bluuebunny/crossref_metadata_2025 huggingface dataset:
The Entire Crust can be Seismogenic: Evidence from Southern Malawi
Authors: Stevens V. L. , Sloan R. A. , Chindandali P. R. , Wedmore L. N. J. , Salomon G. W. , Muir R. A.
Published: June 2021

The Bilila‐Mtakataka Fault (BMF), at the southern end of the western branch of the East African Rift System (EARS), has been used in various scaling relation studies and arguments about the strength of the lithosphere. We present evidence for a similar, though more degraded, frontal scarp on the graben‐bounding synthetic Chirobwe‐Ntcheu Fault (CNF), showing that this fault is active simultaneously with the BMF. We deployed 17 geophones for ∼60 days around the southern end of Lake Malawi, across the footwall and hangingwall of the BMF. Continuous microseismicity can be seen from the surface to ∼35 km depth highlighting a plane dipping ∼42°E. Lower‐crustal earthquakes have previously been found in the EARS, and based on location and focal mechanism have been hypothesized to occur on planes that line up with the surface traces of large faults. However, no previous study of the EARS has revealed a fault plane throughout the crust that shows seismicity along its full length from the surface to the base of the crust. Rather, the lack of seismicity seen at mid‐lower crustal depths, has led some people to the “jelly sandwich” hypothesis. Our results show that the entire crust is seismogenic, so support the “crème brûlée” model. In our two month deployment we recorded 22 aftershocks ML ≥ 2 from the March 8th, 2018 earthquake 200 km south of our array, 7 months after the mainshock, confirming that aftershock sequences in regions of low strain have a long duration, and could be the main component of seismicity in slowly straining regions.
Teleseismic P‐Wave Attenuation Beneath the Southeastern United States
Authors: Shrivastava Ashutosh , Liu Kelly H. , Gao Stephen S.
Published: June 2021

Seismic attenuation is an important parameter for characterizing subsurface morphology and thermal structure. In this study, we use P‐wave amplitude spectra from 588 teleseismic events recorded by 477 broadband seismic stations in the southeastern United States to examine the spatial variations of seismic attenuation in the crust and upper mantle. The resulting seismic attenuation parameter (∆t*) measurements obtained using the spectral ratio technique reveal a zone of relatively low attenuation in the Gulf of Mexico Coastal Plain and the southwestern terminus of the Piedmont province. Spatial coherency analysis of the ∆t* observations suggests that the center of the low attenuation layer is located within the uppermost mantle at about 70 km depth. This low attenuation anomaly lies along the suture zone between Laurentia and Gondwana and approximately coincides with the east‐west trending Brunswick magnetic anomaly. The origin of this low attenuation anomaly can be attributed to low attenuation bodies in the form of remnant lithospheric fragments in the deep crust and the uppermost mantle. The contribution of scattering to the observed ∆t* is estimated by calculating the ratio of amplitude on the transverse and vertical components in the P‐wave window. Relative to the rest of the study area, the Gulf of Mexico Coastal Plain demonstrates weaker scattering which is suggestive of a more homogenous crustal and uppermost mantle structure.
Subauroral Flow Channel Structures and Auroral Undulations Triggered by Kelvin‐Helmholtz Waves
Authors: Horvath Ildiko , Lovell Brian C.
Published: June 2021

We investigate Kelvin‐Helmholtz (K‐H) waves on/near the magnetopause and surface waves near the plasmapause—in the outer region of the plasmasphere: in the hot zone—by utilizing multi‐instrument/satellite observations. Our main aim is to study how the K‐H waves and the K‐H instability mechanisms impacted the subauroral and auroral regions during the geomagnetic storms of May 27–29 and July 16, 2017. For the subauroral region, we specify the structured flows as Sub‐Auroral Polarization Streams Wave Structures (SAPS‐WS) and the combined flows—created by Abnormal Sub‐Auroral Ion Drifts (ASAID) and SAID or SAPS—as a complex equatorward‐poleward ASAID‐SAID or SAPS‐ASAID. For the auroral zone, we identify the large auroral undulations appearing inside the auroral zone. The correlated observations of the K‐H waves, the structured or complex subauroral flows and large auroral undulations, and the local geomagnetic field oscillations confirm the connections of both the subauroral flows and the auroral undulations with the K‐H waves via the eigenfrequency of the Near‐Earth Plasma Sheet (NEPS) resonator activated by the K‐H waves. For the first time, we demonstrate the simultaneous detections of K‐H waves near the magnetopause and surface waves near the plasmapause in the hot zone on July 16, 2017, and conclude their coupling via the NEPS resonator's eigenfrequency. Thus, the surface waves near the plasmapause were the manifestation of the undulating (or rippled) earthward inner boundary of the NEPS that led to the development of ASAID‐SAID/SAPS‐ASAID or SAPS‐WS in the subauroral region and to the large auroral undulation inside the auroral zone.
Efficacy of early warning signals and spectral periodicity for predicting transitions in bipolar patients: An actigraphy study
Authors: Kunkels Yoram K. , Riese Harriëtte , Knapen Stefan E. , Riemersma - van der Lek Rixt F. , George Sandip V. , van Roon Arie M. , Schoevers Robert A. , Wichers Marieke
Published: June 2021

Early-warning signals (EWS) have been successfully employed to predict transitions in research fields such as biology, ecology, and psychiatry. The predictive properties of EWS might aid in foreseeing transitions in mood episodes (i.e. recurrent episodes of mania and depression) in bipolar disorder (BD) patients. We analyzed actigraphy data assessed during normal daily life to investigate the feasibility of using EWS to predict mood transitions in bipolar patients. Actigraphy data of 15 patients diagnosed with BD Type I collected continuously for 180 days were used. Our final sample included eight patients that experienced a mood episode, three manic episodes and five depressed episodes. Actigraphy data derived generic EWS (variance and kurtosis) and context-driven EWS (autocorrelation at lag-720) were used to determine if these were associated to upcoming bipolar episodes. Spectral analysis was used to predict changes in the periodicity of the sleep/wake cycle. The study procedures were pre-registered. Results indicated that in seven out of eight patients at least one of the EWS did show a significant change-up till four weeks before episode onset. For the generic EWS the direction of change was always in the expected direction, whereas for the context-driven EWS the observed effect was often in the direction opposite of what was expected. The actigraphy data derived EWS and spectral analysis showed promise for the prediction of upcoming transitions in mood episodes in bipolar patients. Further studies into false positive rates are suggested to improve effectiveness for EWS to identify upcoming bipolar episode onsets.
Generation of functional liver organoids on combining hepatocytes and cholangiocytes with hepatobiliary connections ex vivo
Authors: Tanimizu Naoki , Ichinohe Norihisa , Sasaki Yasushi , Itoh Tohru , Sudo Ryo , Yamaguchi Tomoko , Katsuda Takeshi , Ninomiya Takafumi , Tokino Takashi , Ochiya Takahiro , Miyajima Atsushi , Mitaka Toshihiro
Published: June 2021

In the liver, the bile canaliculi of hepatocytes are connected to intrahepatic bile ducts lined with cholangiocytes, which remove cytotoxic bile from the liver tissue. Although liver organoids have been reported, it is not clear whether the functional connection between hepatocytes and cholangiocytes is recapitulated in those organoids. Here, we report the generation of a hepatobiliary tubular organoid (HBTO) using mouse hepatocyte progenitors and cholangiocytes. Hepatocytes form the bile canalicular network and secrete metabolites into the canaliculi, which are then transported into the biliary tubular structure. Hepatocytes in HBTO acquire and maintain metabolic functions including albumin secretion and cytochrome P450 activities, over the long term. In this study, we establish functional liver tissue incorporating a bile drainage system ex vivo. HBTO enable us to reproduce the transport of hepatocyte metabolites in liver tissue, and to investigate the way in which the two types of epithelial cells establish functional connections.
HOXA13 in etiology and oncogenic potential of Barrett’s esophagus
Authors: Janmaat Vincent T. , Nesteruk Kateryna , Spaander Manon C. W. , Verhaar Auke P. , Yu Bingting , Silva Rodrigo A. , Phillips Wayne A. , Magierowski Marcin , van de Winkel Anouk , Stadler H. Scott , Sandoval-Guzmán Tatiana , van der Laan Luc J. W. , Kuipers Ernst J. , Smits Ron , Bruno Marco J. , Fuhler Gwenny M. , Clemons Nicholas J. , Peppelenbosch Maikel P.
Published: June 2021

Barrett’s esophagus in gastrointestinal reflux patients constitutes a columnar epithelium with distal characteristics, prone to progress to esophageal adenocarcinoma.HOXgenes are known mediators of position-dependent morphology. Here we showHOXcollinearity in the adult gut while Barrett’s esophagus shows highHOXA13expression in stem cells and their progeny.HOXA13overexpression appears sufficient to explain both the phenotype (through downregulation of the epidermal differentiation complex) and the oncogenic potential of Barrett’s esophagus. Intriguingly, employing a mouse model that contains a reporter coupled to theHOXA13promotor we identify single HOXA13-positive cells distally from the physiological esophagus, which is mirrored in human physiology, but increased in Barrett’s esophagus. Additionally, we observe thatHOXA13expression confers a competitive advantage to cells. We thus propose that Barrett’s esophagus and associated esophageal adenocarcinoma is the consequence of expansion of this gastro-esophagealHOXA13-expressing compartment following epithelial injury.
Robust adaptive optics for localization microscopy deep in complex tissue
Authors: Siemons Marijn E. , Hanemaaijer Naomi A. K. , Kole Maarten H. P. , Kapitein Lukas C.
Published: June 2021

Single-Molecule Localization Microscopy (SMLM) provides the ability to determine molecular organizations in cells at nanoscale resolution, but in complex biological tissues, where sample-induced aberrations hamper detection and localization, its application remains a challenge. Various adaptive optics approaches have been proposed to overcome these issues, but the exact performance of these methods has not been consistently established. Here we systematically compare the performance of existing methods using both simulations and experiments with standardized samples and find that they often provide limited correction or even introduce additional errors. Careful analysis of the reasons that underlie this limited success enabled us to develop an improved method, termed REALM (Robust and Effective Adaptive Optics in Localization Microscopy), which corrects aberrations of up to 1 rad RMS using 297 frames of blinking molecules to improve single-molecule localization. After its quantitative validation, we demonstrate that REALM enables to resolve the periodic organization of cytoskeletal spectrin of the axon initial segment even at 50 μm depth in brain tissue.
Enhanced responsivity and detectivity of fast WSe2 phototransistor using electrostatically tunable in-plane lateral p-n homojunction
Authors: Ghosh Sayantan , Varghese Abin , Thakar Kartikey , Dhara Sushovan , Lodha Saurabh
Published: June 2021

Layered transition metal dichalcogenides have shown tremendous potential for photodetection due to their non-zero direct bandgaps, high light absorption coefficients and carrier mobilities, and ability to form atomically sharp and defect-free heterointerfaces. A critical and fundamental bottleneck in the realization of high performance detectors is their trap-dependent photoresponse that trades off responsivity with speed. This work demonstrates a facile method of attenuating this trade-off by nearly 2x through integration of a lateral, in-plane, electrostatically tunable p-n homojunction with a conventional WSe2 phototransistor. The tunable p-n junction allows modulation of the photocarrier population and width of the conducting channel independently from the phototransistor. Increased illumination current with the lateral p-n junction helps achieve responsivity enhancement upto 2.4x at nearly the same switching speed (14–16 µs) over a wide range of laser power (300 pW–33 nW). The added benefit of reduced dark current enhances specific detectivity (D*) by nearly 25x to yield a maximum measured flicker noise-limited D* of 1.1×1012 Jones. High responsivity of 170 A/W at 300 pW laser power along with the ability to detect sub-1 pW laser switching are demonstrated.
Assessment of protein–protein interfaces in cryo-EM derived assemblies
Authors: Malhotra Sony , Joseph Agnel Praveen , Thiyagalingam Jeyan , Topf Maya
Published: June 2021

Structures of macromolecular assemblies derived from cryo-EM maps often contain errors that become more abundant with decreasing resolution. Despite efforts in the cryo-EM community to develop metrics for map and atomistic model validation, thus far, no specific scoring metrics have been applied systematically to assess the interface between the assembly subunits. Here, we comprehensively assessed protein–protein interfaces in macromolecular assemblies derived by cryo-EM. To this end, we developed Protein Interface-score (PI-score), a density-independent machine learning-based metric, trained using the features of protein–protein interfaces in crystal structures. We evaluated 5873 interfaces in 1053 PDB-deposited cryo-EM models (including SARS-CoV-2 complexes), as well as the models submitted to CASP13 cryo-EM targets and the EM model challenge. We further inspected the interfaces associated with low-scores and found that some of those, especially in intermediate-to-low resolution (worse than 4 Å) structures, were not captured by density-based assessment scores. A combined score incorporating PI-score and fit-to-density score showed discriminatory power, allowing our method to provide a powerful complementary assessment tool for the ever-increasing number of complexes solved by cryo-EM.
Robust detection of translocations in lymphoma FFPE samples using targeted locus capture-based sequencing
Authors: Allahyar Amin , Pieterse Mark , Swennenhuis Joost , Los-de Vries G. Tjitske , Yilmaz Mehmet , Leguit Roos , Meijers Ruud W. J. , van der Geize Robert , Vermaat Joost , Cleven Arjen , van Wezel Tom , Diepstra Arjan , van Kempen Léon C. , Hijmering Nathalie J. , Stathi Phylicia , Sharma Milan , Melquiond Adrien S. J. , de Vree Paula J. P. , Verstegen Marjon J. A. M. , Krijger Peter H. L. , Hajo Karima , Simonis Marieke , Rakszewska Agata , van Min Max , de Jong Daphne , Ylstra Bauke , Feitsma Harma , Splinter Erik , de Laat Wouter
Published: June 2021

In routine diagnostic pathology, cancer biopsies are preserved by formalin-fixed, paraffin-embedding (FFPE) procedures for examination of (intra-) cellular morphology. Such procedures inadvertently induce DNA fragmentation, which compromises sequencing-based analyses of chromosomal rearrangements. Yet, rearrangements drive many types of hematolymphoid malignancies and solid tumors, and their manifestation is instructive for diagnosis, prognosis, and treatment. Here, we present FFPE-targeted locus capture (FFPE-TLC) for targeted sequencing of proximity-ligation products formed in FFPE tissue blocks, and PLIER, a computational framework that allows automated identification and characterization of rearrangements involving selected, clinically relevant, loci. FFPE-TLC, blindly applied to 149 lymphoma and control FFPE samples, identifies the known and previously uncharacterized rearrangement partners. It outperforms fluorescence in situ hybridization (FISH) in sensitivity and specificity, and shows clear advantages over standard capture-NGS methods, finding rearrangements involving repetitive sequences which they typically miss. FFPE-TLC is therefore a powerful clinical diagnostics tool for accurate targeted rearrangement detection in FFPE specimens.
Gold-in-copper at low *CO coverage enables efficient electromethanation of CO2
Authors: Wang Xue , Ou Pengfei , Wicks Joshua , Xie Yi , Wang Ying , Li Jun , Tam Jason , Ren Dan , Howe Jane Y. , Wang Ziyun , Ozden Adnan , Finfrock Y. Zou , Xu Yi , Li Yuhang , Rasouli Armin Sedighian , Bertens Koen , Ip Alexander H. , Graetzel Michael , Sinton David , Sargent Edward H.
Published: June 2021

The renewable-electricity-powered CO2 electroreduction reaction provides a promising means to store intermittent renewable energy in the form of valuable chemicals and dispatchable fuels. Renewable methane produced using CO2 electroreduction attracts interest due to the established global distribution network; however, present-day efficiencies and activities remain below those required for practical application. Here we exploit the fact that the suppression of *CO dimerization and hydrogen evolution promotes methane selectivity: we reason that the introduction of Au in Cu favors *CO protonation vs. C−C coupling under low *CO coverage and weakens the *H adsorption energy of the surface, leading to a reduction in hydrogen evolution. We construct experimentally a suite of Au-Cu catalysts and control *CO availability by regulating CO2 concentration and reaction rate. This strategy leads to a 1.6× improvement in the methane:H2 selectivity ratio compared to the best prior reports operating above 100 mA cm−2. We as a result achieve a CO2-to-methane Faradaic efficiency (FE) of (56 ± 2)% at a production rate of (112 ± 4) mA cm−2.
Full-frame and high-contrast smart windows from halide-exchanged perovskites
Authors: Liu You , Wang Jungan , Wang Fangfang , Cheng Zhengchun , Fang Yinyu , Chang Qing , Zhu Jixin , Wang Lin , Wang Jianpu , Huang Wei , Qin Tianshi
Published: June 2021

Window glazing plays an essential role to modulate indoor light and heat transmission, which is a prospect to save the energy cost in buildings. The latest photovoltachromic technology has been regarded as one of the most ideal solutions, however, to achieve full-frame size (100% active area) and high-contrast ratio (>30% variable in visible wavelength) for smart window applicability is still a challenge. Here we report a photovoltachromic device combining full-transparent perovskite photovoltaic and ion-gel based electrochromic components in a vertical tandem architecture without any intermediated electrode. Most importantly, by accurately adjusting the halide-exchanging period, this photovoltachromic module can realize a high pristine transmittance up to 76%. Moreover, it possesses excellent colour-rendering index to 96, wide contrast ratio (>30%) on average visible transmittance (400-780 nm), and a self-adaptable transmittance adjustment and control indoor brightness and temperature automatically depending on different solar irradiances.
Spatial intimacy of binary active-sites for selective sequential hydrogenation-condensation of nitriles into secondary imines
Authors: Zhang Sai , Xia Zhaoming , Zou Yong , Zhang Mingkai , Qu Yongquan
Published: June 2021

Precisely controlling the spatial intimacy of multiple active sites at sub-nanoscale in heterogeneous catalysts can improve their selectivity and activity. Herein, we realize a highly selective nitrile-to-secondary imine transformation through a cascaded hydrogenation and condensation process by Pt1/CoBOx comprising the binary active sites of the single-dispersed Pt and interfacial Lewis acidic B. Atomic Pt sites with large inter-distances (>nanometers) only activate hydrogen for nitrile hydrogenation, but inhibit condensation. Both adjacent B…B on CoBOx and neighbouring Pt…B pairs with close intimacy of ~0.45 nm can satisfy the spatial prerequisites for condensation. Mechanism investigations demonstrate the energetically favorable pathway occurred on adjacent Lewis acidic B sites through the nitrile adsorption (acid-base interaction), hydrogenation via hydrogen spillover from Pt to B sites and sequential condensation. Strong intermolecular tension and steric hindrance of secondary imines on active sites lead to their effective desorption and thereby a high chemoselectivity of secondary imines.
Intratumoral synthesis of nano-metalchelate for tumor catalytic therapy by ligand field-enhanced coordination
Authors: Yang Bowen , Yao Heliang , Tian Han , Yu Zhiguo , Guo Yuedong , Wang Yuemei , Yang Jiacai , Chen Chang , Shi Jianlin
Published: June 2021

The iron gall ink-triggered chemical corrosion of hand-written documents is a big threat to Western cultural heritages, which was demonstrated to result from the iron gall (GA-Fe) chelate-promoted reactive oxygen species generation. Such a phenomenon has inspired us to apply the pro-oxidative mechanism of GA-Fe to anticancer therapy. In this work, we construct a composite cancer nanomedicine by loading gallate into a Fe-engineered mesoporous silica nanocarrier, which can degrade in acidic tumor to release the doped Fe3+and the loaded gallate, forming GA-Fe nanocomplex in situ. The nanocomplex with a highly reductive ligand field can promote oxygen reduction reactions generating hydrogen peroxide. Moreover, the resultant two-electron oxidation form of GA-Fe is an excellent Fenton-like agent that can catalyze hydrogen peroxide decomposition into hydroxyl radical, finally triggering severe oxidative damage to tumors. Such a therapeutic approach by intratumoral synthesis of GA-Fe nano-metalchelate may be instructive to future anticancer researches.
Deep learning boosts sensitivity of mass spectrometry-based immunopeptidomics
Authors: Wilhelm Mathias , Zolg Daniel P. , Graber Michael , Gessulat Siegfried , Schmidt Tobias , Schnatbaum Karsten , Schwencke-Westphal Celina , Seifert Philipp , de Andrade Krätzig Niklas , Zerweck Johannes , Knaute Tobias , Bräunlein Eva , Samaras Patroklos , Lautenbacher Ludwig , Klaeger Susan , Wenschuh Holger , Rad Roland , Delanghe Bernard , Huhmer Andreas , Carr Steven A. , Clauser Karl R. , Krackhardt Angela M. , Reimer Ulf , Kuster Bernhard
Published: June 2021

Characterizing the human leukocyte antigen (HLA) bound ligandome by mass spectrometry (MS) holds great promise for developing vaccines and drugs for immune-oncology. Still, the identification of non-tryptic peptides presents substantial computational challenges. To address these, we synthesized and analyzed >300,000 peptides by multi-modal LC-MS/MS within the ProteomeTools project representing HLA class I & II ligands and products of the proteases AspN and LysN. The resulting data enabled training of a single model using the deep learning framework Prosit, allowing the accurate prediction of fragment ion spectra for tryptic and non-tryptic peptides. Applying Prosit demonstrates that the identification of HLA peptides can be improved up to 7-fold, that 87% of the proposed proteasomally spliced HLA peptides may be incorrect and that dozens of additional immunogenic neo-epitopes can be identified from patient tumors in published data. Together, the provided peptides, spectra and computational tools substantially expand the analytical depth of immunopeptidomics workflows.
Topographic numerosity maps cover subitizing and estimation ranges
Authors: Cai Yuxuan , Hofstetter Shir , van Dijk Jelle , Zuiderbaan Wietske , van der Zwaag Wietske , Harvey Ben M. , Dumoulin Serge O.
Published: June 2021

Numerosity, the set size of a group of items, helps guide behaviour and decisions. Non-symbolic numerosities are represented by the approximate number system. However, distinct behavioural performance suggests that small numerosities, i.e. subitizing range, are implemented differently in the brain than larger numerosities. Prior work has shown that neural populations selectively responding (i.e. hemodynamic responses) to small numerosities are organized into a network of topographical maps. Here, we investigate how neural populations respond to large numerosities, well into the ANS. Using 7 T fMRI and biologically-inspired analyses, we found a network of neural populations tuned to both small and large numerosities organized within the same topographic maps. These results demonstrate a continuum of numerosity preferences that progressively cover both the subitizing range and beyond within the same numerosity map, suggesting a single neural mechanism. We hypothesize that differences in map properties, such as cortical magnification and tuning width, underlie known differences in behaviour.
Lead halide perovskite for efficient optoacoustic conversion and application toward high-resolution ultrasound imaging
Authors: Du Xinyuan , Li Jiapu , Niu Guangda , Yuan Jun-Hui , Xue Kan-Hao , Xia Mengling , Pan Weicheng , Yang Xiaofei , Zhu Benpeng , Tang Jiang
Published: June 2021

Lead halide perovskites have exhibited excellent performance in solar cells, LEDs and detectors. Thermal properties of perovskites, such as heat capacity and thermal conductivity, have rarely been studied and corresponding devices have barely been explored. Considering the high absorption coefficient (104~105 cm−1), low specific heat capacity (296–326 J kg−1 K−1) and small thermal diffusion coefficient (0.145 mm2 s−1), herein we showcase the successful use of perovskite in optoacoustic transducers. The theoretically calculated phonon spectrum shows that the overlap of optical phonons and acoustic phonons leads to the up-conversion of acoustic phonons, and thus results in experimentally measured low thermal diffusion coefficient. The assembled device of PDMS/MAPbI3/PDMS simultaneously achieves broad bandwidths (−6 dB bandwidth: 40.8 MHz; central frequency: 29.2 MHz), and high conversion efficiency (2.97 × 10−2), while all these parameters are the record values for optoacoustic transducers. We also fabricate miniatured devices by assembling perovskite film onto fibers, and clearly resolve the fine structure of fisheyes, which demonstrates the strong competitiveness of perovskite based optoacoustic transducers for ultrasound imaging.
Autofluorescence as a noninvasive biomarker of senescence and advanced glycation end products in Caenorhabditis elegans
Authors: Komura Tomomi , Yamanaka Mikihiro , Nishimura Kohji , Hara Keita , Nishikawa Yoshikazu
Published: June 2021

To assess the utility of autofluorescence as a noninvasive biomarker of senescence in Caenorhabditis elegans, we measured the autofluorescence of individual nematodes using spectrofluorometry. The fluorescence of each worm increased with age. Animals with lower fluorescence intensity exhibited longer life expectancy. When proteins extracted from worms were incubated with sugars, the fluorescence intensity and the concentration of advanced glycation end products (AGEs) increased over time. Ribose enhanced these changes not only in vitro but also in vivo. The glycation blocker rifampicin suppressed this rise in fluorescence. High-resolution mass spectrometry revealed that vitellogenins accumulated in old worms, and glycated vitellogenins emitted six-fold higher fluorescence than naive vitellogenins. The increase in fluorescence with ageing originates from glycated substances, and therefore could serve as a useful noninvasive biomarker of AGEs. C. elegans can serve as a new model to look for anti-AGE factors and to study the relationship between AGEs and senescence.
Multiomic analysis of stretched osteocytes reveals processes and signalling linked to bone regeneration and cancer
Authors: Santos Lívia , Ugun-Klusek Aslihan , Coveney Clare , Boocock David J.
Published: June 2021

Exercise is a non-pharmacological intervention that can enhance bone regeneration and improve the management of bone conditions like osteoporosis or metastatic bone cancer. Therefore, it is gaining increasing importance in an emerging area of regenerative medicine—regenerative rehabilitation (RR). Osteocytes are mechanosensitive and secretory bone cells that orchestrate bone anabolism and hence postulated to be an attractive target of regenerative exercise interventions. However, the human osteocyte signalling pathways and processes evoked upon exercise remain to be fully identified. Making use of a computer-controlled bioreactor that mimics exercise and the latest omics approaches, RNA sequencing (RNA-seq) and tandem liquid chromatography-mass spectrometry (LC-MS), we mapped the transcriptome and secretome of mechanically stretched human osteocytic cells. We discovered that a single bout of cyclic stretch activated network processes and signalling pathways likely to modulate bone regeneration and cancer. Furthermore, a comparison between the transcriptome and secretome of stretched human and mouse osteocytic cells revealed dissimilar results, despite both species sharing evolutionarily conserved signalling pathways. These findings suggest that osteocytes can be targeted by exercise-driven RR protocols aiming to modulate bone regeneration or metastatic bone cancer.
Novel recombinant keratin degrading subtilisin like serine alkaline protease from Bacillus cereus isolated from marine hydrothermal vent crabs
Authors: Gurunathan Revathi , Huang Bin , Ponnusamy Vinoth Kumar , Hwang Jiang-Shiou , Dahms Hans-Uwe
Published: June 2021

Microbial secondary metabolites from extreme environments like hydrothermal vents are a promising source for industrial applications. In our study the protease gene from Bacillus cereus obtained from shallow marine hydrothermal vents in the East China Sea was cloned, expressed and purified. The protein sequence of 38 kDa protease SLSP-k was retrieved from mass spectrometry and identified as a subtilisin serine proteinase. The novel SLSP-k is a monomeric protein with 38 amino acid signal peptides being active over wide pH (7–11) and temperature (40–80 °C) ranges, with maximal hydrolytic activities at pH 10 and at 50 °C temperature. The hydrolytic activity is stimulated by Ca2+, Co2+, Mn2+, and DTT. It is inhibited by Fe2+, Cd2+, Cu2+, EDTA, and PMSF. The SLSP-k is stable in anionic, non-anionic detergents, and solvents. The ability to degrade keratin in chicken feather and hair indicates that this enzyme is suitable for the degradation of poultry waste without the loss of nutritionally essential amino acids which otherwise are lost in hydrothermal processing. Therefore, the proteinase is efficient in environmental friendly bioconversion of animal waste into fertilizers or value added products such as secondary animal feedstuffs.
Prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer
Authors: Hwang Ki-Tae , Kim Young A. , Kim Jongjin , Oh Hyeon Jeong , Park Jeong Hwan , Choi In Sil , Park Jin Hyun , Oh Sohee , Chu Ajung , Lee Jong Yoon , Hwang Kyu Ri
Published: June 2021

We investigated the prognostic influences of BCL1 and BCL2 expression on disease-free survival in breast cancer patients. BCL1 and BCL2 expression statuses were assessed by immunohistochemistry using tissue microarrays from 393 breast cancer patients. The Kaplan–Meier estimator and log-rank test were used for survival analyses. The Cox proportional hazards model was used to calculate hazard ratio (HR) and the 95% confidence interval (CI) of survival analyses. BCL1 expression revealed no impact on survival. The high BCL2 group showed superior disease-free survival compared with the low BCL2 group (p = 0.002), especially regarding local recurrence-free survival (p = 0.045) and systemic recurrence-free survival (p = 0.002). BCL2 expression was a significant prognostic factor by univariable analysis (HR, 0.528; 95% CI, 0.353–0.790; p = 0.002) and by multivariable analysis (HR, 0.547; 95% CI, 0.362–0.826; p = 0.004). High BCL2 expression was associated with higher disease-free survival in the hormone receptor (HRc)-positive and human epidermal growth factor receptor 2 (HER2)-negative (HRc(+)/HER2(−)) subtype only (p = 0.002). The high BCL2 group was associated with positive estrogen receptor (ER), positive progesterone receptor (PR), low histologic grade, and age ≤ 50 years. BCL1 expression had no prognostic impact, but BCL2 expression was a significant independent prognostic factor. High BCL2 expression was associated with higher disease-free survival, especially regarding local recurrence and systemic recurrence. The prognostic effect of BCL2 expression was effective only in the HRc(+)/HER2(−) subtype. Favorable clinicopathologic features and a strong association with the ER/PR status could partly explain the superior prognosis of the high BCL2 group. BCL2 expression could be utilized to assess the prognosis of breast cancer patients in clinical settings.
ALDH1 expression predicts progression of premalignant lesions to cancer in Type I endometrial carcinomas
Authors: Mah Vei , Elshimali Yahya , Chu Alison , Moatamed Neda A. , Uzzell Jamar P. , Tsui Jessica , Schettler Stephen , Shakeri Hania , Wadehra Madhuri
Published: June 2021

In type 1 endometrial cancer, unopposed estrogen stimulation is thought to lead to endometrial hyperplasia which precedes malignant progression. Recent data from our group and others suggest that ALDH activity mediates stemness in endometrial cancer, but while aldehyde dehydrogenase 1 (ALDH1) has been suggested as a putative cancer stem cell marker in several cancer types, its clinical and prognostic value in endometrial cancer remains debated. The aim of this study was to investigate the clinical value of ALDH1 expression in endometrial hyperplasia and to determine its ability to predict progression to endometrial cancer. Interrogation of the TCGA database revealed upregulation of several isoforms in endometrial cancer, of which the ALDH1 isoforms collectively constituted the largest group. To translate its expression, a tissue microarray was previously constructed which contained a wide sampling of benign and malignant endometrial samples. The array contained a metachronous cohort of samples from individuals who either developed or did not develop endometrial cancer. Immunohistochemical staining was used to determine the intensity and frequency of ALDH1 expression. While benign proliferative and secretory endometrium showed very low levels of ALDH1, slightly higher expression was observed within the stratum basalis. In disease progression, cytoplasmic ALDH1 expression showed a step-wise increase between endometrial hyperplasia, atypical hyperplasia, and endometrial cancer. ALDH1 was also shown to be an early predictor of EC development, suggesting that it can serve as an independent prognostic indicator of patients with endometrial hyperplasia with or without atypia who would progress to cancer (p = 0.012).
Identification of Nrf2-responsive microRNA networks as putative mediators of myocardial reductive stress
Authors: Quiles Justin M. , Pepin Mark E. , Sunny Sini , Shelar Sandeep B. , Challa Anil K. , Dalley Brian , Hoidal John R. , Pogwizd Steven M. , Wende Adam R. , Rajasekaran Namakkal S.
Published: June 2021

Although recent advances in the treatment of acute coronary heart disease have reduced mortality rates, few therapeutic strategies exist to mitigate the progressive loss of cardiac function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, Nrf2) is a transcriptional regulator that is known to confer transient myocardial cytoprotection following acute ischemic insult; however, its sustained activation paradoxically causes a reductive environment characterized by excessive antioxidant activity. We previously identified a subset of 16 microRNAs (miRNA) significantly diminished in Nrf2-ablated (Nrf2−/−) mouse hearts, leading to the hypothesis that increasing levels of Nrf2 activation augments miRNA induction and post-transcriptional dysregulation. Here, we report the identification of distinct miRNA signatures (i.e. “reductomiRs”) associated with Nrf2 overexpression in a cardiac-specific and constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing low (TgL) and high (TgH) levels. We also found several Nrf2 dose-responsive miRNAs harboring proximal antioxidant response elements (AREs), implicating these “reductomiRs” as putative meditators of Nrf2-dependent post-transcriptional regulation. Analysis of mRNA-sequencing identified a complex network of miRNAs and effector mRNAs encoding known pathological hallmarks of cardiac stress-response. Altogether, these data support Nrf2 as a putative regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation to understand the relationship between myocardial reductive stress and cardiac pathophysiology.
Colossal barocaloric effects in the complex hydride Li$$_{2}$$B$$_{12}$$H$$_{12}$$
Authors: Sau Kartik , Ikeshoji Tamio , Takagi Shigeyuki , Orimo Shin-ichi , Errandonea Daniel , Chu Dewei , Cazorla Claudio
Published: June 2021

Traditional refrigeration technologies based on compression cycles of greenhouse gases pose serious threats to the environment and cannot be downscaled to electronic device dimensions. Solid-state cooling exploits the thermal response of caloric materials to changes in the applied external fields (i.e., magnetic, electric and/or mechanical stress) and represents a promising alternative to current refrigeration methods. However, most of the caloric materials known to date present relatively small adiabatic temperature changes ($$|\Delta T| \sim 1$$

|
Δ
T
|
∼
1

to 10 K) and/or limiting irreversibility issues resulting from significant phase-transition hysteresis. Here, we predict by using molecular dynamics simulations the existence of colossal barocaloric effects induced by pressure (isothermal entropy changes of $$|\Delta S| \sim 100$$

|
Δ
S
|
∼
100

 J K$$^{-1}$$

-
1

kg$$^{-1}$$

-
1

) in the energy material Li$$_{2}$$

2

B$$_{12}$$

12

H$$_{12}$$

12

. Specifically, we estimate $$|\Delta S| = 367$$

|
Δ
S
|
=
367

 J K$$^{-1}$$

-
1

kg$$^{-1}$$

-
1

and $$|\Delta T| = 43$$

|
Δ
T
|
=
43

 K for a small pressure shift of P = 0.1 GPa at $$T = 480$$

T
=
480

 K. The disclosed colossal barocaloric effects are originated by a fairly reversible order–disorder phase transformation involving coexistence of Li$$^{+}$$

+

diffusion and (BH)$$_{12}^{-2}$$

12

-
2

reorientational motion at high temperatures.
PM10 and PM2.5 real-time prediction models using an interpolated convolutional neural network
Authors: Chae Sangwon , Shin Joonhyeok , Kwon Sungjun , Lee Sangmok , Kang Sungwon , Lee Donghyun
Published: June 2021

In this paper, we propose a real-time prediction model that can respond to particulate matters (PM) in the air, which are an indication of poor air quality. The model applies interpolation to air quality and weather data and then uses a Convolutional Neural Network (CNN) to predict PM concentrations. The interpolation transforms the irregular spatial data into an equally spaced grid, which the model requires. This combination creates the interpolated CNN (ICNN) model that we use to predict PM10 and PM2.5 concentrations. The PM10 and PM2.5 evaluation results show an effective prediction performance with an R-squared higher than 0.97 and a root mean square error (RMSE) of approximately 16% of the standard deviation. Furthermore, both PM10 and PM2.5 prediction models forecast high concentrations with high reliability, with a probability of detection higher than 0.90 and a critical success index exceeding 0.85. The proposed ICNN prediction model achieves a high prediction performance using spatio-temporal information and presents a new direction in the prediction field.
Identifying molecular pathways and candidate genes associated with knob traits by transcriptome analysis in the goose (Anser cygnoides)
Authors: Ji Wangyang , Hou li E , Yuan Xiaoya , Gu Tiantian , Chen ZhuoYu , Zhang Yu , Zhang Yang , Chen Guohong , Xu Qi , Zhao Wenming
Published: June 2021

Anser cygnoides has a spherical crest on the beak roof, which is described as knob. However, the mechanisms affecting knob morphology are unclear. Here, we investigated the phenotypic characteristics and molecular basis of knob-size differences in Yangzhou geese. Anatomically, the knob was identified as frontal hump in the frontal area of the skull, rather than hump of upper beak. Although the frontal hump length, and height varied greatly in geese with different knob phenotypes, little was changed in the width. Histologically, knob skin in large-size knobs geese have a greater length in the stratum corneum, stratum spinosum, and stratum reticular than that in small-size knobs geese. Moveover, the 415 differentially expressed genes were found between the large knobs and small ones through transcriptome profiling. In addition, GO enrichment and KEGG pathway analysis revealed 455 significant GO terms and 210 KEGG pathways were enriched, respectively. Among these, TGF-β signaling and thyroid hormone synthesis-signaling pathways were identified to determine knob-size phenotype. Furthermore, BMP5, DCN, TSHR and ADCY3 were recognized to involve in the growth and development of knob. Our data provide comprehensive molecular determinants of knob size phenotype, which can potentially promote the genetic improvement of goose knobs.
Selective estrogen receptor modulator lasofoxifene suppresses spondyloarthritis manifestation and affects characteristics of gut microbiota in zymosan-induced SKG mice
Authors: Jeong Hyemin , Kim In Young , Bae Eun-Kyung , Jeon Chan Hong , Ahn Kwang-Sung , Cha Hoon-Suk
Published: June 2021

Ankylosing spondylitis is a male-predominant disease and previous study revealed that estrogens have an anti-inflammatory effect on the spondyloarthritis (SpA) manifestations in zymosan-induced SKG mice. This study aimed to evaluate the effect of selective estrogen receptor modulator (SERM) lasofoxifene (Laso) on disease activity of SpA. Mice were randomized into zymosan-treated, zymosan + 17β-estradiol (E2)-treated, and zymosan + Laso-treated groups. Arthritis was assessed by 18F-fluorodeoxyglucose (18F-FDG) small-animal positron emission tomography/computed tomography and bone mineral density (BMD) was measured. Fecal samples were collected and 16S ribosomal RNA gene sequencing was used to determine gut microbiota differences. Both zymosan + E2-treated mice and zymosan + Laso-treated mice showed lower arthritis clinical scores and lower 18F-FDG uptake than zymosan-treated mice. BMD was significantly higher in zymosan + E2-treated mice and zymosan + Laso-treated mice than zymosan-treated mice, respectively. Fecal calprotectin levels were significantly elevated at 8 weeks after zymosan injection in zymosan-treated mice, but it was not significantly changed in zymosan + E2-treated mice and zymosan + Laso-treated mice. Gut microbiota diversity of zymosan-treated mice was significantly different from zymosan + E2-treated mice and zymosan + Laso-treated mice, respectively. There was no significant difference in gut microbiota diversity between zymosan + E2-treated mice and zymosan + Laso -treated mice. Laso inhibited joint inflammation and enhanced BMD in SKG mice, a model of SpA. Laso also affected the composition and biodiversity of gut microbiota. This study provides new knowledge regarding that selected SpA patients could benefit from SERM treatment.
Analytical quality by design methodology for botanical raw material analysis: a case study of flavonoids in Genkwa Flos
Authors: Kim Min Kyoung , Park Sang Cheol , Park Geonha , Choi Eunjung , Ji Yura , Jang Young Pyo
Published: June 2021

The present study introduces a systematic approach using analytical quality by design (AQbD) methodology for the development of a qualified liquid chromatographic analytical method, which is a challenge in herbal medicinal products due to the intrinsic complex components of botanical sources. The ultra-high-performance liquid chromatography-photodiode array-mass spectrometry (UHPLC-PDA-MS) technique for 11 flavonoids in Genkwa Flos was utilized through the entire analytical processes, from the risk assessment study to the factor screening test, and finally in method optimization employing central composite design (CCD). In this approach, column temperature and mobile solvent slope were found to be critical method parameters (CMPs) and each of the eleven flavonoid peaks’ resolution values were used as critical method attributes (CMAs) through data mining conversion formulas. An optimum chromatographic method in the design space was calculated by mathematical and response surface methodology (RSM). The established chromatographic condition is as follows: acetonitrile and 0.1% formic acid gradient elution (0–13 min, 10–45%; 13–13.5 min, 45–100%; 13.5–14 min, 100–10%; 14–15 min, 10% acetonitrile), column temperature 28℃, detection wavelength 335 nm, and flow rate 0.35 mL/min using C18 (50 × 2.1 mm, 1.7 μm) column. A validation study was also performed successfully for apigenin 7-O-glucuronide, apigenin, and genkwanin. A few important validation results were as follows: linearity over 0.999 coefficient of correlation, detection limit of 2.87–22.41, quantitation limit of 8.70–67.92, relative standard deviation of precision less than 0.22%, and accuracy between 100.13 and 102.49% for apigenin, genkwanin, and apigenin 7-O-glucuronide. In conclusion, the present design-based approach provide a systematic platform that can be effectively applied to ensure pharmaceutically qualified analytical data from complex natural products based botanical drug.
Analysis of the shape of the T-wave in congenital long-QT syndrome type 3 by geometric morphometrics
Authors: Horigome Hitoshi , Ishikawa Yasuhiro , Takahashi Kazuhiro , Yoshinaga Masao , Sumitomo Naokata
Published: June 2021

The characteristic shape of the T-wave in congenital long-QT syndrome type 3 (LQTS3) is considered a late-onset T-wave. We analyzed the difference in the shapes of the T-waves of V5 in the electrocardiograms (ECGs) of LQTS3 cases and normal subjects using generalized Procrustes analysis. The J and Q points of LQTS3 cases are shifted to the upper left compared to those of normal subjects. SdFmax is the point on the ECG where the second derivative is first maximized. SdFmax is the point where the change in the slope of the ascending limb of the T-wave is maximized. SdFmax in LQTS3 cases is shifted to the lower right compared to normal subjects. The interval from J to SdFmax in LQTS3 cases is expanded compared with that of normal subjects. From principal component analysis of the Procrustes mean shape of the T-wave landmarks, the second principal component shows a shift of SdFmax to the lower right. These results can quantitatively explain why the T-wave of LQTS3 cases looks like a late-onset T-wave. After being fitted to a multivariate logistic regression model, LQTS3 cases and normal subjects can be distinguished by the second independent component.