bluuebunny/crossref_metadata_2025_split huggingface dataset:
PERSIST platform provides programmable RNA regulation using CRISPR endoRNases
Authors: DiAndreth Breanna , Wauford Noreen , Hu Eileen , Palacios Sebastian , Weiss Ron 
Published: May 2022

AbstractRegulated transgene expression is an integral component of gene therapies, cell therapies and biomanufacturing. However, transcription factor-based regulation, upon which most applications are based, suffers from complications such as epigenetic silencing that limit expression longevity and reliability. Constitutive transgene transcription paired with post-transcriptional gene regulation could combat silencing, but few such RNA- or protein-level platforms exist. Here we develop an RNA-regulation platform we call “PERSIST" which consists of nine CRISPR-specific endoRNases as RNA-level activators and repressors as well as modular OFF- and ON-switch regulatory motifs. We show that PERSIST-regulated transgenes exhibit strong OFF and ON responses, resist silencing for at least two months, and can be readily layered to construct cascades, logic functions, switches and other sophisticated circuit topologies. The orthogonal, modular and composable nature of this platform as well as the ease in constructing robust and predictable gene circuits promises myriad applications in gene and cell therapies.
Asymmetric electron acceptor enables highly luminescent organic solar cells with certified efficiency over 18%
Authors: He Chengliang , Chen Zeng , Wang Tonghui , Shen Ziqiu , Li Yaokai , Zhou Jiadong , Yu Jianwei , Fang Huiyu , Li Yuhao , Li Shuixing , Lu Xinhui , Ma Wei , Gao Feng , Xie Zengqi , Coropceanu Veaceslav , Zhu Haiming , Bredas Jean-Luc , Zuo Lijian , Chen Hongzheng 
Published: May 2022

AbstractEnhancing the luminescence property without sacrificing the charge collection is one key to high-performance organic solar cells (OSCs), while limited by the severe non-radiative charge recombination. Here, we demonstrate efficient OSCs with high luminescence via the design and synthesis of an asymmetric non-fullerene acceptor, BO-5Cl. Blending BO-5Cl with the PM6 donor leads to a record-high electroluminescence external quantum efficiency of 0.1%, which results in a low non-radiative voltage loss of 0.178 eV and a power conversion efficiency (PCE) over 15%. Importantly, incorporating BO-5Cl as the third component into a widely-studied donor:acceptor (D:A) blend, PM6:BO-4Cl, allows device displaying a high certified PCE of 18.2%. Our joint experimental and theoretical studies unveil that more diverse D:A interfacial conformations formed by asymmetric acceptor induce optimized blend interfacial energetics, which contributes to the improved device performance via balancing charge generation and recombination.
Gasdermin-A3 pore formation propagates along variable pathways
Authors: Mari Stefania A. , Pluhackova Kristyna , Pipercevic Joka , Leipner Matthew , Hiller Sebastian , Engel Andreas , Müller Daniel J. 
Published: May 2022

AbstractGasdermins are main effectors of pyroptosis, an inflammatory form of cell death. Released by proteolysis, the N-terminal gasdermin domain assembles large oligomers to punch lytic pores into the cell membrane. While the endpoint of this reaction, the fully formed pore, has been well characterized, the assembly and pore-forming mechanisms remain largely unknown. To resolve these mechanisms, we characterize mouse gasdermin-A3 by high-resolution time-lapse atomic force microscopy. We find that gasdermin-A3 oligomers assemble on the membrane surface where they remain attached and mobile. Once inserted into the membrane gasdermin-A3 grows variable oligomeric stoichiometries and shapes, each able to open transmembrane pores. Molecular dynamics simulations resolve how the membrane-inserted amphiphilic β-hairpins and the structurally adapting hydrophilic head domains stabilize variable oligomeric conformations and open the pore. The results show that without a vertical collapse gasdermin pore formation propagates along a set of multiple parallel but connected reaction pathways to ensure a robust cellular response.
Copper-catalysed asymmetric reductive cross-coupling of prochiral alkenes
Authors: Yoon Wan Seok , Jang Won Jun , Yoon Woojin , Yun Hoseop , Yun Jaesook 
Published: May 2022

AbstractAsymmetric construction of C(sp3)–C(sp3) bond with good stereocontrol of the two connecting carbon centres retaining all carbon or hydrogen substituents is a challenging target in transition metal catalysis. Transition metal-catalysed reductive coupling of unsaturated π-substrates is considered as a potent tool to expediently develop the molecular complexity with high atom efficiency. However, such an asymmetric and intermolecular process has yet to be developed fully. Herein, we report an efficient strategy to reductively couple two prochiral conjugate alkenes using a copper-catalysed tandem protocol in the presence of diboron. Notably, this transformation incorporates a wide range of terminal and internal enynes as coupling partners and facilitates highly diastereo- and enantioselective synthesis of organoboron derivatives with multiple adjacent stereocentres in a single operation.
TMEM16 scramblases thin the membrane to enable lipid scrambling
Authors: Falzone Maria E. , Feng Zhang , Alvarenga Omar E. , Pan Yangang , Lee ByoungCheol , Cheng Xiaolu , Fortea Eva , Scheuring Simon , Accardi Alessio 
Published: May 2022

AbstractTMEM16 scramblases dissipate the plasma membrane lipid asymmetry to activate multiple eukaryotic cellular pathways. Scrambling was proposed to occur with lipid headgroups moving between leaflets through a membrane-spanning hydrophilic groove. Direct information on lipid-groove interactions is lacking. We report the 2.3 Å resolution cryogenic electron microscopy structure of the nanodisc-reconstituted Ca2+-bound afTMEM16 scramblase showing how rearrangement of individual lipids at the open pathway results in pronounced membrane thinning. Only the groove’s intracellular vestibule contacts lipids, and mutagenesis suggests scrambling does not require specific protein-lipid interactions with the extracellular vestibule. We find scrambling can occur outside a closed groove in thinner membranes and is inhibited in thicker membranes, despite an open pathway. Our results show afTMEM16 thins the membrane to enable scrambling and that an open hydrophilic pathway is not a structural requirement to allow rapid transbilayer movement of lipids. This mechanism could be extended to other scramblases lacking a hydrophilic groove.
Effect of partial distinguishability on quantum supremacy in Gaussian Boson sampling
Authors: Shi Junheng , Byrnes Tim 
Published: May 2022

AbstractGaussian boson sampling (GBS) allows for a way to demonstrate quantum supremacy with the relatively modest experimental resources of squeezed light sources, linear optics, and photon detection. In a realistic experimental setting, numerous effects can modify the complexity of the sampling, in particular loss, partial distinguishability of the photons, and the use of threshold detectors rather than photon counting detectors. In this paper, we investigate GBS with partial distinguishability using an approach based on virtual modes and indistinguishability efficiency. We develop a model using these concepts and derive the probabilities of measuring a specific output pattern from partially distinguishable and lossy GBS for both types of detectors. In the case of threshold detectors, the probability as calculated by the Torontonian is a special case under our framework. By analyzing the expressions of these probabilities we propose an efficient classical simulation algorithm which can be used to calculate the probabilities. Our model and algorithm provide foundations for an approximate method for calculating probabilities. It also allows for a way to design sampling algorithms that are not only compatible with existing algorithms for ideal GBS, but can also reduce their complexity exponentially, depending on the indistinguishability efficiency. Using this we show how the boundary of quantum supremacy in GBS can be affected by partial distinguishability.
Shifts in regional water availability due to global tree restoration
Authors: Hoek van Dijke Anne J. , Herold Martin , Mallick Kaniska , Benedict Imme , Machwitz Miriam , Schlerf Martin , Pranindita Agnes , Theeuwen Jolanda J. E. , Bastin Jean-François , Teuling Adriaan J. 
Published: May 2022

AbstractTree restoration is an effective way to store atmospheric carbon and mitigate climate change. However, large-scale tree-cover expansion has long been known to increase evaporation, leading to reduced local water availability and streamflow. More recent studies suggest that increased precipitation, through enhanced atmospheric moisture recycling, can offset this effect. Here we calculate how 900 million hectares of global tree restoration would impact evaporation and precipitation using an ensemble of data-driven Budyko models and the UTrack moisture recycling dataset. We show that the combined effects of directly enhanced evaporation and indirectly enhanced precipitation create complex patterns of shifting water availability. Large-scale tree-cover expansion can increase water availability by up to 6% in some regions, while decreasing it by up to 38% in others. There is a divergent impact on large river basins: some rivers could lose 6% of their streamflow due to enhanced evaporation, while for other rivers, the greater evaporation is counterbalanced by more moisture recycling. Several so-called hot spots for forest restoration could lose water, including regions that are already facing water scarcity today. Tree restoration significantly shifts terrestrial water fluxes, and we emphasize that future tree-restoration strategies should consider these hydrological effects.
Instantaneous tracking of earthquake growth with elastogravity signals
Authors: Licciardi Andrea , Bletery Quentin , Rouet-Leduc Bertrand , Ampuero Jean-Paul , Juhel Kévin 
Published: May 2022

AbstractRapid and reliable estimation of large earthquake magnitude (above 8) is key to mitigating the risks associated with strong shaking and tsunamis1. Standard early warning systems based on seismic waves fail to rapidly estimate the size of such large earthquakes2–5. Geodesy-based approaches provide better estimations, but are also subject to large uncertainties and latency associated with the slowness of seismic waves. Recently discovered speed-of-light prompt elastogravity signals (PEGS) have raised hopes that these limitations may be overcome6,7, but have not been tested for operational early warning. Here we show that PEGS can be used in real time to track earthquake growth instantaneously after the event reaches a certain magnitude. We develop a deep learning model that leverages the information carried by PEGS recorded by regional broadband seismometers in Japan before the arrival of seismic waves. After training on a database of synthetic waveforms augmented with empirical noise, we show that the algorithm can instantaneously track an earthquake source time function on real data. Our model unlocks ‘true real-time’ access to the rupture evolution of large earthquakes using a portion of seismograms that is routinely treated as noise, and can be immediately transformative for tsunami early warning.
Supporting the gastrointestinal microenvironment during high-dose chemotherapy and stem cell transplantation by inhibiting IL-1 signaling with anakinra
Authors: Wardill H. R. , de Mooij C. E. M. , Da Silva Ferreira A. R. , Havinga H. , Harmsen H. J. M. , van der Velden W. J. F. M. , van Groningen L. F. J. , Tissing W. J. E. , Blijlevens N. M. A. 
Published: May 2022

AbstractHigh-dose chemotherapy causes intestinal inflammation and subsequent breakdown of the mucosal barrier, permitting translocation of enteric pathogens, clinically manifesting as fever. Antibiotics are mainstay for controlling these complications, however, they are increasingly recognized for their detrimental effects, including antimicrobial resistance and dysbiosis. Here, we show that mucosal barrier injury induced by the mucotoxic chemotherapeutic agent, high-dose melphalan (HDM), is characterized by hyper-active IL-1b/CXCL1/neutrophil signaling. Inhibition of this pathway with IL-1RA, anakinra, minimized the duration and intensity of mucosal barrier injury and accompanying clinical symptoms, including diarrhea, weight loss and fever in rats. 16S analysis of fecal microbiome demonstrated a more stable composition in rats receiving anakinra, with reduced pathogen expansion. In parallel, we report through Phase IIA investigation that anakinra is safe in stem cell transplant patients with multiple myeloma after HDM. Ramping-up anakinra (100–300 mg administered intravenously for 15 days) did not cause any adverse events or dose limiting toxicities, nor did it change time to neutrophil recovery. Our results reinforce that strengthening the mucosal barrier may be an effective supportive care strategy to mitigate local and systemic clinical consequences of HDM. We are now conducting a Phase IIB multicenter, placebo-controlled, double-blinded trial to assess clinical efficacy of anakinra (AFFECT-2).Trial registration: ClinicalTrials.gov identifier: NCT03233776.
Whole-genome sequencing of Mycobacterium tuberculosis from Cambodia
Authors: Edokimov Konstantin , Yamada Yoshiyuki , Dary Chhavarath , Miow Qing Hao , Hsu Li-Yang , Ong Rick Twee-Hee , Saphonn Vonthanak 
Published: May 2022

AbstractCambodia has one of the highest tuberculosis (TB) incidence rates in the WHO Western Pacific region. Remarkably though, the prevalence of multidrug-resistant TB (MDR-TB) remains low. We explored the genetic diversity of Mycobacterium tuberculosis (MTB) circulating in this unique setting using whole-genome sequencing (WGS). From October 2017 until January 2018, we collected one hundred sputum specimens from consenting adults older than 21 years of age, newly diagnosed with bacteriologically confirmed TB in 3 districts of Phnom Penh and Takeo provinces of Cambodia before they commence on their TB treatment, where eighty MTB isolates were successfully cultured and sequenced. Majority of the isolates belonged to Lineage 1 (Indo-Oceanic) (69/80, 86.25%), followed by Lineage 2 (East Asian) (10/80, 12.5%) and Lineage 4 (Euro-American) (1/80, 1.25%). Phenotypic resistance to both streptomycin and isoniazid was found in 3 isolates (3/80, 3.75%), while mono-resistance to streptomycin and isoniazid was identical at 2.5% (N = 2 each). None of the isolates tested was resistant to either rifampicin or ethambutol. The specificities of genotypic prediction for resistance to all drugs tested were 100%, while the sensitivities of genotypic resistance predictions to isoniazid and streptomycin were lower at 40% (2/5) and 80% (4/5) respectively. We identified 8 clusters each comprising of two to five individuals all residing in the Takeo province, making up half (28/56, 50%) of all individuals sampled in the province, indicating the presence of multiple ongoing transmission events. All clustered isolates were of Lineage 1 and none are resistant to any of the drugs tested. This study while demonstrating the relevance and utility of WGS in predicting drug resistance and inference of disease transmission, highlights the need to increase the representation of genotype–phenotype TB data from low and middle income countries in Asia and Africa to improve the accuracies for prediction of drug resistance.
COVID-19 infections in infants
Authors: Sobolewska-Pilarczyk Małgorzata , Pokorska-Śpiewak Maria , Stachowiak Anna , Marczyńska Magdalena , Talarek Ewa , Ołdakowska Agnieszka , Kucharek Izabela , Sybilski Adam , Mania Anna , Figlerowicz Magdalena , Mazur-Melewska Katarzyna , Potocka Paulina , Sulik Artur , Hasiec Barbara , Stani Martyna , Frańczak-Chmura Paulina , Szczepańska Barbara , Pałyga-Bysiecka Ilona , Ciechanowski Przemysław , Łasecka-Zadrożna Joanna , Zaleska Izabela , Szenborn Leszek , Dryja Urszula , Kuchar Ernest , Niedźwiecka Sławomira , Kalicki Bolesław , Flisiak Robert , Pawłowska Małgorzata 
Published: May 2022

AbstractThe study aimed to analyse the clinical course of COVID-19 in 300 infants, selected from 1283 children diagnosed with COVID-19 between March and December 2020, registered in the SARSTerPED multicenter database. Most of the infants were registered in October and November 2020. 44% of the group were girls, and 56% were boys. At diagnosis, the most common symptoms were fever in 77% of the children, cough in 40%, catarrh in 37%. Pneumonia associated with COVID-19 was diagnosed in 23% of the children, and gastrointestinal symptoms in 31.3%. In 52% of the infants, elevated levels of D-dimers were observed, and in 40%, elevated levels of IL-6 serum concentration were observed. During the second wave of the pandemic, 6 times more infants were hospitalized, and the children were statistically significantly younger compared to the patients during the first wave (3 months vs 8 months, p < 0.0001 respectively). During the second wave, the infants were hospitalized for longer. COVID-19 in infants usually manifests as a mild gastrointestinal or respiratory infection, but pneumonia is also observed with falls in oxygen saturation, requiring oxygen therapy. Gastrointestinal symptoms are common in infants infected with SARS-CoV-2, and infant appetite disorders may lead to hospitalization. The clinical course of the disease differed significantly between the first and second wave of the pandemic. It seems that infants may play a role in the transmission of SARS-COV-2 infections in households, despite mild or asymptomatic courses; eating disorders in infants should be an indication for COVID-19 testing.
RyR2/IRBIT regulates insulin gene transcript, insulin content, and secretion in the insulinoma cell line INS-1
Authors: Harvey Kyle E. , LaVigne Emily K. , Dar Mohd Saleem , Salyer Amy E. , Pratt Evan P. S. , Sample Paxton A. , Aryal Uma K. , Gowher Humaira , Hockerman Gregory H. 
Published: May 2022

AbstractThe role of ER Ca2+ release via ryanodine receptors (RyR) in pancreatic β-cell function is not well defined. Deletion of RyR2 from the rat insulinoma INS-1 (RyR2KO) enhanced IP3 receptor activity stimulated by 7.5 mM glucose, coincident with reduced levels of the protein IP3Receptor Binding protein released with Inositol 1,4,5 Trisphosphate (IRBIT). Insulin content, basal (2.5 mM glucose) and 7.5 mM glucose-stimulated insulin secretion were reduced in RyR2KO and IRBITKO cells compared to controls. INS2 mRNA levels were reduced in both RyR2KO and IRBITKO cells, but INS1 mRNA levels were specifically decreased in RyR2KO cells. Nuclear localization of S-adenosylhomocysteinase (AHCY) was increased in RyR2KO and IRBITKO cells. DNA methylation of the INS1 and INS2 gene promotor regions was very low, and not different among RyR2KO, IRBITKO, and controls, but exon 2 of the INS1 and INS2 genes was more extensively methylated in RyR2KO and IRBITKO cells. Exploratory proteomic analysis revealed that deletion of RyR2 or IRBIT resulted in differential regulation of 314 and 137 proteins, respectively, with 41 in common. These results suggest that RyR2 regulates IRBIT levels and activity in INS-1 cells, and together maintain insulin content and secretion, and regulate the proteome, perhaps via DNA methylation.
Phase-matched high-order harmonic generation in pre-ionized noble gases
Authors: Finke O. , Vábek J. , Nevrkla M. , Bobrova N. , Hort O. , Jurkovičová L. , Albrecht M. , Jančárek A. , Catoire F. , Skupin S. , Nejdl J. 
Published: May 2022

AbstractOne of the main difficulties of efficiently generating high-order harmonics in long neutral-gas targets is to reach the phase-matching conditions. The issue is that the medium cannot be sufficiently ionized by the driving laser due to plasma defocusing. We propose a method to improve the phase-matching by pre-ionizing the gas using a weak capillary discharge. We have demonstrated this mechanism, for the first time, in absorption-limited XUV generation by an 800 nm femtosecond laser in argon and krypton. The ability to control phase-mismatch is confirmed by an analytical model and numerical simulations of the entire generation process. Our method allows to increase the efficiency of the harmonic generation significantly, paving the way towards photon-hungry applications of these compact short-wavelength sources.
The impact of digital media on children’s intelligence while controlling for genetic differences in cognition and socioeconomic background
Authors: Sauce Bruno , Liebherr Magnus , Judd Nicholas , Klingberg Torkel 
Published: May 2022

AbstractDigital media defines modern childhood, but its cognitive effects are unclear and hotly debated. We believe that studies with genetic data could clarify causal claims and correct for the typically unaccounted role of genetic predispositions. Here, we estimated the impact of different types of screen time (watching, socializing, or gaming) on children’s intelligence while controlling for the confounding effects of genetic differences in cognition and socioeconomic status. We analyzed 9855 children from the USA who were part of the ABCD dataset with measures of intelligence at baseline (ages 9–10) and after two years. At baseline, time watching (r = − 0.12) and socializing (r = − 0.10) were negatively correlated with intelligence, while gaming did not correlate. After two years, gaming positively impacted intelligence (standardized β =  + 0.17), but socializing had no effect. This is consistent with cognitive benefits documented in experimental studies on video gaming. Unexpectedly, watching videos also benefited intelligence (standardized β =  + 0.12), contrary to prior research on the effect of watching TV. Although, in a posthoc analysis, this was not significant if parental education (instead of SES) was controlled for. Broadly, our results are in line with research on the malleability of cognitive abilities from environmental factors, such as cognitive training and the Flynn effect.
Rapid, sensitive, and low-cost detection of Escherichia coli bacteria in contaminated water samples using a phage-based assay
Authors: Alonzo Luis F. , Jain Paras , Hinkley Troy , Clute-Reinig Nick , Garing Spencer , Spencer Ethan , Dinh Van T. T. , Bell David , Nugen Sam , Nichols Kevin P. , Le Ny Anne-Laure M. 
Published: May 2022

AbstractInadequate drinking water quality is among the major causes of preventable mortality, predominantly in young children. Identifying contaminated water sources remains a significant challenge, especially where resources are limited. The current methods for measuring Escherichia coli (E. coli), the WHO preferred indicator for measuring fecal contamination of water, involve overnight incubation and require specialized training. In 2016, UNICEF released a Target Product Profile (TPP) to incentivize product innovations to detect low levels of viable E. coli in water samples in the field in less than 6 h. Driven by this challenge, we developed a phage-based assay to detect and semi-quantify E. coli. We formulated a phage cocktail containing a total of 8 phages selected against an extensive bacterial strain library and recombined with the sensitive NanoLuc luciferase reporter. The assay was optimized to be processed in a microfluidic chip designed in-house and was tested against locally sourced sewage samples and on drinking water sources in Nairobi, Kenya. With this assay, combined with the microfluidic chip platform, we propose a complete automated solution to detect and semi-quantify E. coli at less than 10 MPN/100 mL in 5.5 h by minimally trained personnel.