that language models are very capable, in particular, recent research has demonstrated their utility in the low data regime. In this work, we investigate the capacity of simple language models to learn more  complex distributions of molecules. For this purpose, we introduce several challenging generative modeling tasks by compiling larger, more complex distributions of molecules and we evaluate the ability of language models on each task. The results demonstrate that language models are powerful generative models, capable of adeptly learning complex molecular distributions. Language models can accurately generate: distributions of the highest scoring penalized LogP molecules in ZINC15, multi-modal molecular distributions as well as the largest molecules in PubChem. The results highlight the limitations of some of the most popular and recent graph generative models– many of which cannot scale to these molecular distributions.
Enyne diketones as substrate in asymmetric Nazarov cyclization for construction of chiral allene cyclopentenones
Authors: Tang Shengbiao , Zhang Peng , Shao Ying , Sun Jiangtao
Published: June 2022

The Nazarov cyclization is one of the most powerful tools for the stereoselective synthesis of various cyclopentenone scaffolds. Therefore, developing the new classes substrate of Nazarov reaction is an important endeavor in synthetic chemistry. Herein, we report enyne diketones, enables diastereo- and enantioselective construction of chiral allene cyclopentenones in moderate to good yields with good enantioselectivities (up to 97% ee). Importantly, it is a typical example for asymmetric synthesis of cyclopentanones with allene moiety using Nazarov cyclisation. Mechanistic studies indicate that this metal-organo relay catalysis protocol involves a rhodium-catalyzed tandem oxonium ylide formation/[2,3]-sigmatropic rearrangement/reverse benzylic acid rearrangement, followed by organo-catalyzed asymmetric Nazarov cyclization/alkyne-to-allene isomerization to give the final chiral allene cyclopentenones.
Multi-scale turbulence simulation suggesting improvement of electron heated plasma confinement
Authors: Maeyama Shinya , Watanabe Tomo-Hiko , Nakata Motoki , Nunami Masanori , Asahi Yuuichi , Ishizawa Akihiro
Published: June 2022

Turbulent transport is a key physics process for confining magnetic fusion plasma. Recent theoretical and experimental studies of existing fusion experimental devices revealed the existence of cross-scale interactions between small (electron)-scale and large (ion)-scale turbulence. Since conventional turbulent transport modelling lacks cross-scale interactions, it should be clarified whether cross-scale interactions are needed to be considered in future experiments on burning plasma, whose high electron temperature is sustained with fusion-born alpha particle heating. Here, we present supercomputer simulations showing that electron-scale turbulence in high electron temperature plasma can affect the turbulent transport of not only electrons but also fuels and ash. Electron-scale turbulence disturbs the trajectories of resonant electrons responsible for ion-scale micro-instability and suppresses large-scale turbulent fluctuations. Simultaneously, ion-scale turbulent eddies also suppress electron-scale turbulence. These results indicate a mutually exclusive nature of turbulence with disparate scales. We demonstrate the possibility of reduced heat flux via cross-scale interactions.
Regulatory B cell repertoire defects predispose lung cancer patients to immune-related toxicity following checkpoint blockade
Authors: Patel Akshay J. , Willsmore Zena N. , Khan Naeem , Richter Alex , Naidu Babu , Drayson Mark T. , Papa Sophie , Cope Andrew , Karagiannis Sophia N. , Perucha Esperanza , Middleton Gary W.
Published: June 2022

Checkpoint blockade with Pembrolizumab, has demonstrated durable clinical responses in advanced non-small cell lung cancer, however, treatment is offset by the development of high-grade immune related adverse events (irAEs) in some patients. Here, we show that in these patients a deficient Breg checkpoint fails to limit self-reactive T cell enhanced activity and auto-antibody formation enabled by PD-1/PD-L1 blockade, leading to severe auto-inflammatory sequelae. Principally a failure of IL-10 producing regulatory B cells as demonstrated through functional ex vivo assays and deep phenotyping mass cytometric analysis, is a major and significant finding in patients who develop high-grade irAEs when undergoing treatment with anti-PD1/PD-L1 checkpoint blockade. There is currently a lack of biomarkers to identify a priori those patients at greatest risk of developing severe auto-inflammatory syndrome. Pre-therapy B cell profiling could provide an important tool to identify lung cancer patients at high risk of developing severe irAEs on checkpoint blockade.
Serotonin and dopamine modulate aging in response to food odor and availability
Authors: Miller Hillary A. , Huang Shijiao , Dean Elizabeth S. , Schaller Megan L. , Tuckowski Angela M. , Munneke Allyson S. , Beydoun Safa , Pletcher Scott D. , Leiser Scott F.
Published: June 2022

An organism’s ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
Enhanced BRAF engagement by NRAS mutants capable of promoting melanoma initiation
Authors: Murphy Brandon M. , Terrell Elizabeth M. , Chirasani Venkat R. , Weiss Tirzah J. , Lew Rachel E. , Holderbaum Andrea M. , Dhakal Aastha , Posada Valentina , Fort Marie , Bodnar Michael S. , Carey Leiah M. , Chen Min , Burd Craig J. , Coppola Vincenzo , Morrison Deborah K. , Campbell Sharon L. , Burd Christin E.
Published: June 2022

A distinct profile of NRAS mutants is observed in each tumor type. It is unclear whether these profiles are determined by mutagenic events or functional differences between NRAS oncoproteins. Here, we establish functional hallmarks of NRAS mutants enriched in human melanoma. We generate eight conditional, knock-in mouse models and show that rare melanoma mutants (NRAS G12D, G13D, G13R, Q61H, and Q61P) are poor drivers of spontaneous melanoma formation, whereas common melanoma mutants (NRAS Q61R, Q61K, or Q61L) induce rapid tumor onset with high penetrance. Molecular dynamics simulations, combined with cell-based protein–protein interaction studies, reveal that melanomagenic NRAS mutants form intramolecular contacts that enhance BRAF binding affinity, BRAF-CRAF heterodimer formation, and MAPK > ERK signaling. Along with the allelic series of conditional mouse models we describe, these results establish a mechanistic basis for the enrichment of specific NRAS mutants in human melanoma.
Oxidation of Archean upper mantle caused by crustal recycling
Authors: Gao Lei , Liu Shuwen , Cawood Peter A. , Hu Fangyang , Wang Jintuan , Sun Guozheng , Hu Yalu
Published: June 2022

The redox evolution of Archean upper mantle impacted mantle melting and the nature of chemical equilibrium between mantle, ocean and atmosphere of the early Earth. Yet, the origin of these variations in redox remain controversial. Here we show that a global compilation of ∼3.8-2.5 Ga basalts can be subdivided into group B-1, showing modern mid-ocean ridge basalt-like features ((Nb/La)PM ≥ 0.75), and B-2, which are similar to contemporary island arc-related basalts ((Nb/La)PM < 0.75). Our V-Ti redox proxy indicates a more reducing upper mantle, and the results of both ambient and modified mantle obtained from B-1 and B-2 samples, respectively, exhibit a ∼1.0 log unit increase in their temporal evolution for most cratons. Increases in mantle oxygen fugacity are coincident with the changes in basalt Th/Nb ratios and Nd isotope ratios, indicating that crustal recycling played a crucial role, and this likely occurred either via plate subduction or lithospheric drips.
Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure
Authors: Oelen Roy , de Vries Dylan H. , Brugge Harm , Gordon M. Grace , Vochteloo Martijn ,   single-cell eQTLGen consortium,   BIOS Consortium, Ye Chun J. , Westra Harm-Jan , Franke Lude , van der Wijst Monique G. P.
Published: June 2022

The host’s gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host’s genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on theCLEC12Agene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity andCLEC12Aco-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies thatCLEC12Amight be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease.
Cell fate roadmap of human primed-to-naive transition reveals preimplantation cell lineage signatures
Authors: Bi Yan , Tu Zhifen , Zhou Jianfeng , Zhu Xuehao , Wang Hong , Gao Shaorong , Wang Yixuan
Published: June 2022

Human naive pluripotent stem cells offer a unique window into early embryogenesis studies. Recent studies have reported several strategies to obtain cells in the naive state. However, cell fate transitions and the underlying mechanisms remain poorly understood. Here, by a dual fluorescent reporter system, we depict the cell fate dynamics from primed state toward naive pluripotency with ALPG activation followed by the activation of OCT4-distal enhancer. Integration of transcription profiles and the chromatin accessibility landscape reveals the appearance of primitive endoderm and trophectoderm signatures in the transitioning subpopulations, with the capacities for derivation of extra-embryonic endoderm and trophoblast stem cell lines, respectively. Furthermore, despite different fluorescent dynamics, all transitioning intermediates are capable of reaching the naive state with prolonged induction, showing their developmental plasticity and potential. Overall, our study describes a global cell roadmap toward naive pluripotency and provides hints for embryo modeling-related studies.
Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes
Authors: Han Ji Seul , Jeon Yong Geun , Oh Minsik , Lee Gung , Nahmgoong Hahn , Han Sang Mun , Choi Jeehye , Kim Ye Young , Shin Kyung Cheul , Kim Jiwon , Jo Kyuri , Choe Sung Sik , Park Eun Jung , Kim Sun , Kim Jae Bum
Published: June 2022

Thermogenic adipocytes generate heat to maintain body temperature against hypothermia in response to cold. Although tight regulation of thermogenesis is required to prevent energy sources depletion, the molecular details that tune thermogenesis are not thoroughly understood. Here, we demonstrate that adipocyte hypoxia-inducible factor α (HIFα) plays a key role in calibrating thermogenic function upon cold and re-warming. In beige adipocytes, HIFα attenuates protein kinase A (PKA) activity, leading to suppression of thermogenic activity. Mechanistically, HIF2α suppresses PKA activity by inducing miR-3085-3p expression to downregulate PKA catalytic subunit α (PKA Cα). Ablation of adipocyte HIF2α stimulates retention of beige adipocytes, accompanied by increased PKA Cα during re-warming after cold stimuli. Moreover, administration of miR-3085-3p promotes beige-to-white transition via downregulation of PKA Cα and mitochondrial abundance in adipocyte HIF2α deficient mice. Collectively, these findings suggest that HIF2α-dependent PKA regulation plays an important role as a thermostat through dynamic remodeling of beige adipocytes.
Small reorganization energy acceptors enable low energy losses in non-fullerene organic solar cells
Authors: Shi Yanan , Chang Yilin , Lu Kun , Chen Zhihao , Zhang Jianqi , Yan Yangjun , Qiu Dingding , Liu Yanan , Adil Muhammad Abdullah , Ma Wei , Hao Xiaotao , Zhu Lingyun , Wei Zhixiang
Published: June 2022

Minimizing energy loss is of critical importance in the pursuit of attaining high-performance organic solar cells. Interestingly, reorganization energy plays a crucial role in photoelectric conversion processes. However, the understanding of the relationship between reorganization energy and energy losses has rarely been studied. Here, two acceptors, Qx-1 and Qx-2, were developed. The reorganization energies of these two acceptors during photoelectric conversion processes are substantially smaller than the conventional Y6 acceptor, which is beneficial for improving the exciton lifetime and diffusion length, promoting charge transport, and reducing the energy loss originating from exciton dissociation and non-radiative recombination. So, a high efficiency of 18.2% with high open circuit voltage above 0.93 V in the PM6:Qx-2 blend, accompanies a significantly reduced energy loss of 0.48 eV. This work underlines the importance of the reorganization energy in achieving small energy losses and paves a way to obtain high-performance organic solar cells.
The 3D mutational constraint on amino acid sites in the human proteome
Authors: Li Bian , Roden Dan M. , Capra John A.
Published: June 2022

Quantification of the tolerance of protein sites to genetic variation has become a cornerstone of variant interpretation. We hypothesize that the constraint on missense variation at individual amino acid sites is largely shaped by direct interactions with 3D neighboring sites. To quantify this constraint, we introduce a framework called COntact Set MISsense tolerance (or COSMIS) and comprehensively map the landscape of 3D mutational constraint on 6.1 million amino acid sites covering 16,533 human proteins. We show that 3D mutational constraint is pervasive and that the level of constraint is strongly associated with disease relevance both at the site and the protein level. We demonstrate that COSMIS performs significantly better at variant interpretation tasks than other population-based constraint metrics while also providing structural insight into the functional roles of constrained sites. We anticipate that COSMIS will facilitate the interpretation of protein-coding variation in evolution and prioritization of sites for mechanistic investigation.
A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance
Authors: Leshchiner Dmitry , Rosconi Federico , Sundaresh Bharathi , Rudmann Emily , Ramirez Luisa Maria Nieto , Nishimoto Andrew T. , Wood Stephen J. , Jana Bimal , Buján Noemí , Li Kaicheng , Gao Jianmin , Frank Matthew , Reeve Stephanie M. , Lee Richard E. , Rock Charles O. , Rosch Jason W. , van Opijnen Tim
Published: June 2022

Detailed knowledge on how bacteria evade antibiotics and eventually develop resistance could open avenues for novel therapeutics and diagnostics. It is thereby key to develop a comprehensive genome-wide understanding of how bacteria process antibiotic stress, and how modulation of the involved processes affects their ability to overcome said stress. Here we undertake a comprehensive genetic analysis of how the human pathogen Streptococcus pneumoniae responds to 20 antibiotics. We build a genome-wide atlas of drug susceptibility determinants and generated a genetic interaction network that connects cellular processes and genes of unknown function, which we show can be used as therapeutic targets. Pathway analysis reveals a genome-wide atlas of cellular processes that can make a bacterium less susceptible, and often tolerant, in an antibiotic specific manner. Importantly, modulation of these processes confers fitness benefits during active infections under antibiotic selection. Moreover, screening of sequenced clinical isolates demonstrates that mutations in genes that decrease antibiotic sensitivity and increase tolerance readily evolve and are frequently associated with resistant strains, indicating such mutations could be harbingers for the emergence of antibiotic resistance.
Elucidating the origin of chiroptical activity in chiral 2D perovskites through nano-confined growth
Authors: Ma Sunihl , Jung Young-Kwang , Ahn Jihoon , Kyhm Jihoon , Tan Jeiwan , Lee Hyungsoo , Jang Gyumin , Lee Chan Uk , Walsh Aron , Moon Jooho
Published: June 2022

Chiral perovskites are being extensively studied as a promising candidate for spintronic- and polarization-based optoelectronic devices due to their interesting spin-polarization properties. However, the origin of chiroptical activity in chiral perovskites is still unknown, as the chirality transfer mechanism has been rarely explored. Here, through the nano-confined growth of chiral perovskites (MBA2PbI4(1-x)Br4x), we verified that the asymmetric hydrogen-bonding interaction between chiral molecular spacers and the inorganic framework plays a key role in promoting the chiroptical activity of chiral perovskites. Based on this understanding, we observed remarkable asymmetry behavior (absorption dissymmetry of 2.0 × 10−3 and anisotropy factor of photoluminescence of 6.4 × 10−2 for left- and right-handed circularly polarized light) in nanoconfined chiral perovskites even at room temperature. Our findings suggest that electronic interactions between building blocks should be considered when interpreting the chirality transfer phenomena and designing hybrid materials for future spintronic and polarization-based devices.
Engineered non-covalent π interactions as key elements for chiral recognition
Authors: Jin Ming Yu , Zhen Qianqian , Xiao Dengmengfei , Tao Guanyu , Xing Xiangyou , Yu Peiyuan , Xu Chen
Published: June 2022

Molecular recognition and self-assembly are often mediated by intermolecular forces involving aromatic π-systems. Despite the ubiquity of such interactions in biological systems and in the design of functional materials, the elusive nature of aromatic π interaction results in that they have been seldom used as a design element for promoting challenging chemical reactions. Described here is a well-engineered catalytic system into which non-covalent π interactions are directly incorporated. Enabled by a lone pair-π interaction and a π-π stacking interaction operating collectively, efficient chiral recognition is successfully achieved in the long-pursued dihydroxylation-based kinetic resolution. Density functional theory calculations shed light on the crucial role played by the lone pair-π interaction between the carbonyl oxygen of the cinchona alkaloid ligand and the electron-deficient phthalazine π moiety of the substrate in the stereoselectivity-determining transition states. This discovery serves as a proof-of-principle example showing how the weak non-covalent π interactions, if ingeniously designed, could be a powerful guide in attaining highly enantioselective catalysis.
Scrutinizing pathogenicity of the USH2A c.2276 G > T; p.(Cys759Phe) variant
Authors: Reurink Janine , de Vrieze Erik , Li Catherina H. Z. , van Berkel Emma , Broekman Sanne , Aben Marco , Peters Theo , Oostrik Jaap , Neveling Kornelia , Venselaar Hanka , Ramos Mariana Guimarães , Gilissen Christian , Astuti Galuh D. N. , Galbany Jordi Corominas , van Lith-Verhoeven Janneke J. C. , Ockeloen Charlotte W. , Haer-Wigman Lonneke , Hoyng Carel B. , Cremers Frans P. M. , Kremer Hannie , Roosing Susanne , van Wijk Erwin
Published: June 2022

The USH2A variant c.2276 G > T (p.(Cys759Phe)) has been described by many authors as a frequent cause of autosomal recessive retinitis pigmentosa (arRP). However, this is in contrast with the description of two asymptomatic individuals homozygous for this variant. We therefore assessed pathogenicity of the USH2A c.2276 G > T variant using extensive genetic and functional analyses. Whole genome sequencing and optical genome mapping were performed for three arRP cases homozygous for USH2A c.2276 G > T to exclude alternative genetic causes. A minigene splice assay was designed to investigate the effect of c.2276 G > T on pre-mRNA splicing, in presence or absence of the nearby c.2256 T > C variant. Moreover, an ush2ap.(Cys771Phe) zebrafish knock-in model mimicking human p.(Cys759Phe) was generated and characterized using functional and immunohistochemical analyses. Besides the homozygous c.2276 G > T USH2A variant, no alternative genetic causes were identified. Evaluation of the ush2ap.(Cys771Phe) zebrafish model revealed strongly reduced levels of usherin expression at the photoreceptor periciliary membrane, increased levels of rhodopsin localization in the photoreceptor cell body and decreased electroretinogram (ERG) b-wave amplitudes compared to wildtype controls. In conclusion, we confirmed pathogenicity of USH2A c.2276 G > T (p.(Cys759Phe)). Consequently, cases homozygous for c.2276 G > T can now receive a definite genetic diagnosis and can be considered eligible for receiving future QR-421a-mediated exon 13 skipping therapy.
Highly efficient fiber-shaped organic solar cells toward wearable flexible electronics
Authors: Lv Dan , Jiang Qianqing , Shang Yuanyuan , Liu Dianyi
Published: June 2022

Fiber-shaped solar cells (FSCs) show great potential to act as the power source in the wearable electronics field. Due to the unique advantages of the fiber-shaped organic solar cells (FOSCs), such as all-solid-state, ease of fabrication, and environmental friendliness, FOSCs are the strongest candidate among all types of FSCs for wearable electronics. However, the development of FOSCs is seriously lagging behind other types of FSCs. In this work, we demonstrate the efficient FOSCs with non-fullerene-acceptors (NFAs)-based light-harvesting materials. The FOSCs present efficiencies exceeding 9% under AM 1.5 G irradiation conditions. The performance influence factors including hole/electron transport layers, active layer, counter electrodes, solvents, and especially, the environmental humidity is systematically studied. The FOSCs not only can easily drive the electrical devices but also can be woven into the textile to charge the smartwatch. The study exhibits the great potential to apply the FOSCs as the power supply source in the wearable electronic field.
Balancing efficiency and transparency in organic transparent photovoltaics
Authors: Meng Ruiqian , Jiang Qianqing , Liu Dianyi
Published: June 2022

The challenges in transparent photovoltaic (TPV) fields are still that the device transparency and efficiency are difficult to be balanced to meet the requirements of practical applications. In this study, we systematically investigated the interrelationship between photovoltaic film properties, optical transmission, and photovoltaic performances in the near-infrared harvesting organic TPVs. The results indicate that the photovoltaic film thickness determines the TPV’s transparency and meanwhile affects the device efficiency; by contrast, the donor–acceptor ratio only affects device efficiency and has little effect on transparency. By controlling the film thickness and donor–acceptor ratio, the average visible transmission (AVT) of TPVs can be precisely managed in the range of 40% - 85%, and the device efficiency can achieve as high as 4.06% and 2.38% while the AVT exceeds 70% and 80%, respectively. Importantly, the large area (~10 cm2) TPV modules and ultra-flexible devices were then successfully prepared based on the systematical study.
Performance fluctuations and evaluation of a piston type integrated high pressure pump-energy recovery device
Authors: Zhang Yin , Song Daiwang , Wang Haitao , Wang Xiaoli , Jiang Lidong , Wang Chengpeng , Fan Man , Zhao Jingzhou
Published: June 2022

The development of energy recovery device (ERD) is a decisive factor for the recent prevalence of reverse osmosis (RO) technology in the seawater desalination field. Unlike broadly studied large scale ERDs, the investigations of small scale ERDs are scarcely reported, especially on the performance fluctuations under variable operating conditions. Based on an authors’ exploratory research on a piston type integrated high pressure pump-energy recovery device (HPP-ERD), further performance exploitation of the HPP-ERD is conducted. With a constructed experiment platform, the influences of inlet seawater temperature, inlet seawater salinity, as well as the operating frequency on the performance of the HPP-ERD coupled with seawater reverse osmosis (SWRO) desalination system are investigated. The temperature and salinity of the inlet seawater are numerically correlated with the specific energy consumption (SEC) of the HPP-ERD. With the correlated equation, the marine hydrological data of two observatories acquired from a national authoritative database, and the annualized life cycle cost approach incorporated, annual performance assessment is proposed for an SWRO desalination system equipped with the HPP-ERD in the light of energy and economic indices. The study results indicate that the proposed HPP-ERD is competent under various operating conditions for SWRO desalination systems.
QMugs, quantum mechanical properties of drug-like molecules
Authors: Isert Clemens , Atz Kenneth , Jiménez-Luna José , Schneider Gisbert
Published: June 2022

Machine learning approaches in drug discovery, as well as in other areas of the chemical sciences, benefit from curated datasets of physical molecular properties. However, there currently is a lack of data collections featuring large bioactive molecules alongside first-principle quantum chemical information. The open-access QMugs (Quantum-Mechanical Properties of Drug-like Molecules) dataset fills this void. The QMugs collection comprises quantum mechanical properties of more than 665 k biologically and pharmacologically relevant molecules extracted from the ChEMBL database, totaling ~2 M conformers. QMugs contains optimized molecular geometries and thermodynamic data obtained via the semi-empirical method GFN2-xTB. Atomic and molecular properties are provided on both the GFN2-xTB and on the density-functional levels of theory (DFT, ωB97X-D/def2-SVP). QMugs features molecules of significantly larger size than previously-reported collections and comprises their respective quantum mechanical wave functions, including DFT density and orbital matrices. This dataset is intended to facilitate the development of models that learn from molecular data on different levels of theory while also providing insight into the corresponding relationships between molecular structure and biological activity.
DoE-derived continuous and robust process for manufacturing of pharmaceutical-grade wide-range LNPs for RNA-vaccine/drug delivery
Authors: Nag Kakon , Sarker Md. Enamul Haq , Kumar Samir , Khan Habiba , Chakraborty Sourav , Islam Md. Jikrul , Baray Juwel Chandra , Khan Maksudur Rahman , Mahmud Asif , Barman Uttam , Bhuiya Eleus Hussain , Mohiuddin Mohammad , Sultana Naznin
Published: June 2022

Lipid nanoparticle (LNP) technology has become extremely demanding for delivering RNA-products and other drugs. However, there is no platform to manufacture pharmaceutical-grade LNPs with desired particle size from a wide range in continuous mode. We have developed a unique platform to obtain any specific size-range of LNPs from 60 to 180 nm satisfying pharmaceutical regulatory requirements for polydispersity index, sterility, dose uniformity and bio-functionality. We applied design of experiment (DoE) methodology and identified the critical process parameters to establish the process for global application. Cross-point validation within the response map of DoE confirmed that the platform is robust to produce specific size (± 10 nm) of LNPs within the design-range. The technology is successfully transformed to production scale and validated. Products from R&D, pilot and production batches for a candidate SARS-CoV-2 mRNA-vaccine generated equivalent biological responses. The data collectively established the robustness and bio-uniformity of doses for global RNA-vaccine/drug formulation.
Pingers are effective in reducing net entanglement of river dolphins
Authors: Kolipakam Vishnupriya , Jacob Merin , Gayathri Aaranya , Deori Sunny , Sarma Hiyashri , Tasfia Syeda Tabassum , Rokade Anurag , Negi Ranjana , Wakid Abdul , Qureshi Qamar
Published: June 2022

Ganges River dolphins echolocate, but this mechanism is inadequate for poor sonar-echoing objects such as the monofilament gillnets, causing considerable net entanglement related mortalities. Net entanglement related deaths are one of the major causes of cetacean population decline around the world. Experiments were carried out to understand the use of pingers—an acoustic deterrent, in aiding the deterrence of dolphins from fishing nets. Based on the dolphin clicks recorded, in an experimental setup spanning 36 days, a 90% deterrence was found; 22.87 ± 0.71 SE dolphin detection positive minutes per hour near non-pingered nets versus 2.20 ± 0.33 SE per hour near pingered net. Within 30 m radii of nets, visual encounters of non-calf reduced by 52% and calf by 9%, in the presence of pingers. No evidence of habituation to pingers, habitat avoidance in dolphins after pinger removal or a change in fish catch in nets because of pingers was found during the study. While the effectiveness of pingers on calves and fish catch needs further experimentation, the use of pingers to minimize net entanglement mortalities in the Ganges River dolphins seems to be the most promising solution currently available. These results have critical implications for the conservation of other species of river dolphins around the world.
IFN-τ mediated miR-26a targeting PTEN to activate PI3K/AKT signalling to alleviate the inflammatory damage of bEECs
Authors: Liu Junfeng , Liang Qin , Wang Tianyang , Ma Bei , Wang Xin , Li Ping , Shaukat Aftab , Guo Xuefeng , Deng Ganzhen
Published: June 2022

Endometritis is the failure of embryo implantation and an important cause of infertility in dairy cows. IFN-τ is a type I interferon unique to ruminants. In regulating the process of inflammatory response, IFN-τ can be expressed through MicroRNAs (miRNAs) to regulate the process of inflammation. However, IFN-τ regulates lipopolysaccharide (LPS)-induced inflammatory injury of bEECs through the highly conserved miR-26a in mammals, and the mechanism remains unclear. Bovine endometrial epithelial cells (bEECs)were isolated and cultured to establish an inflammatory injury model. RT–qPCR and ELISA were used to detect the secretion of inflammatory factors. Dual-luciferase assays and target gene silencing assays determine the regulatory role of miRNAs. The target protein was detected by immunofluorescence and western blotting. This study showed that the expression of miR-26a was significantly down-regulated in mouse endometrium inflammatory injury tissue and LPS stimulated bEECs; and IFN-τ reversed the expression of miR-26a. The study also showed that the overexpression of miR-26a significantly inhibited the secretion of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. In addition, studies have shown that miR-26a inhibits its translation by targeting PTEN 3′-UTR, which in turn activates the Phosphatidylinositide 3-kinases/protein kinase B (PI3K/AKT) pathway, so that nuclear factor kappa-B (NF-κB) signaling is inhibited. In summary, the results of this study further confirm that IFN-τ as an anti-inflammatory agent can up-regulate the expression of miR-26a and target the PTEN gene to inhibit the inflammatory damage of bEECs.
Metagenomic pipeline for identifying co-infections among distinct SARS-CoV-2 variants of concern: study cases from Alpha to Omicron
Authors: Molina-Mora Jose Arturo , Cordero-Laurent Estela , Calderón-Osorno Melany , Chacón-Ramírez Edgar , Duarte-Martínez Francisco
Published: June 2022

Concomitant infection or co-infection with distinct SARS-CoV-2 genotypes has been reported as part of the epidemiological surveillance of the COVID-19 pandemic. In the context of the spread of more transmissible variants during 2021, co-infections are not only important due to the possible changes in the clinical outcome, but also the chance to generate new genotypes by recombination. However, a few approaches have developed bioinformatic pipelines to identify co-infections. Here we present a metagenomic pipeline based on the inference of multiple fragments similar to amplicon sequence variant (ASV-like) from sequencing data and a custom SARS-CoV-2 database to identify the concomitant presence of divergent SARS-CoV-2 genomes, i.e., variants of concern (VOCs). This approach was compared to another strategy based on whole-genome (metagenome) assembly. Using single or pairs of sequencing data of COVID-19 cases with distinct SARS-CoV-2 VOCs, each approach was used to predict the VOC classes (Alpha, Beta, Gamma, Delta, Omicron or non-VOC and their combinations). The performance of each pipeline was assessed using the ground-truth or expected VOC classes. Subsequently, the ASV-like pipeline was used to analyze 1021 cases of COVID-19 from Costa Rica to investigate the possible occurrence of co-infections. After the implementation of the two approaches, an accuracy of 96.2% was revealed for the ASV-like inference approach, which contrasts with the misclassification found (accuracy 46.2%) for the whole-genome assembly strategy. The custom SARS-CoV-2 database used for the ASV-like analysis can be updated according to the appearance of new VOCs to track co-infections with eventual new genotypes. In addition, the application of the ASV-like approach to all the 1021 sequenced samples from Costa Rica in the period October 12th–December 21th 2021 found that none corresponded to co-infections with VOCs. In conclusion, we developed a metagenomic pipeline based on ASV-like inference for the identification of co-infection with distinct SARS-CoV-2 VOCs, in which an outstanding accuracy was achieved. Due to the epidemiological, clinical, and molecular relevance of the concomitant infection with distinct genotypes, this work represents another piece in the process of the surveillance of the COVID-19 pandemic in Costa Rica and worldwide.
Deep learning-based lesion subtyping and prediction of clinical outcomes in COVID-19 pneumonia using chest CT
Authors: Bermejo-Peláez David , San José Estépar Raúl , Fernández-Velilla María , Palacios Miras Carmelo , Gallardo Madueño Guillermo , Benegas Mariana , Gotera Rivera Carolina , Cuerpo Sandra , Luengo-Oroz Miguel , Sellarés Jacobo , Sánchez Marcelo , Bastarrika Gorka , Peces Barba German , Seijo Luis M. , Ledesma-Carbayo María J.
Published: June 2022

The main objective of this work is to develop and evaluate an artificial intelligence system based on deep learning capable of automatically identifying, quantifying, and characterizing COVID-19 pneumonia patterns in order to assess disease severity and predict clinical outcomes, and to compare the prediction performance with respect to human reader severity assessment and whole lung radiomics. We propose a deep learning based scheme to automatically segment the different lesion subtypes in nonenhanced CT scans. The automatic lesion quantification was used to predict clinical outcomes. The proposed technique has been independently tested in a multicentric cohort of 103 patients, retrospectively collected between March and July of 2020. Segmentation of lesion subtypes was evaluated using both overlapping (Dice) and distance-based (Hausdorff and average surface) metrics, while the proposed system to predict clinically relevant outcomes was assessed using the area under the curve (AUC). Additionally, other metrics including sensitivity, specificity, positive predictive value and negative predictive value were estimated. 95% confidence intervals were properly calculated. The agreement between the automatic estimate of parenchymal damage (%) and the radiologists’ severity scoring was strong, with a Spearman correlation coefficient (R) of 0.83. The automatic quantification of lesion subtypes was able to predict patient mortality, admission to the Intensive Care Units (ICU) and need for mechanical ventilation with an AUC of 0.87, 0.73 and 0.68 respectively. The proposed artificial intelligence system enabled a better prediction of those clinically relevant outcomes when compared to the radiologists’ interpretation and to whole lung radiomics. In conclusion, deep learning lesion subtyping in COVID-19 pneumonia from noncontrast chest CT enables quantitative assessment of disease severity and better prediction of clinical outcomes with respect to whole lung radiomics or radiologists’ severity score.
Rotor strength and critical speed analysis of a vertical long shaft fire pump connected with different shaft lengths
Authors: Song Haiqin , Zhang Jinfeng , Zhang Fan
Published: June 2022

The vertical long shaft fire pump (VLSFP) is mainly used in fire-fighting places far away from land and lacking large amounts of water supply. The paper selected the XBC18-178-240LC3 model of VLSFP as the research object. First, the experimental–numerical hydraulic performance of the single-VLSFP was carried out, and then the hydraulic performance of the multi-VLSFP was analyzed by the same numerical simulation method as single-VLSFP. After that, three rotor models (Z4 model, Z5 model-original model and Z6 model) were designed by modeling software, connected by different length and number of the shaft section under the same total length of the intermediate shafts. Finally, the rotor’s strength and critical speed of three models were analyzed and checked via the CFD simulation and the Workbench software. The study mainly found: (1) Through the strength check of the impeller, maximum equivalent stress of the three models was less than the allowable stress of the rotor material, which indicated the structural design of them met the safety requirement; (2) Through the critical speed check of the shafting rotor, the working speed of the VLSFP was lower than 0.8 times the first-order critical speed of the three models, which indicated the rotor could avoid the resonance and the structure of the three models met the dynamic design requirement. According to the stress check of the impeller and the critical speed check of the shafting rotor, combining the time and labor cost when the VLSFP was installed and disassembled many times before and after the test or operation, the paper selected the Z4 model to be the optimal model, which could provide a theoretical support for the subsequent structure design optimization of the vertical long shaft fire pump.
Dimorphic life cycle through transverse division in burrowing hard coral Deltocyathoides orientalis
Authors: Sentoku Asuka , Shimizu Keisuke , Naka Tsubasa , Tokuda Yuki
Published: June 2022

The azooxanthellate solitary scleractinian Deltocyathoides orientalis (family Turbinoliidae), which has bowl-shaped costate corallites, exhibits burrowing behavior on soft substrates and can adapt to an infaunal mode of life. Here, we describe previously unknown aspects of their life history and asexual mode of reproduction based on morphological and molecular phylogenetic analyses. The findings reveal that (1) D. orientalis exhibits asexual reproduction by transverse division; (2) smaller bowl-shaped costate anthocyathus derived from cylindrical to tympanoid anthocaulus were attached to hard substrates, including shell fragments and gravels on soft substrates; and (3) anthocyathus only reproduce sexually after division, and anthocaulus was found to regrow and repeatedly produce anthocyathi through transverse division. The bowl-shaped corallum morphology of the anthocyathus just after division might reduce the time required for skeletal formation to enable infaunal adaption after transverse division. Immediately after division, D. orientalis can smoothly shift to a burrowing lifestyle that efficiently utilizes soft-substrate environments, thus increasing its survival rate. The morphological formation of prospective anthocyathus in the anthocaulus stage is consequently thought to involve an increase in clonal individuals as well as adaptations for a burrowing free-living mode of life in the anthocyathus stage.
Triplet–triplet annihilation-based photon-upconversion to broaden the wavelength spectrum for photobiocatalysis
Authors: Hwang Se-Yeun , Song Dayoon , Seo Eun-Ji , Hollmann Frank , You Youngmin , Park Jin-Byung
Published: June 2022

Photobiocatalysis is a growing field of biocatalysis. Especially light-driven enzyme catalysis has contributed significantly to expanding the scope of synthetic organic chemistry. However, photoenzymes usually utilise a rather narrow wavelength range of visible (sun)light. Triplet–triplet annihilation-based upconversion (TTA-UC) of long wavelength light to shorter wavelength light may broaden the wavelength range. To demonstrate the feasibility of light upconversion we prepared TTA-UC poly(styrene) (PS) nanoparticles doped with platinum(II) octaethylporphyrin (PtOEP) photosensitizer and 9,10-diphenylanthracene (DPA) annihilator (PtOEP:DPA@PS) for application in aqueous solutions. Photoexcitation of PtOEP:DPA@PS nanoparticles with 550 nm light led to upconverted emission of DPA 418 nm. The TTA-UC emission could photoactivate flavin-dependent photodecarboxylases with a high energy transfer efficiency. This allowed the photodecarboxylase from Chlorella variabilis NC64A to catalyse the decarboxylation of fatty acids into long chain secondary alcohols under green light (λ = 550 nm).
Gene expression of the endocannabinoid system in endometrium through menstrual cycle
Authors: Tanaka Keisuke , Amoako Akwasi A. , Mortlock Sally , Rogers Peter A. W. , Holdsworth-Carson Sarah J. , Donoghue Jacqueline F. , Teh Wan Tinn , Montgomery Grant W. , McKinnon Brett
Published: June 2022

Endocannabinoids mediate cellular functions and their activity is controlled by a complex system of enzymes, membrane receptors and transport molecules. Endocannabinoids are present in endometrium, a cyclical regenerative tissue requiring tightly regulated cellular mechanisms for maturation. The objective of this study was to investigate the gene expression of key elements involved in the endocannabinoid system across the menstrual cycle. RNA was isolated from endometrial tissue and genome-wide gene expression datasets were generated using RNA-sequencing. An a priori set of 70 genes associated with endocannabinoid system were selected from published literature. Gene expression across the menstrual cycle was analyzed using a moderated t test, corrected for multiple testing with Bonferroni’s method. A total of 40 of the 70 genes were present in > 90% of the samples, and significant differential gene expression identified for 29 genes. We identified 4 distinct regulation patterns for synthesizing enzymes, as well as a distinct regulation pattern for degradations and transporting enzymes. This study charts the expression of endometrial endocannabinoid system genes across the menstrual cycle. Altered expression of genes that control endocannabinoid may allow fine control over endocannabinoid concentrations and their influence on cellular function, maturation and differentiation as the endometrium matures through the menstrual cycle.
Method of calculating shear strength of rock mass joint surface considering cyclic shear degradation
Authors: Dong Shan , Zhang Heng , Peng Yulin , Lu Zhichun , Hou Weihua
Published: June 2022

When a rock mass shears along a joint surface, the shear resistance is affected by joint surface undulations and friction between the contact regions. During an earthquake, the seismic load causes dynamic deterioration of the joint surface mechanical properties, mostly reflected as follows. (1) The peak shear strength of the joint surface decreases with an increase in the shear rate. (2) Under a seismic load cyclic shear, the undulant angle αk decreases. (3) Under a dynamic load, the friction coefficient of the joint surface is reduced. By studying the cyclic shear test of the joint surface, the strength deterioration effect of the joint surface under cyclic shearing is first analysed, and the equations of the dilatation angle and the basic friction angle of the joint surface under the cyclic shearing load are proposed. Then, starting with the effect of cyclic shear deterioration on the joint surface in the rock mass and the reduction in the dynamic friction coefficient between sliding rock blocks caused by relative velocity, an equation for calculating the shear strength of a rock mass joint surface under cyclic shear loading is recommended. Through two case calculations, the shear strength obtained using the proposed method is compared with the experimental results. The results show that the model proposed in this study is in good agreement with the experimental results and can also be used to calculate the structural surface shear strength of the asperity-rich sample. However, when the calculation equation is used to estimate the cyclic shear strength of the joint surface where the sum of the initial undulation angle and the basic friction angle is greater than 70°, there may be some errors in the calculation results.