bluuebunny/crossref_metadata_2025_split huggingface dataset:
Design of a methotrexate-controlled chemical dimerization system and its use in bio-electronic devices
Authors: Guo Zhong , Smutok Oleh , Johnston Wayne A. , Walden Patricia , Ungerer Jacobus P. J. , Peat Thomas S. , Newman Janet , Parker Jake , Nebl Tom , Hepburn Caryn , Melman Artem , Suderman Richard J. , Katz Evgeny , Alexandrov Kirill 
Published: December 2021

AbstractNatural evolution produced polypeptides that selectively recognize chemical entities and their polymers, ranging from ions to proteins and nucleic acids. Such selective interactions serve as entry points to biological signaling and metabolic pathways. The ability to engineer artificial versions of such entry points is a key goal of synthetic biology, bioengineering and bioelectronics. We set out to map the optimal strategy for developing artificial small molecule:protein complexes that function as chemically induced dimerization (CID) systems. Using several starting points, we evolved CID systems controlled by a therapeutic drug methotrexate. Biophysical and structural analysis of methotrexate-controlled CID system reveals the critical role played by drug-induced conformational change in ligand-controlled protein complex assembly. We demonstrate utility of the developed CID by constructing electrochemical biosensors of methotrexate that enable quantification of methotrexate in human serum. Furthermore, using the methotrexate and functionally related biosensor of rapamycin we developed a multiplexed bioelectronic system that can perform repeated measurements of multiple analytes. The presented results open the door for construction of genetically encoded signaling systems for use in bioelectronics and diagnostics, as well as metabolic and signaling network engineering.
Human miRNA miR-675 inhibits DUX4 expression and may be exploited as a potential treatment for Facioscapulohumeral muscular dystrophy
Authors: Saad Nizar Y. , Al-Kharsan Mustafa , Garwick-Coppens Sara E. , Chermahini Gholamhossein Amini , Harper Madison A. , Palo Andrew , Boudreau Ryan L. , Harper Scott Q. 
Published: December 2021

AbstractFacioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the DUX4 gene in skeletal muscles. Effective therapies will likely involve DUX4 inhibition. RNA interference (RNAi) is one powerful approach to inhibit DUX4, and we previously described a RNAi gene therapy to achieve DUX4 silencing in FSHD cells and mice using engineered microRNAs. Here we report a strategy to direct RNAi against DUX4 using the natural microRNA miR-675, which is derived from the lncRNA H19. Human miR-675 inhibits DUX4 expression and associated outcomes in FSHD cell models. In addition, miR-675 delivery using gene therapy protects muscles from DUX4-associated death in mice. Finally, we show that three known miR-675-upregulating small molecules inhibit DUX4 and DUX4-activated FSHD biomarkers in FSHD patient-derived myotubes. To our knowledge, this is the first study demonstrating the use of small molecules to suppress a dominant disease gene using an RNAi mechanism.
Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM
Authors: Wu Runrun , Bakelar Jeremy W. , Lundquist Karl , Zhang Zijian , Kuo Katie M. , Ryoo David , Pang Yui Tik , Sun Chen , White Tommi , Klose Thomas , Jiang Wen , Gumbart James C. , Noinaj Nicholas 
Published: December 2021

AbstractIn Gram-negative bacteria, the biogenesis of β-barrel outer membrane proteins is mediated by the β-barrel assembly machinery (BAM). The mechanism employed by BAM is complex and so far- incompletely understood. Here, we report the structures of BAM in nanodiscs, prepared using polar lipids and native membranes, where we observe an outward-open state. Mutations in the barrel domain of BamA reveal that plasticity in BAM is essential, particularly along the lateral seam of the barrel domain, which is further supported by molecular dynamics simulations that show conformational dynamics in BAM are modulated by the accessory proteins. We also report the structure of BAM in complex with EspP, which reveals an early folding intermediate where EspP threads from the underside of BAM and incorporates into the barrel domain of BamA, supporting a hybrid-barrel budding mechanism in which the substrate is folded into the membrane sequentially rather than as a single unit.
Engineering Bacillus subtilis for the formation of a durable living biocomposite material
Authors: Kang Sun-Young , Pokhrel Anaya , Bratsch Sara , Benson Joey J. , Seo Seung-Oh , Quin Maureen B. , Aksan Alptekin , Schmidt-Dannert Claudia 
Published: December 2021

AbstractEngineered living materials (ELMs) are a fast-growing area of research that combine approaches in synthetic biology and material science. Here, we engineer B. subtilis to become a living component of a silica material composed of self-assembling protein scaffolds for functionalization and cross-linking of cells. B. subtilis is engineered to display SpyTags on polar flagella for cell attachment to SpyCatcher modified secreted scaffolds. We engineer endospore limited B. subtilis cells to become a structural component of the material with spores for long-term storage of genetic programming. Silica biomineralization peptides are screened and scaffolds designed for silica polymerization to fabricate biocomposite materials with enhanced mechanical properties. We show that the resulting ELM can be regenerated from a piece of cell containing silica material and that new functions can be incorporated by co-cultivation of engineered B. subtilis strains. We believe that this work will serve as a framework for the future design of resilient ELMs.
Carbohydrates from Pseudomonas aeruginosa biofilms interact with immune C-type lectins and interfere with their receptor function
Authors: Singh Sonali , Almuhanna Yasir , Alshahrani Mohammad Y. , Lowman Douglas W. , Rice Peter J. , Gell Chris , Ma Zuchao , Graves Bridget , Jackson Darryl , Lee Kelly , Juarez Rucha , Koranteng Janice , Muntaka Sirina , Daniel A. Mitchell  , da Silva Ana C. , Hussain Farah , Yilmaz Gokhan , Mastrotto Francesca , Irie Yasuhiko , Williams Paul , Williams David L. , Cámara Miguel , Martinez-Pomares Luisa 
Published: December 2021

AbstractBacterial biofilms represent a challenge to the healthcare system because of their resilience against antimicrobials and immune attack. Biofilms consist of bacterial aggregates embedded in an extracellular polymeric substance (EPS) composed of polysaccharides, nucleic acids and proteins. We hypothesised that carbohydrates could contribute to immune recognition ofPseudomonas aeruginosabiofilms by engaging C-type lectins. Here we show binding of Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN, CD209), mannose receptor (MR, CD206) and Dectin-2 toP. aeruginosabiofilms. We also demonstrate that DC-SIGN, unlike MR and Dectin-2, recognises planktonicP. aeruginosacultures and this interaction depends on the presence of the common polysaccharide antigen. Within biofilms DC-SIGN, Dectin-2 and MR ligands appear as discrete clusters with dispersed DC-SIGN ligands also found among bacterial aggregates. DC-SIGN, MR and Dectin-2 bind to carbohydrates purified fromP. aeruginosabiofilms, particularly the high molecular weight fraction (HMW; >132,000 Da), with KDs in the nM range. These HMW carbohydrates contain 74.9–80.9% mannose, display α-mannan segments, interfere with the endocytic activity of cell-associated DC-SIGN and MR and inhibit Dectin-2-mediated cellular activation. In addition, biofilm carbohydrates reduce the association of the DC-SIGN ligand Lewisx, but not fucose, to human monocyte-derived dendritic cells (moDCs), and alter moDC morphology without affecting early cytokine production in response to lipopolysaccharide orP. aeruginosacultures. This work identifies the presence of ligands for three important C-type lectins withinP. aeruginosabiofilm structures and purified biofilm carbohydrates and highlights the potential for these receptors to impact immunity toP. aeruginosainfection.
Incidence and characteristics of death from peptic ulcer among cancer patients in the United States
Authors: Yang Pengcheng , Zheng Yongqiang , Zhang Lei , Hou Xiaohua 
Published: December 2021

AbstractMost cancer patients die of non-cancer causes, and peptic ulcer is one cause that deserves attention. To characterize the incidence and risk factors of death from peptic ulcer among cancer patients, we extracted the data of cancer patients registered in the Surveillance Epidemiology and End Results (SEER) program from 1975 to 2016. Out of the 8,471,051 patients extracted from SEER, 4,698 died from peptic ulcer, with a mortality rate of 9.08/100,000 person-years. Meanwhile, the mortality rate in the general population was 5.09/100,000 person-years, giving a standardized mortality ratio (SMR) of 1.78 (95% confidence interval, 1.73–1.84). Patients who are female, of other race, unmarried, and with distant tumor stage have greater SMRs. A higher SMR was associated with a younger age at diagnosis. Among those aged < 40 years at diagnosis, the plurality of fatal peptic ulcers occurred in patients with leukemia and lymphoma, while in patients aged > 40 years, the majority occurred in those with prostate, breast, colorectum, and lung cancer. Patients with upper digestive system malignancies had the highest SMRs and hazard ratios (HRs), which could be ascribed to radiotherapy-induced damage to the gastroduodenum. The risk declined rapidly one year after diagnosis. However, the SMRs in the upper digestive system cancer survivors increased significantly over ten years after diagnosis. Upper digestive system cancers adjacent to the gastroduodenum were associated with higher SMRs and HRs compared with other types of cancer, possibly contributing partially to the damage caused by radiotherapy on the radiosensitive gastroduodenum.
Observation of a giant nonlinear wave-packet on the surface of the ocean
Authors: Onorato Miguel , Cavaleri Luigi , Randoux Stephane , Suret Pierre , Ruiz Maria Isabel , de Alfonso Marta , Benetazzo Alvise 
Published: December 2021

AbstractIn many physical systems such as ocean waves, nonlinear optics, plasma physics etc., extreme events and rare fluctuations of a wave field have been widely observed and discussed. In the field of oceanography and naval architecture, their understanding is fundamental for a correct design of platforms and ships, and for performing safe operations at sea. Here, we report a measurement of an impressive and unique wave packet recorded in the Bay of Biscay in the North-East of the Atlantic Ocean. An analysis of the spatial extension of the packet that includes three large waves reveals that it extents for more than 1 km, with individual crests moving faster than 100 km/h. The central and largest wave in the packet was 27.8 m high in a sea with significant wave height of 11 m. A detailed analysis of the data using the nonlinear Fourier analysis reveals that the wave packet is characterized by a non trivial nonlinear content. This observation opens a new paradigm which requires new understanding of the dynamics of ocean waves and, more in general, of nonlinear and dispersive waves.
Evaluation of a 5-HT2B receptor agonist in a murine model of amyotrophic lateral sclerosis
Authors: Arnoux Alizée , Ayme-Dietrich Estelle , Dieterle Stéphane , Goy Marc-Antoine , Schann Stephan , Frauli Mélanie , Monassier Laurent , Dupuis Luc 
Published: December 2021

AbstractDegeneration of brainstem serotonin neurons has been demonstrated in ALS patients and mouse models and was found responsible for the development of spasticity. Consistent with involvement of central serotonin pathways, 5-HT2B receptor (5-HT2BR) was upregulated in microglia of ALS mice. Its deletion worsened disease outcome in the Sod1G86R mouse model and led to microglial degeneration. In ALS patients, a polymorphism in HTR2B gene leading to higher receptor expression in CNS, was associated with increased survival in patients as well as prevention of microglial degeneration. Thus, the aim of our study was to determine the effect of a 5-HT2BR agonist : BW723C86 (BW), in the Sod1G86R mouse model. Despite good pharmacokinetic and pharmacological profiles, BW did not ameliorate disease outcome or motor neuron degeneration in a fast progressing mouse model of ALS despite evidence of modulation of microglial gene expression.
Tailoring interfacial effect in multilayers with Dzyaloshinskii–Moriya interaction by helium ion irradiation
Authors: Sud A. , Tacchi S. , Sagkovits D. , Barton C. , Sall M. , Diez L. H. , Stylianidis E. , Smith N. , Wright L. , Zhang S. , Zhang X. , Ravelosona D. , Carlotti G. , Kurebayashi H. , Kazakova O. , Cubukcu M. 
Published: December 2021

AbstractWe show a method to control magnetic interfacial effects in multilayers with Dzyaloshinskii–Moriya interaction (DMI) using helium (He$$^{+}$$

+

) ion irradiation. We report results from SQUID magnetometry, ferromagnetic resonance as well as Brillouin light scattering results on multilayers with DMI as a function of irradiation fluence to study the effect of irradiation on the magnetic properties of the multilayers. Our results show clear evidence of the He$$^{+}$$

+

irradiation effects on the magnetic properties which is consistent with interface modification due to the effects of the He$$^{+}$$

+

irradiation. This external degree of freedom offers promising perspectives to further improve the control of magnetic skyrmions in multilayers, that could push them towards integration in future technologies.
Development of a sticker sealed microfluidic device for in situ analytical measurements using synchrotron radiation
Authors: Neckel Itamar T. , de Castro Lucas F. , Callefo Flavia , Teixeira Verônica C. , Gobbi Angelo L. , Piazzetta Maria H. , de Oliveira Ricardo A. G. , Lima Renato S. , Vicente Rafael A. , Galante Douglas , Tolentino Helio C. N. 
Published: December 2021

AbstractShedding synchrotron light on microfluidic systems, exploring several contrasts in situ/operando at the nanoscale, like X-ray fluorescence, diffraction, luminescence, and absorption, has the potential to reveal new properties and functionalities of materials across diverse areas, such as green energy, photonics, and nanomedicine. In this work, we present the micro-fabrication and characterization of a multifunctional polyester/glass sealed microfluidic device well-suited to combine with analytical X-ray techniques. The device consists of smooth microchannels patterned on glass, where three gold electrodes are deposited into the channels to serve in situ electrochemistry analysis or standard electrical measurements. It has been efficiently sealed through an ultraviolet-sensitive sticker-like layer based on a polyester film, and The burst pressure determined by pumping water through the microchannel(up to 0.22 MPa). Overall, the device has demonstrated exquisite chemical resistance to organic solvents, and its efficiency in the presence of biological samples (proteins) is remarkable. The device potentialities, and its high transparency to X-rays, have been demonstrated by taking advantage of the X-ray nanoprobe Carnaúba/Sirius/LNLS, by obtaining 2D X-ray nanofluorescence maps on the microchannel filled with water and after an electrochemical nucleation reaction. To wrap up, the microfluidic device characterized here has the potential to be employed in standard laboratory experiments as well as in in situ and in vivo analytical experiments using a wide electromagnetic window, from infrared to X-rays, which could serve experiments in many branches of science.
All-fiber ultrafast amplifier at 1.9 μm based on thulium-doped normal dispersion fiber and LMA fiber compressor
Authors: Voropaev Vasilii , Batov Daniil , Voronets Andrey , Vlasov Dmitrii , Jafari Rana , Donodin Aleksandr , Tarabrin Mikhail , Trebino Rick , Lazarev Vladimir 
Published: December 2021

AbstractThe duration reduction and the peak power increase of ultrashort pulses generated by all-fiber sources at a wavelength of $$1.9\,\upmu \hbox {m}$$

1.9

μ
m

are urgent tasks. Finding an effective and easy way to improve these characteristics of ultrafast lasers can allow a broad implementation of wideband coherent supercontinuum sources in the mid-IR range required for various applications. As an alternative approach to sub-100 fs pulse generation, we present an ultrafast all-fiber amplifier based on a normal-dispersion germanosilicate thulium-doped active fiber and a large-mode-area silica-fiber compressor. The output pulses have the following characteristics: the central wavelength of $$1.9\,\upmu \hbox {m}$$

1.9

μ
m

, the repetition rate of 23.8 MHz, the energy per pulse period of 25 nJ, the average power of 600 mW, and a random output polarization. The pulse intensity and phase profiles were measured via the second-harmonic-generation frequency-resolved optical gating technique for a linearly polarized pulse. The linearly polarized pulse has a duration of 71 fs and a peak power of 128.7 kW. The maximum estimated peak power for all polarizations is 220 kW. The dynamics of ultrashort-pulse propagation in the amplifier were analyzed using numerical simulations.
Decoding accelerometry for classification and prediction of critically ill patients with severe brain injury
Authors: Bhattacharyay Shubhayu , Rattray John , Wang Matthew , Dziedzic Peter H. , Calvillo Eusebia , Kim Han B. , Joshi Eshan , Kudela Pawel , Etienne-Cummings Ralph , Stevens Robert D. 
Published: December 2021

AbstractOur goal is to explore quantitative motor features in critically ill patients with severe brain injury (SBI). We hypothesized that computational decoding of these features would yield information on underlying neurological states and outcomes. Using wearable microsensors placed on all extremities, we recorded a median 24.1 (IQR: 22.8–25.1) hours of high-frequency accelerometry data per patient from a prospective cohort (n = 69) admitted to the ICU with SBI. Models were trained using time-, frequency-, and wavelet-domain features and levels of responsiveness and outcome as labels. The two primary tasks were detection of levels of responsiveness, assessed by motor sub-score of the Glasgow Coma Scale (GCSm), and prediction of functional outcome at discharge, measured with the Glasgow Outcome Scale–Extended (GOSE). Detection models achieved significant (AUC: 0.70 [95% CI: 0.53–0.85]) and consistent (observation windows: 12 min–9 h) discrimination of SBI patients capable of purposeful movement (GCSm > 4). Prediction models accurately discriminated patients of upper moderate disability or better (GOSE > 5) with 2–6 h of observation (AUC: 0.82 [95% CI: 0.75–0.90]). Results suggest that time series analysis of motor activity yields clinically relevant insights on underlying functional states and short-term outcomes in patients with SBI.
Biophysical characterization of the inactivation of E. coli transketolase by aqueous co-solvents
Authors: Morris Phattaraporn , García-Arrazola Ribia , Rios-Solis Leonardo , Dalby Paul A. 
Published: December 2021

AbstractTransketolase (TK) has been previously engineered, using semi-rational directed evolution and substrate walking, to accept increasingly aliphatic, cyclic, and then aromatic substrates. This has ultimately led to the poor water solubility of new substrates, as a potential bottleneck to further exploitation of this enzyme in biocatalysis. Here we used a range of biophysical studies to characterise the response of both E. coli apo- and holo-TK activity and structure to a range of polar organic co-solvents: acetonitrile (AcCN), n-butanol (nBuOH), ethyl acetate (EtOAc), isopropanol (iPrOH), and tetrahydrofuran (THF). The mechanism of enzyme deactivation was found to be predominantly via solvent-induced local unfolding. Holo-TK is thermodynamically more stable than apo-TK and yet for four of the five co-solvents it retained less activity than apo-TK after exposure to organic solvents, indicating that solvent tolerance was not simply correlated to global conformational stability. The co-solvent concentrations required for complete enzyme inactivation was inversely proportional to co-solvent log(P), while the unfolding rate was directly proportional, indicating that the solvents interact with and partially unfold the enzyme through hydrophobic contacts. Small amounts of aggregate formed in some cases, but this was not sufficient to explain the enzyme inactivation. TK was found to be tolerant to 15% (v/v) iPrOH, 10% (v/v) AcCN, or 6% (v/v) nBuOH over 3 h. This work indicates that future attempts to engineer the enzyme to better tolerate co-solvents should focus on increasing the stability of the protein to local unfolding, particularly in and around the cofactor-binding loops.
INTS8 is a therapeutic target for intrahepatic cholangiocarcinoma via the integration of bioinformatics analysis and experimental validation
Authors: Zhou Qi , Ji Li , Shi Xueying , Deng Dawei , Guo Fangyue , Wang Zhengpeng , Liu Wenhui , Zhang Jinnan , Xia Shilin , Shang Dong 
Published: December 2021

AbstractIntrahepatic cholangiocarcinoma (CHOL) remains a rare malignancy, ranking as the leading lethal primary liver cancer worldwide. However, the biological functions of integrator complex subunit 8 (INTS8) in CHOL remain unknown. Thus, this research aimed to explore the potential role of INTS8 as a novel diagnostic or therapeutic target in CHOL. Differentially expressed genes (DEGs) in two Gene Expression Omnibus (GEO) datasets were obtained by the “RRA” package in R software. The “maftools” package was used to visualize the CHOL mutation data from The Cancer Genome Atlas (TCGA) database. The expression of INTS8 was detected by performing quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemistry in cell lines and human samples. The association between subtypes of tumour-infiltrating immune cells (TIICs) and INTS8 expression in CHOL was determined by using CIBERSORT tools. We evaluated the correlations between INTS8 expression and mismatch repair (MMR) genes and DNA methyltransferases (DNMTs) in pan-cancer analysis. Finally, the pan-cancer prognostic signature of INTS8 was identified by univariate analysis. We obtained the mutation landscapes of an RRA gene set in CHOL. The expression of INTS8 was upregulated in CHOL cell lines and human CHOL samples. Furthermore, INTS8 expression was closely associated with a distinct landscape of TIICs, MMR genes, and DNMTs in CHOL. In addition, the high INTS8 expression group presented significantly poor outcomes, including overall survival (OS), disease-specific survival (DSS) and disease-free interval (DFI) (p < 0.05) in pan-cancer. INTS8 contributes to the tumorigenesis and progression of CHOL. Our study highlights the significant role of INTS8 in CHOL and pan-cancers, providing a valuable molecular target for cancer research.