bluuebunny/crossref_metadata_2025 huggingface dataset:
THE MATRÍCULA DE TRIBUTOS: STYLISTIC AND MATERIAL OBSERVATIONS INTO ITS DATING AND ORIGINAL CONTEXT
Authors: Tejada Jorge Gómez
Published: August 2021

This essay considers the possibility that the Matrícula de Tributos was made from a collection of folios that incorporates material from several related documents, some from as early as the eve of the Spanish invasion in 1521, and others from as late as the 1560s. The diverse styles identifiable throughout the manuscript, as well as the many interventions of different kinds in its pages, support this claim. This article further asks whether the Matrícula de Tributos might be the last extant exemplar of a larger group of taxation-related documents that circulated through Mexico on the eve of the Spanish invasion and well into the second half of the sixteenth century. Finally, the essay considers the possibility of placing the Matrícula de Tributos within the context of documents that kept or presented a record of pre-Conquest tributary practices for purposes that may have been as diverse as presenting evidence of past tributary obligations or as a means to assert authority and other political claims among the surviving native elite.
The pulmonary vascular bed in patients with functionally univentricular physiology and a Fontan circulation
Authors: Krimly Ahmed , Jain C. Charles , Egbe Alexander , Alzahrani Ahmed , Al Najashi Khalid , Albert-Brotons Dimpna , Veldtman Gruschen R.
Published: August 2021

Fontan palliation represents one of the most remarkable surgical advances in the management of individuals born with functionally univentricular physiology. The operation secures adult survival for all but a few with unfavourable anatomy and/or physiology. Inherent to the physiology is passive transpulmonary blood flow, which produces a vulnerability to adequate filling of the systemic ventricle at rest and during exertion. Similarly, the upstream effects of passive flow in the lungs are venous congestion and venous hypertension, especially marked during physical activity. The pulmonary vascular bed has emerged as a defining character on the stage of Fontan circulatory behaviour and clinical outcomes. Its pharmacologic regulation and anatomic rehabilitation therefore seem important strategic therapeutic targets. This review seeks to delineate the important aspects of pulmonary artery development and maturation in functionally univentricular physiology patients, pulmonary artery biology, pulmonary vascular reserve with exercise, and pulmonary artery morphologic and pharmacologic rehabilitation.
Expecting the unexpected: Code-switching as a facilitatory cue in online sentence processing
Authors: Tomić Aleksandra , Valdés Kroff Jorge R.
Published: August 2021

Despite its prominent use among bilinguals, psycholinguistic studies reported code-switch processing costs (e.g., Meuter & Allport, 1999). This paradox may partly be due to the focus on the code-switch itself instead of its potential subsequent benefits. Motivated by corpus studies on CS patterns and sociopragmatic functions of CS, we asked whether bilinguals use code-switches as a cue to the lexical characteristics of upcoming speech. We report a visual world study testing whether code-switching facilitates the anticipation of lower-frequency words. Results confirm that US Spanish–English bilinguals (n = 30) use minority (Spanish) to majority (English) language code-switches in real-time language processing as a cue that a less frequent word would ensue, as indexed by increased looks at images representing lower- vs. higher-frequency words in the code-switched condition, prior to the target word onset. These results highlight the need to further integrate sociolinguistic and corpus observations into the experimental study of code-switching.
Sweetpotato response to reduced rates of dicamba
Authors: Shankle Mark W. , Harvey Lorin M. , Meyers Stephen L. , Morris Callie J.
Published: August 2021

A field study was conducted in Mississippi to determine the effect of reduced dicamba rates on sweetpotato crop tolerance and storage root yield, simulating off-target movement or sprayer tank contamination. Treatments included a nontreated control and four rates of dicamba [70 g ae ha−1 (1/8×), 35 g ae ha−1 (1/16×), 8.65 g ae ha−1 (1/64×), and 1.09 g ae ha−1 (1/512×)] applied either 3 d before transplanting (DBP) or 1, 3, 5, or 7 wk after transplanting (WAP). An additional treatment consisted of 560 g ae ha−1 (1×) dicamba applied 3 DBP. Crop injury ratings were taken 1, 2, 3, and 4 wk after treatment (WAT). Across application timings, predicted sweetpotato plant injury 1, 2, 3, and 4 WAT increased from 3T to 22%, 3% to 32%, 2% to 58%, and 1% to 64% as dicamba rate increased from 0 to 70 g ha−1 (1/8×), respectively. As dicamba rate increased from 1/512× to 1/8×, predicted No. 1 yield decreased from 127% to 55%, 103% to 69%, 124% to 31%, and 124% to 41% of the nontreated control for applications made 1, 3, 5, and 7 WAP, respectively. Similarly, as dicamba rate increased from 1/512× to 1/8×, predicted marketable yield decreased from 123% to 57%, 107% to 77%, 121% to 44%, and 110% to 53% of the nontreated control for applications made 1, 3, 5, and 7 WAP, respectively. Dicamba residue (5.3 to 14.3 parts per billion) was detected in roots treated with 1/16× or 1/8× dicamba applied 5 or 7 WAP and 1/64× dicamba applied 7 WAP with the highest residue detected in roots harvested from sweetpotato plants treated at 7 WAP. Collectively, care should be taken to avoid sweetpotato exposure to dicamba especially at 1/8× and 1/16× rates during the growing season.
Frequency Considerations in GIC Applications
Authors: Trichtchenko L.
Published: August 2021

Geomagnetically induced currents (GIC) are a phenomenon well known for its negative effects on the operations of power systems. To efficiently mitigate them requires different types of power system modeling, from GIC to alternating current harmonic generation, to three‐dimensional finite element models of transformers. GIC are initiated by variations of the geomagnetic field in the presence of the conductive Earth, that is, the geophysical variables characterized by continuous frequency spectra, making GIC also exhibit continuous spectra. In order to adequately estimate their variations and peak values for mitigation purposes, an analysis is required of how sampling rate and spectral frequency content impact the measured characteristics of GIC and harmonics. The study is based on the geomagnetic measurements and the power network data (i.e., GIC and harmonics) with high sampling rates recorded during two geomagnetic storms, March 31, 2001 and July 26–27, 2004. Availability of data covering both the source and the result of geomagnetic storm impacts on power grid allows (a) analysis of the influence of spectral content on adequate representation of both geomagnetic and geoelectric variations during the intervals with significant increases in GIC and harmonics and (b) identifying the sampling rate sufficient to usefully represent the network response presented as GIC and harmonics variations. In summary, the adequate sampling rate is suggested and the deficiencies associated with undersampling of the geoelectric and GIC variations are identified and discussed.
Southern Ocean Oxygenation Changes Inferred From Redox‐Sensitive Trace Metals Across Marine Isotope Stage 11
Authors: Rohde E. E. , Hayes C. T. , Redmond N. , Glasscock S. K.
Published: August 2021

Changes in the circulation of the Southern Ocean are known to have impacted global nutrient, heat, and carbon cycles during the glacial and interglacial periods of the late Pleistocene. Proxy‐based records of these changes deserve continued scrutiny as the implications may be important for constraining future change. A record of authigenic uranium from the South Atlantic has been used to infer changes in deep‐sea oxygenation and organic matter export over the past 0.5 million years. Since sedimentary uranium has the possible complication of remobilization, it is prudent to investigate the behavior of other redox‐sensitive trace metals to confidently interpret temporal changes in oxygenation. Focusing here on the exceptionally long interglacial warm period, Marine Isotope Stage (MIS) 11, we found concurrent authigenic enrichments of uranium (U) and rhenium (Re) throughout MIS 12 to 10, overall supporting prior interpretations of low‐oxygen periods. However, there are differential responses of Re and U to oxygen changes and some evidence of small‐scale Re remobilization, which may involve differences in molecular‐level reduction mechanisms. Peaks in authigenic manganese (Mn) intervening with peaks in Re and U indicate increases in porewater oxygenation which likely relate to increased Antarctic Bottom Water circulation at the onset of MIS11c and during the peak warmth of the interglacial around 400 ka.
780 Thousand Years of Upper‐Crustal Construction at a Melt‐Rich Segment of the Ultraslow Spreading Southwest Indian Ridge 50°28′E
Authors: Chen Jie , Cannat Mathilde , Tao Chunhui , Sauter Daniel , Munschy Marc
Published: August 2021

Melt supply at the ultraslow‐spreading Southwest Indian Ridge (SWIR) has been shown to vary from nearly amagmatic, leading to ultramafic seafloor, to magmatically robust, producing fully volcanic seafloor. The center of the SWIR 50°28′E segment represents a magmatically robust endmember. High‐resolution bathymetry and backscatter, near‐bottom magnetic data, and visual observations were acquired to infer spatiotemporal variations in upper‐crustal construction over the past 780 kyr. Tectonic strain inferred from observed faults represents <8% of the total plate divergence during this period. Mapped seafloor and lava morphologies show a prevalence of smooth seafloor and smooth hummocky seafloor (64% mapped area), corresponding to a dominance of high‐effusion‐rate, sheet‐lobate lavas, over hummocky seafloor (29%) that mostly comprises low‐effusion‐rate pillow lavas. This prevalence is most pronounced within a ∼5 km‐long domain at the segment center, while hummocky seafloor prevails to its east and west, indicating a substantial along‐axis decrease in average eruption rate. Across‐axis changes of seafloor morphologies and faulting pattern indicate two successive cycles of upper‐crustal construction. These cycles last ∼300 kyr, interpreted as waxing and waning magmatic phases. During waxing phases, shallow axial melt lenses (AMLs) form beneath the segment center, feeding narrow diking systems that build high‐eruption‐rate smooth domal volcanos. During waning phases, lower frequencies of melt replenishment may cause the AML to become deeper and ultimately disappear. This configuration triggers diking and hummocky‐dominated eruptions over a wider axial domain, with more faults. We propose that modes of upper‐crustal construction at slow and ultraslow mid‐ocean ridges are influenced by melt supply more than spreading rate.
Joint InSAR and Field Constraints on Faulting During the Mw 6.4, July 23, 2020, Nima/Rongma Earthquake in Central Tibet
Authors: Li Kang , Li Yongsheng , Tapponnier Paul , Xu Xiwei , Li Dewen , He Zhongtai
Published: August 2021

The accumulation and partitioning of crustal strain in central Tibet remain debated. July 23, 2020, Mw 6.4 earthquake in the Nima region (≈86.864°E/33.144°N) thus provides an opportunity to gain insight into local, ongoing deformation. Here, we use Sentinel‐1 SAR data to assess co‐seismic deformation during that earthquake, and nonlinear/linear inversions to determine the location and geometry of the source and the finite fault slip distribution. The results show that the maximum surface subsidence was ≈25 cm, the causative fault had a ≈N28°E strike and ≈48° dip eastwards, and that the largest normal slip, with a peak of ≈1.5 m, occurred between 5 and 10 km depths. Details of the earthquake surface rupture were derived from a UAV‐based field survey. At three distinct sites, the high‐resolution UAV images revealed discontinuous, ≈N35°E‐trending arrays of fresh en‐echelon cracks and ≤20 cm‐high, free‐faced normal scarps, along a ≈10 km‐long, ≈20 m‐wide zone following the ≈ vertically projected western limit of maximum interferometric synthetic aperture radar slip at depth. These results, consistent with an earthquake intensity distribution based on building damage inspection, show that 2020 earthquake only broke a short segment of the west Yibu Chaka normal fault, along the middle stretch of the 300 km‐long Riganpei Co‐Yibu Chaka‐Jiangai Zangbo fault zone. Regional Coulomb stress changes suggest that larger, Mw 7+ earthquakes should be expected on the geomorphologically more prominent, ≈50 km‐long normal faults bounding the east side of the Yibu Chaka lake pull‐apart, and on the 120 km‐long, sinistral Riganpei‐Co fault to the southwest.
Modification of Lithospheric Mantle by Melts/Fluids With Different Sulfur Fugacities During the Wilson Cycle: Insights From Lesvos and Global Ophiolitic Peridotites
Authors: Xu Yong , Li Danni , Li Dongxu , Dong Guo‐Chen , Pearson D. Graham , Liu Jingao
Published: August 2021

The Lesvos ophiolite, Greece, was recently identified as an analog to the External Liguride Unit formed at an ocean‐continent‐transition (OCT) setting. To further study the evolutionary history of this body, we analyzed highly siderophile element abundances and Re‐Os isotopic compositions of 14 Lesvos peridotites, in combination with petrology, bulk‐rock major, and trace element geochemistry. Almost all the Lesvos peridotites fall within the field of global OCT and mid‐ocean‐ridge (MOR) peridotites, indicating that these rocks have not experienced subduction‐related processes. The near‐horizontal 187Os/188Os versus Al2O3 trend over a wide range of Al2O3 (0.45–3.66 wt. %) may have been caused by recent melt depletion during rifting and thinning of the Lesvos lithosphere. Combining data from available global ophiolitic peridotites, we find that a large proportion of the more Al‐depleted supra‐subduction‐zone (SSZ) peridotites show lower Os/Ir, higher Pd/Ir and remarkably elevated radiogenic Os relative to other tectonic environments (OCT and MOR). By linking this kind of geochemical evolution to the Wilson Cycle, a complete picture emerges: (a) In the OCT to MOR stages, the extensional rifting environment may lead to mild to moderate melt depletion, followed by, or associated with, infiltration of S‐saturated (high fS2) basaltic magmas; (b) when progressing into the SSZ stage, more extreme degrees of mantle melt depletion may be driven by aqueous fluids in the sub‐arc mantle. During this stage, high‐fO2 slab‐derived fluids and/or S‐undersaturated (low fS2) boninitic magmas may infiltrate the sub‐arc mantle, followed by subsequent S‐saturated forearc basaltic magma infiltration.
MEMS inductor fabrication and emerging applications in power electronics and neurotechnologies
Authors: Le Hoa Thanh , Haque Rubaiyet I. , Ouyang Ziwei , Lee Seung Woo , Fried Shelley I. , Zhao Ding , Qiu Min , Han Anpan
Published: August 2021

MEMS inductors are used in a wide range of applications in micro- and nanotechnology, including RF MEMS, sensors, power electronics, and Bio-MEMS. Fabrication technologies set the boundary conditions for inductor design and their electrical and mechanical performance. This review provides a comprehensive overview of state-of-the-art MEMS technologies for inductor fabrication, presents recent advances in 3D additive fabrication technologies, and discusses the challenges and opportunities of MEMS inductors for two emerging applications, namely, integrated power electronics and neurotechnologies. Among the four top-down MEMS fabrication approaches, 3D surface micromachining and through-substrate-via (TSV) fabrication technology have been intensively studied to fabricate 3D inductors such as solenoid and toroid in-substrate TSV inductors. While 3D inductors are preferred for their high-quality factor, high power density, and low parasitic capacitance, in-substrate TSV inductors offer an additional unique advantage for 3D system integration and efficient thermal dissipation. These features make in-substrate TSV inductors promising to achieve the ultimate goal of monolithically integrated power converters. From another perspective, 3D bottom-up additive techniques such as ice lithography have great potential for fabricating inductors with geometries and specifications that are very challenging to achieve with established MEMS technologies. Finally, we discuss inspiring and emerging research opportunities for MEMS inductors.
Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation
Authors: Meier Stefanie , Cantilena Sandra , Niklison Chirou Maria Victoria , Anderson John , Hargrave Darren , Salomoni Paolo , de Boer Jasper , Michod David
Published: August 2021

Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects. This shows that there is a strong need for improved treatment approaches. Here, we highlight the potential for repurposing disulfiram to treat pediatric gliomas. Disulfiram is a drug used to support the treatment of chronic alcoholism and was found to be effective against diverse cancer types in preclinical studies. Our results show that disulfiram efficiently kills pediatric glioma cell lines as well as patient-derived glioma stem cells. We propose a novel mechanism of action to explain disulfiram’s anti-oncogenic activities by providing evidence that disulfiram induces the degradation of the oncoprotein MLL. Our results further reveal that disulfiram treatment and MLL downregulation induce similar responses at the level of histone modifications and gene expression, further strengthening that MLL is a key target of the drug and explaining its anti-oncogenic properties.
Regulation of Bax-dependent apoptosis by mitochondrial deubiquitinase USP30
Authors: Yan Ding , Li Xiaofen , Yang Qianqian , Huang Qingtian , Yao Leyi , Zhang Peiquan , Sun Wenshuang , Lin Shuhui , Dou Q. Ping , Liu Jinbao , Chen Xin
Published: August 2021

Deubiquitinates (DUBs) have been suggested as novel promising targets for cancer therapies. Accumulating experimental evidence suggests that some metal compounds have the potential to induce cancer cell death via inhibition of DUBs. We previously reported that auranofin, a gold(I)-containing agent used for the treatment of rheumatoid arthritis in clinics, can induce cell death by inhibiting proteasomal DUBs in a series of cancer cell lines. Unfortunately, currently available gold compounds are not potent in inhibiting DUBs. Here, we report that: (i) aumdubin, a synthetic derivative of auranofin, exhibited stronger DUB-inhibiting and apoptosis-inducing activities than auranofin in lung cancer cells; (ii) aumdubin shows high affinity for mitochondrial DUB USP30; (iii) aumdubin induces apoptosis by increasing the ubiquitination and mitochondrial location of Bax protein; and (iv) USP30 inhibition may contribute to Bax-dependent apoptosis induced by aumdubin in lung cancer cells. These results suggest that gold(I)-containing agent aumdubin induces Bax-dependent apoptosis partly through inhibiting the mitochondrial DUB USP30, which could open new avenues for lung cancer therapy.
CTCF is a barrier for 2C-like reprogramming
Authors: Olbrich Teresa , Vega-Sendino Maria , Tillo Desiree , Wu Wei , Zolnerowich Nicholas , Pavani Raphael , Tran Andy D. , Domingo Catherine N. , Franco Mariajose , Markiewicz-Potoczny Marta , Pegoraro Gianluca , FitzGerald Peter C. , Kruhlak Michael J. , Lazzerini-Denchi Eros , Nora Elphege P. , Nussenzweig André , Ruiz Sergio
Published: August 2021

Totipotent cells have the ability to generate embryonic and extra-embryonic tissues. Interestingly, a rare population of cells with totipotent-like potential, known as 2 cell (2C)-like cells, has been identified within ESC cultures. They arise from ESC and display similar features to those found in the 2C embryo. However, the molecular determinants of 2C-like conversion have not been completely elucidated. Here, we show that the CCCTC-binding factor (CTCF) is a barrier for 2C-like reprogramming. Indeed, forced conversion to a 2C-like state by the transcription factor DUX is associated with DNA damage at a subset of CTCF binding sites. Depletion of CTCF in ESC efficiently promotes spontaneous and asynchronous conversion to a 2C-like state and is reversible upon restoration of CTCF levels. This phenotypic reprogramming is specific to pluripotent cells as neural progenitor cells do not show 2C-like conversion upon CTCF-depletion. Furthermore, we show that transcriptional activation of the ZSCAN4 cluster is necessary for successful 2C-like reprogramming. In summary, we reveal an unexpected relationship between CTCF and 2C-like reprogramming.
Chd1 protects genome integrity at promoters to sustain hypertranscription in embryonic stem cells
Authors: Bulut-Karslioglu Aydan , Jin Hu , Kim Yun-Kyo , Cho Brandon , Guzman-Ayala Marcela , Williamson Andrew J. K. , Hejna Miroslav , Stötzel Maximilian , Whetton Anthony D. , Song Jun S. , Ramalho-Santos Miguel
Published: August 2021

Stem and progenitor cells undergo a global elevation of nascent transcription, or hypertranscription, during key developmental transitions involving rapid cell proliferation. The chromatin remodeler Chd1 mediates hypertranscription in pluripotent cells but its mechanism of action remains poorly understood. Here we report a novel role for Chd1 in protecting genome integrity at promoter regions by preventing DNA double-stranded break (DSB) accumulation in ES cells. Chd1 interacts with several DNA repair factors including Atm, Parp1, Kap1 and Topoisomerase 2β and its absence leads to an accumulation of DSBs at Chd1-bound Pol II-transcribed genes and rDNA. Genes prone to DNA breaks in Chd1 KO ES cells are longer genes with GC-rich promoters, a more labile nucleosomal structure and roles in chromatin regulation, transcription and signaling. These results reveal a vulnerability of hypertranscribing stem cells to accumulation of endogenous DNA breaks, with important implications for developmental and cancer biology.
Protein interface redesign facilitates the transformation of nanocage building blocks to 1D and 2D nanomaterials
Authors: Zhang Xiaorong , Liu Yu , Zheng Bowen , Zang Jiachen , Lv Chenyan , Zhang Tuo , Wang Hongfei , Zhao Guanghua
Published: August 2021

Although various artificial protein nanoarchitectures have been constructed, controlling the transformation between different protein assemblies has largely been unexplored. Here, we describe an approach to realize the self-assembly transformation of dimeric building blocks by adjusting their geometric arrangement. Thermotoga maritima ferritin (TmFtn) naturally occurs as a dimer; twelve of these dimers interact with each other in a head-to-side manner to generate 24-meric hollow protein nanocage in the presence of Ca2+ or PEG. By tuning two contiguous dimeric proteins to interact in a fully or partially side-by-side fashion through protein interface redesign, we can render the self-assembly transformation of such dimeric building blocks from the protein nanocage to filament, nanorod and nanoribbon in response to multiple external stimuli. We show similar dimeric protein building blocks can generate three kinds of protein materials in a manner that highly resembles natural pentamer building blocks from viral capsids that form different protein assemblies.
Gut microbiome-mediated metabolism effects on immunity in rural and urban African populations
Authors: Stražar Martin , Temba Godfrey S. , Vlamakis Hera , Kullaya Vesla I. , Lyamuya Furaha , Mmbaga Blandina T. , Joosten Leo A. B. , van der Ven Andre J. A. M. , Netea Mihai G. , de Mast Quirijn , Xavier Ramnik J.
Published: August 2021

The human gut microbiota is increasingly recognized as an important factor in modulating innate and adaptive immunity through release of ligands and metabolites that translocate into circulation. Urbanizing African populations harbor large intestinal diversity due to a range of lifestyles, providing the necessary variation to gauge immunomodulatory factors. Here, we uncover a gradient of intestinal microbial compositions from rural through urban Tanzanian, towards European samples, manifested both in relative abundance and genomic variation observed in stool metagenomics. The rural population shows increased Bacteroidetes, led by Prevotella copri, but also presence of fungi. Measured ex vivo cytokine responses were significantly associated with 34 immunomodulatory microbes, which have a larger impact on circulating metabolites than non-significant microbes. Pathway effects on cytokines, notably TNF-α and IFN-γ, differential metabolome analysis and enzyme copy number enrichment converge on histidine and arginine metabolism as potential immunomodulatory pathways mediated by Bifidobacterium longum and Akkermansia muciniphila.
Structural basis for Ca2+ activation of the heteromeric PKD1L3/PKD2L1 channel
Authors: Su Qiang , Chen Mengying , Wang Yan , Li Bin , Jing Dan , Zhan Xiechao , Yu Yong , Shi Yigong
Published: August 2021

The heteromeric complex between PKD1L3, a member of the polycystic kidney disease (PKD) protein family, and PKD2L1, also known as TRPP2 or TRPP3, has been a prototype for mechanistic characterization of heterotetrametric TRP-like channels. Here we show that a truncated PKD1L3/PKD2L1 complex with the C-terminal TRP-fold fragment of PKD1L3 retains both Ca2+ and acid-induced channel activities. Cryo-EM structures of this core heterocomplex with or without supplemented Ca2+ were determined at resolutions of 3.1 Å and 3.4 Å, respectively. The heterotetramer, with a pseudo-symmetric TRP architecture of 1:3 stoichiometry, has an asymmetric selectivity filter (SF) guarded by Lys2069 from PKD1L3 and Asp523 from the three PKD2L1 subunits. Ca2+-entrance to the SF vestibule is accompanied by a swing motion of Lys2069 on PKD1L3. The S6 of PKD1L3 is pushed inward by the S4-S5 linker of the nearby PKD2L1 (PKD2L1-III), resulting in an elongated intracellular gate which seals the pore domain. Comparison of the apo and Ca2+-loaded complexes unveils an unprecedented Ca2+ binding site in the extracellular cleft of the voltage-sensing domain (VSD) of PKD2L1-III, but not the other three VSDs. Structure-guided mutagenic studies support this unconventional site to be responsible for Ca2+-induced channel activation through an allosteric mechanism.
Loss of grand histone H3 lysine 27 trimethylation domains mediated transcriptional activation in esophageal squamous cell carcinoma
Authors: Yuan Jian , Jiang Qi , Gong Tongyang , Fan Dandan , Zhang Ji , Chen Fukun , Zhu Xiaolin , Wang Xinyu , Qiao Yunbo , Chen Hongyan , Liu Zhihua , Su Jianzhong
Published: August 2021

Trimethylation of histone H3 lysine 27 trimethylation (H3K27me3) may be recruited by repressive Polycomb complexes to mediate gene silencing, which is critical for maintaining embryonic stem cell pluripotency and differentiation. However, the roles of aberrant H3K27me3 patterns in tumorigenesis are not fully understood. Here, we discovered that grand silencer domains (breadth > 50 kb) for H3K27me3 were significantly associated with epithelial cell differentiation and exhibited high gene essentiality and conservation in human esophageal epithelial cells. These grand H3K27me3 domains exhibited high modification signals involved in gene silencing, and preferentially occupied the entirety of topologically associating domains and interact with each other. We found that widespread loss of the grand H3K27me3 domains in of esophageal squamous cell carcinomas (ESCCs) were enriched in genes involved in epithelium and endothelium differentiation, which were significantly associated with overexpression with increase of active modifications of H3K4me3, H3K4me1, and H3K27ac marks, as well as DNA hypermethylation in the gene bodies. A total of 208 activated genes with loss of grand H3K27me3 domains in ESCC were identified, where the higher expression and mutation of T-box transcription factor 20 (TBX20) were associated with worse patients’ outcomes. Our results showed that knockdown of TBX20 may have led to a striking defect in esophageal cancer cell growth and carcinogenesis-related pathway, including cell cycle and homologous recombination. Together, our results reveal that loss of grand H3K27me3 domains represent a catalog of remarkable activating regulators involved in carcinogenesis.
Diesel exhaust particles increase nasal symptoms and IL-17A in house dust mite-induced allergic mice
Authors: Jung Hahn Jin , Ko Young-Kyung , Shim Woo Sub , Kim Hyun Jik , Kim Dong-Young , Rhee Chae-Seo , Park Moo Kyun , Han Doo Hee
Published: August 2021

Diesel exhaust particles (DEPs), traffic-related air pollutants, are considered environmental factors adversely affecting allergic diseases. However, the immunological basis for the adjuvant effects of DEP in allergic rhinitis (AR) remains unclear. Therefore, this study aimed to investigate the effect of DEP exposure on AR using a mouse model. BALB/c mice sensitized to house dust mite (HDM) were intranasally challenged with HDM in the presence and absence of DEP. Allergic symptom scores, serum total and HDM-specific immunoglobulins (Igs), eosinophil infiltration in the nasal mucosa, cytological profiles in bronchoalveolar lavage fluid (BALF), and cytokine levels in the nasal mucosa and spleen cell culture were analyzed. Mice co-exposed to HDM and DEP showed increased allergic symptom scores compared with mice exposed to HDM alone. Reduced total IgE and HDM-specific IgE and IgG1 levels, decreased eosinophil infiltration in the nasal mucosa, and increased proportion of neutrophils in BALF were found in mice co-exposed to HDM and DEP. Interleukin (IL)-17A level was found to be increased in the nasal mucosa of the co-exposure group compared with that in the HDM-exposed group. The levels of IL-4, IL-13, interferon-γ, IL-25, IL-33, and TSLP expression showed no difference between the groups with and without DEP treatment. Increased expression of IL-17A in the nasal mucosa may contribute to DEP-mediated exacerbation of AR in HDM-sensitized murine AR model.
Overexpression of cathepsin S exacerbates lupus pathogenesis through upregulation TLR7 and IFN-α in transgenic mice
Authors: Lee Jinhee , Jang Soyoung , Choi Minjee , Kang Mincheol , Lim Su-Geun , Kim SI-Yong , Jang Soyeon , Ko Jiwon , Kim Eungyung , Yi Junkoo , Choo Yeonsik , Kim Myoung Ok , Ryoo Zae Young
Published: August 2021

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs. Recent studies suggest relevance between cysteine protease cathepsin S (CTSS) expression and SLE. To investigate the mechanism of CTSS in SLE, CTSS-overexpressing transgenic (TG) mice were generated, and induced lupus-like symptoms. Eight months later, the TG mice spontaneously developed typical SLE symptoms regardless of the inducement. Furthermore, we observed increased toll-like receptor 7 (TLR7) expression with increased monocyte and neutrophil populations in the TG mice. In conclusion, overexpression of CTSS in mice influences TLR7 expression, autoantibodies and IFN-α, which leads to an autoimmune reaction and exacerbates lupus-like symptoms.
Molecular characteristics and spatial distribution of adult human corneal cell subtypes
Authors: Ligocki Ann J. , Fury Wen , Gutierrez Christian , Adler Christina , Yang Tao , Ni Min , Bai Yu , Wei Yi , Lehmann Guillermo L. , Romano Carmelo
Published: August 2021

Bulk RNA sequencing of a tissue captures the gene expression profile from all cell types combined. Single-cell RNA sequencing identifies discrete cell-signatures based on transcriptomic identities. Six adult human corneas were processed for single-cell RNAseq and 16 cell clusters were bioinformatically identified. Based on their transcriptomic signatures and RNAscope results using representative cluster marker genes on human cornea cross-sections, these clusters were confirmed to be stromal keratocytes, endothelium, several subtypes of corneal epithelium, conjunctival epithelium, and supportive cells in the limbal stem cell niche. The complexity of the epithelial cell layer was captured by eight distinct corneal clusters and three conjunctival clusters. These were further characterized by enriched biological pathways and molecular characteristics which revealed novel groupings related to development, function, and location within the epithelial layer. Moreover, epithelial subtypes were found to reflect their initial generation in the limbal region, differentiation, and migration through to mature epithelial cells. The single-cell map of the human cornea deepens the knowledge of the cellular subsets of the cornea on a whole genome transcriptional level. This information can be applied to better understand normal corneal biology, serve as a reference to understand corneal disease pathology, and provide potential insights into therapeutic approaches.
The zinc finger/RING domain protein Unkempt regulates cognitive flexibility
Authors: Vinsland Elin , Baskaran Pranetha , Mihaylov Simeon R. , Hobbs Carl , Wood Hannah , Bouybayoune Ihssane , Shah Kriti , Houart Corinne , Tee Andrew R. , Murn Jernej , Fernandes Cathy , Bateman Joseph M.
Published: August 2021

Correct orchestration of nervous system development is a profound challenge that involves coordination of complex molecular and cellular processes. Mechanistic target of rapamycin (mTOR) signaling is a key regulator of nervous system development and synaptic function. The mTOR kinase is a hub for sensing inputs including growth factor signaling, nutrients and energy levels. Activation of mTOR signaling causes diseases with severe neurological manifestations, such as tuberous sclerosis complex and focal cortical dysplasia. However, the molecular mechanisms by which mTOR signaling regulates nervous system development and function are poorly understood. Unkempt is a conserved zinc finger/RING domain protein that regulates neurogenesis downstream of mTOR signaling in Drosophila. Unkempt also directly interacts with the mTOR complex I component Raptor. Here we describe the generation and characterisation of mice with a conditional knockout of Unkempt (UnkcKO) in the nervous system. Loss of Unkempt reduces Raptor protein levels in the embryonic nervous system but does not affect downstream mTORC1 targets. We also show that nervous system development occurs normally in UnkcKO mice. However, we find that Unkempt is expressed in the adult cerebellum and hippocampus and behavioural analyses show that UnkcKO mice have improved memory formation and cognitive flexibility to re-learn. Further understanding of the role of Unkempt in the nervous system will provide novel mechanistic insight into the role of mTOR signaling in learning and memory.
Graphyne-3: a highly efficient candidate for separation of small gas molecules from gaseous mixtures
Authors: Azizi Khatereh , Vaez Allaei S. Mehdi , Fathizadeh Arman , Sadeghi Ali , Sahimi Muhammad
Published: August 2021

Two-dimensional nanosheets, such as the general family of graphenes have attracted considerable attention over the past decade, due to their excellent thermal, mechanical, and electrical properties. We report on the result of a study of separation of gaseous mixtures by a model graphyne-3 membrane, using extensive molecular dynamics simulations and density functional theory. Four binary and one ternary mixtures of H$$_2$$

2

, CO$$_2$$

2

, CH$$_4$$

4

and C$$_2$$

2

H$$_6$$

6

were studied. The results indicate the excellence of graphyne-3 for separation of small gas molecules from the mixtures. In particular, the H$$_2$$

2

permeance through the membrane is on the order of $$10^7$$

10
7

gas permeation unit, by far much larger than those in other membranes, and in particular in graphene. To gain deeper insights into the phenomenon, we also computed the density profiles and the residence times of the gases near the graphyne-3 surface, as well as their interaction energies with the membrane. The results indicate clearly the tendency of H$$_2$$

2

to pass through the membrane at high rates, leaving behind C$$_2$$

2

H$$_6$$

6

and larger molecules on the surface. In addition, the possibility of chemisorption is clearly ruled out. These results, together with the very good mechanical properties of graphyne-3, confirm that it is an excellent candidate for separating small gas molecules from gaseous mixtures, hence opening the way for its industrial use.
Cytotoxic effects on cancerous and non-cancerous cells of trans-cinnamaldehyde, carvacrol, and eugenol
Authors: Ranjitkar Saurav , Zhang Delong , Sun Fei , Salman Saleh , He Wu , Venkitanarayanan Kumar , Tulman Edan R. , Tian Xiuchun
Published: August 2021

Essential oils and their active components, referred here as plant derived antimicrobials (PDAs), have been used for their antimicrobial, anti-inflammatory and antioxidant properties. Many reports also document PDAs’ cytotoxic effects on cancerous cells, raising the hope that they could be used for cancer treatments. Due to the lack of specificity, we hypothesize that PDAs are cytotoxic to both cancerous and non-cancerous cells. Trans-cinnamaldehyde (TCA), carvacrol, and eugenol were assessed for their cytotoxicity on cancerous HeLa cells and normal skin fibroblasts (CCD-1123Sk, CCD) by MTT and LDH assays, flow cytometry, and reverse transcription quantitative PCR (RT-qPCR). After 24 h of treatment, carvacrol and TCA significantly decreased cell viability (by more than 50%) at 100 µg/ml, whereas eugenol was ineffective up to 400 µg/ml. Cell detachment and significantly increased apoptosis were observed with 100 µg/ml of TCA on both cell types. RT-qPCR for apoptotic genes (BCL2, CASP3 and CASP8) and necrosis genes (MLKL, RIPK1 and RIPK3) did not show significant differences between control and treated cells of both types, with the exception of eugenol-treated HeLa cells in which expression of BCL2, MLKL and RIPK1 was significantly higher than controls. Taken together, we conclude that the three PDAs studied here exhibited similar cytotoxic effects on both cancerous and non-cancerous cells.
Altered platelet and coagulation function in moderate-to-severe COVID-19
Authors: Litvinov Rustem I. , Evtugina Natalia G. , Peshkova Alina D. , Safiullina Svetlana I. , Andrianova Izabella A. , Khabirova Alina I. , Nagaswami Chandrasekaran , Khismatullin Rafael R. , Sannikova Svetlana S. , Weisel John W.
Published: August 2021

To reveal if coagulopathies relate to the course of COVID-19, we examined 255 patients with moderate and severe COVID-19, receiving anticoagulants and immunosuppressive drugs. Coagulopathy manifested predominantly as hypercoagulability that correlated directly with systemic inflammation, disease severity, comorbidities, and mortality risk. The prolonged clotting tests in about ¼ of cases were associated with high levels of C-reactive protein and antiphospholipid antibodies, which impeded coagulation in vitro. Contraction of blood clots was hindered in about ½ of patients, especially in severe and fatal cases, and correlated directly with prothrombotic parameters. A decrease in platelet contractility was due to moderate thrombocytopenia in combination with platelet dysfunction. Clots with impaired contraction were porous, had a low content of compressed polyhedral erythrocytes (polyhedrocytes) and an even distribution of fibrin, suggesting that the uncompacted intravital clots are more obstructive but patients could also be prone to bleeding. The absence of consumption coagulopathy suggests the predominance of local and/or regional microthrombosis rather than disseminated intravascular coagulation. The results obtained (i) confirm the importance of hemostatic disorders in COVID-19 and their relation to systemic inflammation; (ii) justify monitoring of hemostasis, including the kinetics of blood clot contraction; (iii) substantiate the active prophylaxis of thrombotic complications in COVID-19.
On the effectiveness of tracking and testing in SEIR models for improving health vs. economy trade-offs
Authors: Kolumbus Yoav , Nisan Noam
Published: August 2021

We study the effectiveness of tracking and testing policies for suppressing epidemic outbreaks. We evaluate the performance of tracking-based intervention methods on a network SEIR model, which we augment with an additional parameter to model pre-symptomatic and asymptomatic individuals, and study the effectiveness of these methods in combination with or as an alternative to quarantine and global lockdown policies. Our focus is on the basic trade-off between human-lives lost and economic costs, and on how this trade-off changes under different quarantine, lockdown, tracking, and testing policies. Our main findings are as follows: (1) Tests combined with patient quarantines reduce both economic costs and mortality, however, an extensive-scale testing capacity is required to achieve a significant improvement. (2) Tracking significantly reduces both economic costs and mortality. (3) Tracking combined with a moderate testing capacity can achieve containment without lockdowns. (4) In the presence of a flow of new incoming infections, dynamic “On–Off” lockdowns are more efficient than fixed lockdowns. In this setting as well, tracking strictly improves efficiency. The results show the extreme usefulness of policies that combine tracking and testing for reducing mortality and economic costs, and their potential to contain outbreaks without imposing any social distancing restrictions. This highlights the difficult social question of trading-off these gains against patient privacy, which is inevitably infringed by tracking.
Linking genetic determinants with salinity tolerance and ion relationships in eggplant, tomato and pepper
Authors: Suarez Donald L. , Celis Nydia , Ferreira Jorge F. S. , Reynolds Trevor , Sandhu Devinder
Published: August 2021

The Solanaceae family includes commercially important vegetable crops characterized by their relative sensitivity to salinity. Evaluation of 8 eggplant (Solanum melongena), 7 tomato (Solanum lycopersicum), and 8 pepper (Capsicum spp.) heirloom cultivars from different geographic regions revealed significant variation in salt tolerance. Relative fruit yield under salt treatment varied from 52 to 114% for eggplant, 56 to 84% for tomato, and 52 to 99% for pepper. Cultivars from all three crops, except Habanero peppers, restricted Na transport from roots to shoots under salinity. The high salt tolerance level showed a strong association with low leaf Na concentration. Additionally, the leaf K-salinity/K-control ratio was critical in determining the salinity tolerance of a genotype. Differences in relative yield under salinity were regulated by several component traits, which was consistent with the gene expression of relevant genes. Gene expression analyses using 12 genes associated with salt tolerance showed that, for eggplant and pepper, Na+ exclusion was a vital component trait, while sequestration of Na+ into vacuoles was critical for tomato plants. The high variability for salt tolerance found in heirloom cultivars helped characterize genotypes based on component traits of salt tolerance and will enable breeders to increase the salt tolerance of Solanaceae cultivars.
Diffusion of sylvatic yellow fever in the state of São Paulo, Brazil
Authors: Lacerda Alec Brian , del Castillo Saad Leila , Ikefuti Priscilla Venâncio , Pinter Adriano , Chiaravalloti-Neto Francisco
Published: August 2021

We investigated the sylvatic yellow fever (SYF) diffusion process in São Paulo (SP) between 2016 and 2019. We developed an ecological study of SYF through autochthonous human cases and epizootics of non-human primates (NHPs) that were spatiotemporally evaluated. We used kriging to obtain maps with isochrones representative of the evolution of the outbreak and characterized its diffusion pattern. We confirmed 648 human cases of SYF in SP, with 230 deaths and 843 NHP epizootics. Two outbreak waves were identified: one from West to East (2016 and 2017), and another from the Campinas region to the municipalities bordering Rio de Janeiro, Minas Gerais, and Paraná and those of the SP coast (2017–2019). The SYF outbreak diffusion process was by contagion. The disease did not exhibit jumps between municipalities, indicating that the mosquitoes and NHPs were responsible for transmitting the virus. There were not enough vaccines to meet the population at risk; hence, health authorities used information about the epizootic occurrence in NHPs in forest fragments to identify priority populations for vaccination.
Identification of non-ribosomal peptide synthetase in Ganoderma boninense Pat. that was expressed during the interaction with oil palm
Authors: Shokrollahi Neda , Ho Chai-Ling , Zainudin Nur Ain Izzati Mohd , Wahab Mohd As’wad Bin Abul , Wong Mui-Yun
Published: August 2021

Basal stem rot (BSR) of oil palm is a disastrous disease caused by a white-rot fungus Ganoderma boninense Pat. Non-ribosomal peptides (NRPs) synthesized by non-ribosomal peptide synthetases (NRPSs) are a group of secondary metabolites that act as fungal virulent factors during pathogenesis in the host. In this study, we aimed to isolate NRPS gene of G. boninense strain UPMGB001 and investigate the role of this gene during G. boninense-oil palm interaction. The isolated NRPS DNA fragment of 8322 bp was used to predict the putative peptide sequence of different domains and showed similarity with G. sinense (85%) at conserved motifs of three main NRPS domains. Phylogenetic analysis of NRPS peptide sequences demonstrated that NRPS of G. boninense belongs to the type VI siderophore family. The roots of 6-month-old oil palm seedlings were artificially inoculated for studying NRPS gene expression and disease severity in the greenhouse. The correlation between high disease severity (50%) and high expression (67-fold) of G. boninense NRPS gene at 4 months after inoculation and above indicated that this gene played a significant role in the advancement of BSR disease. Overall, these findings increase our knowledge on the gene structure of NRPS in G. boninense and its involvement in BSR pathogenesis as an effector gene.
Differential and shared effects of eicosapentaenoic acid and docosahexaenoic acid on serum metabolome in subjects with chronic inflammation
Authors: Chang Wan-Chi , So Jisun , Lamon-Fava Stefania
Published: August 2021

The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) affect cell function and metabolism, but the differential effects of EPA and DHA are not known. In a randomized, controlled, double-blind, crossover study, we assessed the effects of 10-week supplementation with EPA-only and DHA-only (3 g/d), relative to a 4-week lead-in phase of high oleic acid sunflower oil (3 g/day, defined as baseline), on fasting serum metabolites in 21 subjects (9 men and 12 post-menopausal women) with chronic inflammation and some characteristics of metabolic syndrome. Relative to baseline, EPA significantly lowered the tricarboxylic acid (TCA) cycle intermediates fumarate and α-ketoglutarate and increased glucuronate, UDP-glucuronate, and non-esterified DHA. DHA significantly lowered the TCA cycle intermediates pyruvate, citrate, isocitrate, fumarate, α-ketoglutarate, and malate, and increased succinate and glucuronate. Pathway analysis showed that both EPA and DHA significantly affected the TCA cycle, the interconversion of pentose and glucuronate, and alanine, and aspartate and glutamate pathways (FDR < 0.05) and that DHA had a significantly greater effect on the TCA cycle than EPA. Our results indicate that EPA and DHA exhibit both common and differential effects on cell metabolism in subjects with chronic inflammation and some key aspects of metabolic syndrome.