bluuebunny/crossref_metadata_2025 huggingface dataset:
When Pushkin's Blackness Was in Vogue: Rediscovering the Racialization of Russia's Preeminent Poet and His Descendants
Authors: Garibaldi Korey , Wang Emily
Published: September 2021

This essay investigates interconnections between the novelist, Henry James, Ivan Turgenev, and Aleksandr Pushkin and identifies the racial subtext of these associations. Several scholars have connected Pushkin and James. But none of this scholarship has speculated on whether it was the poet's African heritage that was at the root of hidden connections between these authors. Moreover, though most scholarship on Pushkin's reception in the United States focuses on twentieth-century African American literature, his African heritage was publicized much earlier. In fact, nineteenth-century commentators on both sides of the Atlantic frequently discussed Pushkin's racial heritage as a canonical European writer of African descent. This essay recovers how Henry James used Pushkin's daughter, the morganatic Countess Merenberg, as a model for the racially ambiguous “morganatic” Baroness Münster in The Europeans (1878). A decade later, James seems to have invoked the Countess Merenberg once more in his rewriting of Pushkin's “The Queen of Spades” (1833) in The Aspern Papers (1888). While James publicly attributed Byron and Shelley as inspirations, the discourse surrounding the African heritage of Pushkin and his heirs helps explain why the novelist minimized and erased the racial lineage at the center of The Europeans and The Aspern Papers.
Kalmyk DPs and the Narration of Displacement in Post-World War II Europe
Authors: Churyumova Elvira , Holland Edward C.
Published: September 2021

Based on interview files and archival materials, this paper reconstructs the experiences of Kalmyk displaced persons (DPs) against the backdrop of the shifting international refugee regime in post-World War II Europe. Kalmyks came to western Europe in two waves: at the conclusion of the Russian Civil War in 1920 and during the German retreat from the Soviet Union in 1943–44. After the war, the majority of Kalmyks were repatriated; those who remained in Europe primarily ended up in DP camps in the American zone of western Germany. This paper details the strategies used by Kalmyk DPs to avoid repatriation to the Soviet Union and eventually secure resettlement in the United States in 1951. Individual histories offer insight into how the Kalmyks as a group made themselves legible to the international community in light of a changing geopolitical environment and evolving racial regimes.
Regional Soil Nutrient Balances for Cropland in 1920s Catalonia, Spain
Authors: Galán Elena
Published: September 2021

Understanding the replacement of soil nutrients removed by harvests makes it possible to understand the influence of humans on long-term soil fertility. This article calculates nitrogen, phosphorous, and potassium balances for cropland in 1920 for three agroecoregions distinguished by particular historical settlement patterns, land use, geography, and climatic characteristics in Catalonia, Spain. The analysis assesses and compares the regional potential for farmers to have returned the nutrients extracted from croplands at a time of transition, when only a few synthetic fertilizers were yet available. From sustainability science, the article borrows a methodology to reconstruct soil nutrient balances in historical agroecosystems from available regional historical sources. The soil balances indicate that nutrient extractions were balanced with the additions in Catalonia’s wetter Pyrenees and eastern regions, but were in deficit in the arid western regions, where less livestock manure was available. In Barcelona province, farmers made considerable use of synthetic fertilizers already in 1920. Such fertilizers were mainly intended to supplement phosphorus in the eastern region, suggesting that they played an important role there too, where there was not enough manure.
Sicklepod [Senna obtusifolia (L.) H. S. Irwin & Barneby] “Getting sleepy?”
Authors: Sosnoskie Lynn M. , Steckel Sandy , Steckel Lawrence E.
Published: September 2021

Sicklepod [Senna obtusifolia (L.) H. S. Irwin & Barneby], also known as Cassia obtusifolia (L.), is an annual, herbaceous, dicotyledonous plant in the Fabaceae (Leguminosae) family, which is commonly known as the bean, legume, and pea family. The Fabaceae consist of herbs, shrubs, vines, or trees; the family has a cosmopolitan distribution with members numbering approximately 751 genera and 19,500 species (Christenhusz and Byng 2016). Characteristics of the Fabaceae include alternate, stipulate, and compound leaves. Leaflets often have pulvini (i.e., cushion-like swellings at the base of leaves that are subject to changes in turgor pressure), which are responsible for growth-independent or “sleep” movements. Another interesting anatomical feature exhibited by many species in the family is the formation of parenchymatous root nodules that are generated in association with nitrogen-fixing bacteria (Zomlefer 1994). The ovary of the Fabaceae usually develops into a dehiscent legume (e.g., pod). Although some Fabaceae may be weedy pests, others are important food crops [e.g., soybean, Glycine max (L.) Merr.] and fodder and forage plants (e.g., alfalfa, Medicago sativa L.). Some members of the Fabaceae produce valuable gums [e.g., gum arabic, Acacia senegal (L.) Britton] and dyes (e.g., indigo, Indigofera tinctoria L.), whereas others are prized as desirable ornamentals (e.g., eastern redbud, Cercis canadensis L.). Many species in the Fabaceae produce alkaloids or cyanogenic glycosides in different plant structures. Rotenone, an isoflavone insecticide, is derived from Derris eclipta (Wall.) Benth.
Impact of auxin herbicides on Palmer amaranth (Amaranthus palmeri) groundcover
Authors: Priess Grant L. , Norsworthy Jason K. , Farr Rodger B. , Mauromoustakos Andy , Butts Thomas R. , Roberts Trenton L.
Published: September 2021

In current and next-generation weed control technologies, sequential applications of contact and systemic herbicides for postemergence control of troublesome weeds are needed to mitigate the evolution of herbicide resistance. A clear understanding of the impact auxin herbicide symptomology has on Palmer amaranth groundcover will aid optimization of sequential herbicide applications. Field and greenhouse experiments were conducted in Fayetteville, AR, and a laboratory experiment was conducted in Lonoke, AR, in 2020 to evaluate changes in Palmer amaranth groundcover following an application of 2,4-D and dicamba with various nozzles, droplet sizes, and velocities. Field experiments utilized three nozzles: Extended Range (XR), Air Induction Extended Range (AIXR), and Turbo TeeJet® Induction (TTI), to assess the effect of spray droplet size on changes in Palmer amaranth groundcover. Nozzle did not affect Palmer amaranth groundcover when dicamba was applied. However, nozzle selection did impact groundcover when 2,4-D was applied; the following nozzle order XR > AIXR > TTI reduced Palmer amaranth groundcover the most in both site-years of the field experiment. This result (XR > AIXR > TTI) matches percent spray coverage data for 2,4-D and is inversely related to spray droplet size data. Rapid reductions of Palmer amaranth groundcover from 100% at time zero to 39.4% to 64.1% and 60.0% to 85.8% were observed 180 min after application in greenhouse and field experiments, respectively, regardless of herbicide or nozzle. In one site-year of the greenhouse and field experiments, regrowth of Palmer amaranth occurred 10,080 min (14 d) after an application of either 2,4-D or dicamba to larger than labeled weeds. In all experiments, complete reduction of live Palmer amaranth tissue was not observed 21 d after application with any herbicide or nozzle combination. Control of Palmer amaranth escapes with reduced groundcover may potentially lead to increased selection pressure on sequentially applied herbicides due to a reduction in spray solution contact with the targeted pest.
„Mit Worten malen und mit Bildern schreiben …“
Authors: Staudacher Diana
Published: September 2021

Zusammenfassung. „Bildergeschichten“ des Krankheitserlebens bringen weit mehr zum Ausdruck als traditionelles Edukationsmaterial: Erlebtes und Gedachtes, Gefühltes und Gefürchtetes, Erwünschtes und Erhofftes. Dank mündlicher Rede und einfacher Sprache sind Graphic Novels leicht zu verstehen. Wer die Geschichten liest, wird „in sie hineingezogen“ und verbindet sie mit eigenen Erfahrungen. Welches Potenzial bieten Graphic Novels für die Patientenedukation? Welche Zielgruppe sprechen sie primär an? Und wo liegen die Grenzen, die es beim Einsatz von Graphic Novels zu beachten gilt?
Single-step-fabricated disordered metasurfaces for enhanced light extraction from LEDs
Authors: Mao Peng , Liu Changxu , Li Xiyan , Liu Mengxia , Chen Qiang , Han Min , Maier Stefan A. , Sargent Edward H. , Zhang Shuang
Published: September 2021

While total internal reflection (TIR) lays the foundation for many important applications, foremost fibre optics that revolutionised information technologies, it is undesirable in some other applications such as light-emitting diodes (LEDs), which are a backbone for energy-efficient light sources. In the case of LEDs, TIR prevents photons from escaping the constituent high-index materials. Advances in material science have led to good efficiencies in generating photons from electron–hole pairs, making light extraction the bottleneck of the overall efficiency of LEDs. In recent years, the extraction efficiency has been improved, using nanostructures at the semiconductor/air interface that outcouple trapped photons to the outside continuum. However, the design of geometrical features for light extraction with sizes comparable to or smaller than the optical wavelength always requires sophisticated and time-consuming fabrication, which causes a gap between lab demonstration and industrial-level applications. Inspired by lightning bugs, we propose and realise a disordered metasurface for light extraction throughout the visible spectrum, achieved with single-step fabrication. By applying such a cost-effective light extraction layer, we improve the external quantum efficiency by a factor of 1.65 for commercialised GaN LEDs, demonstrating a substantial potential for global energy-saving and sustainability.
Nitrous oxide respiring bacteria in biogas digestates for reduced agricultural emissions
Authors: Jonassen Kjell Rune , Hagen Live H , Vick Silas H W , Arntzen Magnus Ø , Eijsink Vincent G H , Frostegård Åsa , Lycus Pawel , Molstad Lars , Pope Phillip B , Bakken Lars R
Published: September 2021

Inoculating agricultural soils with nitrous oxide respiring bacteria (NRB) can reduce N2O-emission, but would be impractical as a standalone operation. Here we demonstrate that digestates obtained after biogas production are suitable substrates and vectors for NRB. We show that indigenous NRB in digestates grew to high abundance during anaerobic enrichment under N2O. Gas-kinetics and meta-omic analyses showed that these NRB’s, recovered as metagenome-assembled genomes (MAGs), grew by harvesting fermentation intermediates of the methanogenic consortium. Three NRB’s were isolated, one of which matched the recovered MAG of a Dechloromonas, deemed by proteomics to be the dominant producer of N2O-reductase in the enrichment. While the isolates harbored genes required for a full denitrification pathway and could thus both produce and sequester N2O, their regulatory traits predicted that they act as N2O sinks in soil, which was confirmed experimentally. The isolates were grown by aerobic respiration in digestates, and fertilization with these NRB-enriched digestates reduced N2O emissions from soil. Our use of digestates for low-cost and large-scale inoculation with NRB in soil can be taken as a blueprint for future applications of this powerful instrument to engineer the soil microbiome, be it for enhancing plant growth, bioremediation, or any other desirable function.
Translating polygenic risk scores for clinical use by estimating the confidence bounds of risk prediction
Authors: Sun Jiangming , Wang Yunpeng , Folkersen Lasse , Borné Yan , Amlien Inge , Buil Alfonso , Orho-Melander Marju , Børglum Anders D. , Hougaard David M. ,   Regeneron Genetics Center, Lotta Luca Andrea , Jones Marcus , Baras Aris , Melander Olle , Engström Gunnar , Werge Thomas , Lage Kasper
Published: September 2021

A promise of genomics in precision medicine is to provide individualized genetic risk predictions. Polygenic risk scores (PRS), computed by aggregating effects from many genomic variants, have been developed as a useful tool in complex disease research. However, the application of PRS as a tool for predicting an individual’s disease susceptibility in a clinical setting is challenging because PRS typically provide a relative measure of risk evaluated at the level of a group of people but not at individual level. Here, we introduce a machine-learning technique, Mondrian Cross-Conformal Prediction (MCCP), to estimate the confidence bounds of PRS-to-disease-risk prediction. MCCP can report disease status conditional probability value for each individual and give a prediction at a desired error level. Moreover, with a user-defined prediction error rate, MCCP can estimate the proportion of sample (coverage) with a correct prediction.
Disrupting biological sensors of force promotes tissue regeneration in large organisms
Authors: Chen Kellen , Kwon Sun Hyung , Henn Dominic , Kuehlmann Britta A. , Tevlin Ruth , Bonham Clark A. , Griffin Michelle , Trotsyuk Artem A. , Borrelli Mimi R. , Noishiki Chikage , Padmanabhan Jagannath , Barrera Janos A. , Maan Zeshaan N. , Dohi Teruyuki , Mays Chyna J. , Greco Autumn H. , Sivaraj Dharshan , Lin John Q. , Fehlmann Tobias , Mermin-Bunnell Alana M. , Mittal Smiti , Hu Michael S. , Zamaleeva Alsu I. , Keller Andreas , Rajadas Jayakumar , Longaker Michael T. , Januszyk Michael , Gurtner Geoffrey C.
Published: September 2021

Tissue repair and healing remain among the most complicated processes that occur during postnatal life. Humans and other large organisms heal by forming fibrotic scar tissue with diminished function, while smaller organisms respond with scarless tissue regeneration and functional restoration. Well-established scaling principles reveal that organism size exponentially correlates with peak tissue forces during movement, and evolutionary responses have compensated by strengthening organ-level mechanical properties. How these adaptations may affect tissue injury has not been previously examined in large animals and humans. Here, we show that blocking mechanotransduction signaling through the focal adhesion kinase pathway in large animals significantly accelerates wound healing and enhances regeneration of skin with secondary structures such as hair follicles. In human cells, we demonstrate that mechanical forces shift fibroblasts toward pro-fibrotic phenotypes driven by ERK-YAP activation, leading to myofibroblast differentiation and excessive collagen production. Disruption of mechanical signaling specifically abrogates these responses and instead promotes regenerative fibroblast clusters characterized by AKT-EGR1.
Integrating pheromonal and spatial information in the amygdalo-hippocampal network
Authors: Villafranca-Faus María , Vila-Martín Manuel Esteban , Esteve Daniel , Merino Esteban , Teruel-Sanchis Anna , Cervera-Ferri Ana , Martínez-Ricós Joana , Lloret Ana , Lanuza Enrique , Teruel-Martí Vicent
Published: September 2021

Vomeronasal information is critical in mice for territorial behavior. Consequently, learning the territorial spatial structure should incorporate the vomeronasal signals indicating individual identity into the hippocampal cognitive map. In this work we show in mice that navigating a virtual environment induces synchronic activity, with causality in both directionalities, between the vomeronasal amygdala and the dorsal CA1 of the hippocampus in the theta frequency range. The detection of urine stimuli induces synaptic plasticity in the vomeronasal pathway and the dorsal hippocampus, even in animals with experimentally induced anosmia. In the dorsal hippocampus, this plasticity is associated with the overexpression of pAKT and pGSK3β. An amygdalo-entorhino-hippocampal circuit likely underlies this effect of pheromonal information on hippocampal learning. This circuit likely constitutes the neural substrate of territorial behavior in mice, and it allows the integration of social and spatial information.
Cellular model system to dissect the isoform-selectivity of Akt inhibitors
Authors: Quambusch Lena , Depta Laura , Landel Ina , Lubeck Melissa , Kirschner Tonia , Nabert Jonas , Uhlenbrock Niklas , Weisner Jörn , Kostka Michael , Levy Laura M. , Schultz-Fademrecht Carsten , Glanemann Franziska , Althoff Kristina , Müller Matthias P. , Siveke Jens T. , Rauh Daniel
Published: September 2021

The protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms’ distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.
Dissecting esophageal squamous-cell carcinoma ecosystem by single-cell transcriptomic analysis
Authors: Zhang Xiannian , Peng Linna , Luo Yingying , Zhang Shaosen , Pu Yang , Chen Yamei , Guo Wenjia , Yao Jiacheng , Shao Mingming , Fan Wenyi , Cui Qionghua , Xi Yiyi , Sun Yanxia , Niu Xiangjie , Zhao Xuan , Chen Liping , Wang Yuqian , Liu Yachen , Yang Xinyu , Wang Chengcheng , Zhong Ce , Tan Wen , Wang Jianbin , Wu Chen , Lin Dongxin
Published: September 2021

Esophageal squamous-cell carcinoma (ESCC), one of the most prevalent and lethal malignant disease, has a complex but unknown tumor ecosystem. Here, we investigate the composition of ESCC tumors based on 208,659 single-cell transcriptomes derived from 60 individuals. We identify 8 common expression programs from malignant epithelial cells and discover 42 cell types, including 26 immune cell and 16 nonimmune stromal cell subtypes in the tumor microenvironment (TME), and analyse the interactions between cancer cells and other cells and the interactions among different cell types in the TME. Moreover, we link the cancer cell transcriptomes to the somatic mutations and identify several markers significantly associated with patients’ survival, which may be relevant to precision care of ESCC patients. These results reveal the immunosuppressive status in the ESCC TME and further our understanding of ESCC.
Moisture-induced autonomous surface potential oscillations for energy harvesting
Authors: Long Yu , He Peisheng , Shao Zhichun , Li Zhaoyang , Kim Han , Yao Archie Mingze , Peng Yande , Xu Renxiao , Ahn Christine Heera , Lee Seung-Wuk , Zhong Junwen , Lin Liwei
Published: September 2021

A variety of autonomous oscillations in nature such as heartbeats and some biochemical reactions have been widely studied and utilized for applications in the fields of bioscience and engineering. Here, we report a unique phenomenon of moisture-induced electrical potential oscillations on polymers, poly([2-(methacryloyloxy)ethyl] dimethyl-(3-sulfopropyl) ammonium hydroxide-co-acrylic acid), during the diffusion of water molecules. Chemical reactions are modeled by kinetic simulations while system dynamic equations and the stability matrix are analyzed to show the chaotic nature of the system which oscillates with hidden attractors to induce the autonomous surface potential oscillation. Using moisture in the ambient environment as the activation source, this self-excited chemoelectrical reaction could have broad influences and usages in surface-reaction based devices and systems. As a proof-of-concept demonstration, an energy harvester is constructed and achieved the continuous energy production for more than 15,000 seconds with an energy density of 16.8 mJ/cm2. A 2-Volts output voltage has been produced to power a liquid crystal display toward practical applications with five energy harvesters connected in series.
C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers
Authors: Nanaura Hitoki , Kawamukai Honoka , Fujiwara Ayano , Uehara Takeru , Aiba Yuichiro , Nakanishi Mari , Shiota Tomo , Hibino Masaki , Wiriyasermkul Pattama , Kikuchi Sotaro , Nagata Riko , Matsubayashi Masaya , Shinkai Yoichi , Niwa Tatsuya , Mannen Taro , Morikawa Naritaka , Iguchi Naohiko , Kiriyama Takao , Morishima Ken , Inoue Rintaro , Sugiyama Masaaki , Oda Takashi , Kodera Noriyuki , Toma-Fukai Sachiko , Sato Mamoru , Taguchi Hideki , Nagamori Shushi , Shoji Osami , Ishimori Koichiro , Matsumura Hiroyoshi , Sugie Kazuma , Saio Tomohide , Yoshizawa Takuya , Mori Eiichiro
Published: September 2021

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-β2 (Kapβ2) at 1:1 ratio. The nuclear magnetic resonances of Kapβ2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapβ2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.
Conformational dynamics linked to domain closure and substrate binding explain the ERAP1 allosteric regulation mechanism
Authors: Maben Zachary , Arya Richa , Georgiadis Dimitris , Stratikos Efstratios , Stern Lawrence J.
Published: September 2021

The endoplasmic-reticulum aminopeptidase ERAP1 processes antigenic peptides for loading on MHC-I proteins and recognition by CD8 T cells as they survey the body for infection and malignancy. Crystal structures have revealed ERAP1 in either open or closed conformations, but whether these occur in solution and are involved in catalysis is not clear. Here, we assess ERAP1 conformational states in solution in the presence of substrates, allosteric activators, and inhibitors by small-angle X-ray scattering. We also characterize changes in protein conformation by X-ray crystallography, and we localize alternate C-terminal binding sites by chemical crosslinking. Structural and enzymatic data suggest that the structural reconfigurations of ERAP1 active site are physically linked to domain closure and are promoted by binding of long peptide substrates. These results clarify steps required for ERAP1 catalysis, demonstrate the importance of conformational dynamics within the catalytic cycle, and provide a mechanism for the observed allosteric regulation and Lys/Arg528 polymorphism disease association.
Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens
Authors: Hwang Michael S. , Miller Michelle S. , Thirawatananond Puchong , Douglass Jacqueline , Wright Katharine M. , Hsiue Emily Han-Chung , Mog Brian J. , Aytenfisu Tihitina Y. , Murphy Michael B. , Aitana Azurmendi P. , Skora Andrew D. , Pearlman Alexander H. , Paul Suman , DiNapoli Sarah R. , Konig Maximilian F. , Bettegowda Chetan , Pardoll Drew M. , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Zhou Shibin , Gabelli Sandra B.
Published: September 2021

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of therapeutic agents, generating remarkable responses in the clinic for a subset of human cancers. One major challenge precluding the wider implementation of CAR therapy is the paucity of tumor-specific antigens. Here, we describe the development of a CAR targeting the tumor-specific isocitrate dehydrogenase 2 (IDH2) with R140Q mutation presented on the cell surface in complex with a common human leukocyte antigen allele, HLA-B*07:02. Engineering of the hinge domain of the CAR, as well as crystal structure-guided optimization of the IDH2R140Q-HLA-B*07:02-targeting moiety, enhances the sensitivity and specificity of CARs to enable targeting of this HLA-restricted neoantigen. This approach thus holds promise for the development and optimization of immunotherapies specific to other cancer driver mutations that are difficult to target by conventional means.
Colossal thermo-hydro-electrochemical voltage generation for self-sustainable operation of electronics
Authors: Zhang Yufan , Sohn Ahrum , Chakraborty Anirban , Yu Choongho
Published: September 2021

Thermoelectrics are suited to converting dissipated heat into electricity for operating electronics, but the small voltage (~0.1 mV K−1) from the Seebeck effect has been one of the major hurdles in practical implementation. Here an approach with thermo-hydro-electrochemical effects can generate a large thermal-to-electrical energy conversion factor (TtoE factor), −87 mV K−1 with low-cost carbon steel electrodes and a solid-state polyelectrolyte made of polyaniline and polystyrene sulfonate (PANI:PSS). We discovered that the thermo-diffusion of water in PANI:PSS under a temperature gradient induced less (or more) water on the hotter (or colder) side, raising (or lowering) the corrosion overpotential in the hotter (or colder) side and thereby generating output power between the electrodes. Our findings are expected to facilitate subsequent research for further increasing the TtoE factor and utilizing dissipated thermal energy.
A functional genomics pipeline identifies pleiotropy and cross-tissue effects within obesity-associated GWAS loci
Authors: Joslin Amelia C. , Sobreira Débora R. , Hansen Grace T. , Sakabe Noboru J. , Aneas Ivy , Montefiori Lindsey E. , Farris Kathryn M. , Gu Jing , Lehman Donna M. , Ober Carole , He Xin , Nóbrega Marcelo A.
Published: September 2021

Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.
Brown adipose tissue monocytes support tissue expansion
Authors: Gallerand Alexandre , Stunault Marion I. , Merlin Johanna , Luehmann Hannah P. , Sultan Deborah H. , Firulyova Maria M. , Magnone Virginie , Khedher Narges , Jalil Antoine , Dolfi Bastien , Castiglione Alexia , Dumont Adelie , Ayrault Marion , Vaillant Nathalie , Gilleron Jérôme , Barbry Pascal , Dombrowicz David , Mack Matthias , Masson David , Bertero Thomas , Becher Burkhard , Williams Jesse W. , Zaitsev Konstantin , Liu Yongjian , Guinamard Rodolphe R. , Yvan-Charvet Laurent , Ivanov Stoyan
Published: September 2021

Monocytes are part of the mononuclear phagocytic system. Monocytes play a central role during inflammatory conditions and a better understanding of their dynamics might open therapeutic opportunities. In the present study, we focused on the characterization and impact of monocytes on brown adipose tissue (BAT) functions during tissue remodeling. Single-cell RNA sequencing analysis of BAT immune cells uncovered a large diversity in monocyte and macrophage populations. Fate-mapping experiments demonstrated that the BAT macrophage pool requires constant replenishment from monocytes. Using a genetic model of BAT expansion, we found that brown fat monocyte numbers were selectively increased in this scenario. This observation was confirmed using a CCR2-binding radiotracer and positron emission tomography. Importantly, in line with their tissue recruitment, blood monocyte counts were decreased while bone marrow hematopoiesis was not affected. Monocyte depletion prevented brown adipose tissue expansion and altered its architecture. Podoplanin engagement is strictly required for BAT expansion. Together, these data redefine the diversity of immune cells in the BAT and emphasize the role of monocyte recruitment for tissue remodeling.
Integrated exome and RNA sequencing of TFE3-translocation renal cell carcinoma
Authors: Sun Guangxi , Chen Junru , Liang Jiayu , Yin Xiaoxue , Zhang Mengni , Yao Jin , He Ning , Armstrong Cameron M. , Zheng Linmao , Zhang Xingming , Zhu Sha , Sun Xiaomeng , Yang Xiaoxia , Zhao Wanbin , Liao Banghua , Pan Xiuyi , Nie Ling , Yang Ling , Chen Yuntian , Zhao Jinge , Zhang Haoran , Dai Jindong , Shen Yali , Liu Jiyan , Huang Rui , Liu Jiandong , Wang Zhipeng , Ni Yuchao , Wei Qiang , Li Xiang , Zhou Qiao , Huang Haojie , Liu Zhenhua , Shen Pengfei , Chen Ni , Zeng Hao
Published: September 2021

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.
The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling
Authors: Shen Chen , Nayak Anmada , Neitzel Leif R. , Adams Amber A. , Silver-Isenstadt Maya , Sawyer Leah M. , Benchabane Hassina , Wang Huilan , Bunnag Nawat , Li Bin , Wynn Daniel T. , Yang Fan , Garcia-Contreras Marta , Williams Charles H. , Dakshanamurthy Sivanesan , Hong Charles C. , Ayad Nagi G. , Capobianco Anthony J. , Ahmed Yashi , Lee Ethan , Robbins David J.
Published: September 2021

Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the β-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease.
Polymerized small molecular acceptor based all-polymer solar cells with an efficiency of 16.16% via tuning polymer blend morphology by molecular design
Authors: Du Jiaqi , Hu Ke , Zhang Jinyuan , Meng Lei , Yue Jiling , Angunawela Indunil , Yan Hongping , Qin Shucheng , Kong Xiaolei , Zhang Zhanjun , Guan Bo , Ade Harald , Li Yongfang
Published: September 2021

All-polymer solar cells (all-PSCs) based on polymerized small molecular acceptors (PSMAs) have made significant progress recently. Here, we synthesize two A-DA’D-A small molecule acceptor based PSMAs of PS-Se with benzo[c][1,2,5]thiadiazole A’-core and PN-Se with benzotriazole A’-core, for the studies of the effect of molecular structure on the photovoltaic performance of the PSMAs. The two PSMAs possess broad absorption with PN-Se showing more red-shifted absorption than PS-Se and suitable electronic energy levels for the application as polymer acceptors in the all-PSCs with PBDB-T as polymer donor. Cryogenic transmission electron microscopy visualizes the aggregation behavior of the PBDB-T donor and the PSMA in their solutions. In addition, a bicontinuous-interpenetrating network in the PBDB-T:PN-Se blend film with aggregation size of 10~20 nm is clearly observed by the photoinduced force microscopy. The desirable morphology of the PBDB-T:PN-Se active layer leads its all-PSC showing higher power conversion efficiency of 16.16%.
Infection-induced type I interferons critically modulate the homeostasis and function of CD8+ naïve T cells
Authors: Jergović Mladen , Coplen Christopher P. , Uhrlaub Jennifer L. , Besselsen David G. , Cheng Shu , Smithey Megan J. , Nikolich-Žugich Janko
Published: September 2021

Naïve T (Tn) cells require two homeostatic signals for long-term survival: tonic T cell receptor:self-peptide–MHC contact and IL-7 stimulation. However, how microbial exposure impacts Tn homeostasis is still unclear. Here we show that infections can lead to the expansion of a subpopulation of long-lived, Ly6C+ CD8+ Tn cells with accelerated effector function. Mechanistically, mono-infection with West Nile virus transiently, and polymicrobial exposure persistently, enhances Ly6C expression selectively on CD5hiCD8+ cells, which in the case of polyinfection translates into a numerical CD8+ Tn cell increase in the lymph nodes. This conversion and expansion of Ly6C+ Tn cells depends on IFN-I, which upregulates MHC class I expression and enhances tonic TCR signaling in differentiating Tn cells. Moreover, for Ly6C+CD8+ Tn cells, IFN-I-mediated signals optimize their homing to secondary sites, extend their lifespan, and enhance their effector differentiation and antibacterial function, particularly for low-affinity clones. Our results thus uncover significant regulation of Tn homeostasis and function via infection-driven IFN-I, with potential implications for immunotherapy.
Determination of X-ray detection limit and applications in perovskite X-ray detectors
Authors: Pan Lei , Shrestha Shreetu , Taylor Neil , Nie Wanyi , Cao Lei R.
Published: September 2021

X-ray detection limit and sensitivity are important figure of merits for perovskite X-ray detectors, but literatures lack a valid mathematic expression for determining the lower limit of detection for a perovskite X-ray detector. In this work, we present a thorough analysis and new method for X-ray detection limit determination based on a statistical model that correlates the dark current and the X-ray induced photocurrent with the detection limit. The detection limit can be calculated through the measurement of dark current and sensitivity with an easy-to-follow practice. Alternatively, the detection limit may also be obtained by the measurement of dark current and photocurrent when repeatedly lowering the X-ray dose rate. While the material quality is critical, we show that the device architecture and working mode also have a significant influence on the sensitivity and the detection limit. Our work establishes a fair comparison metrics for material and detector development.
Small-molecule suppression of calpastatin degradation reduces neuropathology in models of Huntington’s disease
Authors: Hu Di , Sun Xiaoyan , Magpusao Anniefer , Fedorov Yuriy , Thompson Matthew , Wang Benlian , Lundberg Kathleen , Adams Drew J. , Qi Xin
Published: September 2021

Mitochondrial dysfunction is a common hallmark of neurological disorders, and reducing mitochondrial damage is considered a promising neuroprotective therapeutic strategy. Here, we used high-throughput small molecule screening to identify CHIR99021 as a potent enhancer of mitochondrial function. CHIR99021 improved mitochondrial phenotypes and enhanced cell viability in several models of Huntington’s disease (HD), a fatal inherited neurodegenerative disorder. Notably, CHIR99201 treatment reduced HD-associated neuropathology and behavioral defects in HD mice and improved mitochondrial function and cell survival in HD patient-derived neurons. Independent of its known inhibitory activity against glycogen synthase kinase 3 (GSK3), CHIR99021 treatment in HD models suppressed the proteasomal degradation of calpastatin (CAST), and subsequently inhibited calpain activation, a well-established effector of neural death, and Drp1, a driver of mitochondrial fragmentation. Our results established CAST-Drp1 as a druggable signaling axis in HD pathogenesis and highlighted CHIR99021 as a mitochondrial function enhancer and a potential lead for developing HD therapies.
Chinese gut microbiota and its associations with staple food type, ethnicity, and urbanization
Authors: Lu Jing , Zhang Li , Zhai Qixiao , Zhao Jianxin , Zhang Hao , Lee Yuan-Kun , Lu Wenwei , Li Mingkun , Chen Wei
Published: September 2021

The gut microbiota could affect human health and disease. Although disease-associated microbiota alteration has been extensively investigated in the Chinese population, a nationwide Chinese gut microbiota baseline is still lacking. Here we performed 16 S rRNA gene sequencing on fecal samples from 2678 healthy Chinese individuals, who belonged to eight ethnic groups and resided in 63 counties/cities of 28 provinces. We identified four enterotypes, three of which were enriched forPrevotella,Bacteroides,andEscherichia, respectively, whereas the fourth one had no dominant genus. By assessing the association between the gut microbiota and 20 variables belonging to six categories, geography, demography, diet, urbanization, lifestyle, and sampling month, we revealed that geography explained the largest microbiota variation, and clarified the distinct patterns in the associations with staple food type, ethnicity, and urban/rural residence. Specifically, the gut microbiota of Han Chinese and ethnic minority groups from the same sites was more alike than that of the same ethnic minority groups from different sites. Individuals consuming wheat as staple food were predicted to have more microbial genes involving in glucan 1,3-beta-glucosidase andS-adenosyl-l-methionine biosynthesis than those who consumed rice, based on functional prediction. Besides, an appreciable effect of urbanization on decreased intra-individual diversity, increased inter-individual diversity, and increased proportion of theBacteroidesenterotype was observed. Collectively, our study provided a nationwide gut microbiota baseline of the Chinese population and knowledge on important covariates, which are fundamental to translational microbiota research.
Evaluation of disseminated tumor cells and circulating tumor cells in patients with breast cancer receiving adjuvant zoledronic acid
Authors: Vidula Neelima , Greenberg Sally , Petrillo Laura , Hwang Jimmy , Melisko Michelle , Goga Andrei , Moasser Mark , Magbanua Mark , Park John W. , Rugo Hope S.
Published: September 2021

We evaluated disseminated tumor cells (DTCs) and circulating tumor cells (CTCs) in patients with stage I-III breast cancer with >4 MM/mL DTC at baseline who received adjuvant zoledronic acid (ZOL). ZOL was administered every 4 weeks for 24 months, and patients underwent bone marrow aspiration at baseline, and 12 and 24 months of ZOL. Complete DTC response (<4 DTC/mL), serial CTCs, survival, recurrence, and toxicity were determined. Forty-five patients received ZOL. Median baseline DTC was 13.3/mL. Significant reduction in median DTC occurred from baseline to 12 months, and 24 months. Complete DTC response was seen in 32% at 12 months, and 26% at 24 months. Nine patients developed recurrence. Baseline DTC > 30/mL and CTC > 0.8/mL were significantly associated with recurrence and death. Serial reduction in DTCs occurred. Higher baseline DTC > 30/mL and CTC > 0.8/mL correlated with recurrence and death.
Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells
Authors: Lee Jeong Hyun , Toy Laura , Kos Justin T. , Safonova Yana , Schief William R. , Havenar-Daughton Colin , Watson Corey T. , Crotty Shane
Published: September 2021

A successful HIV vaccine eliciting broadly neutralizing antibodies (bnAbs) must overcome the hurdle of being able to activate naive precursor B cells encoding features within their germline B cell receptors (BCR) that allow recognition of broadly neutralizing epitopes. Knowledge of whether bnAb precursor B cells are circulating at sufficient frequencies within individuals in communities heavily impacted by HIV may be important. Using a germline-targeting eOD-GT8 immunogen and high-throughput droplet-based single-cell BCR sequencing, we demonstrate that large numbers of paired BCR sequences from multiple donors can be efficiently screened to elucidate precursor frequencies of rare, naive VRC01-class B cells. Further, we analyzed IGHV1-2 allelic usage among three different cohorts; we find that IGHV1-2 alleles traditionally thought to be incompatible with VRC01-class responses are relatively common in various human populations and that germline variation within IGHV1-2 associates with gene usage frequencies in the naive BCR repertoire.
The short-term mortality fluctuation data series, monitoring mortality shocks across time and space
Authors: Jdanov Dmitri A. , Galarza Ainhoa Alustiza , Shkolnikov Vladimir M. , Jasilionis Domantas , Németh László , Leon David A. , Boe Carl , Barbieri Magali
Published: September 2021

The COVID-19 pandemic has revealed substantial coverage and quality gaps in existing international and national statistical monitoring systems. It is striking that obtaining timely, accurate, and comparable across countries data in order to adequately respond to unexpected epidemiological threats is very challenging. The most robust and reliable approach to quantify the mortality burden due to short-term risk factors is based on estimating weekly excess deaths. This approach is more reliable than monitoring deaths with COVID-19 diagnosis or calculating incidence or fatality rates affected by numerous problems such as testing coverage and comparability of diagnostic approaches. In response to the emerging data challenges, a new data resource on weekly mortality has been established. The Short-term Mortality Fluctuations (STMF, available at www.mortality.org) data series is the first international database providing open-access harmonized, uniform, and fully documented data on weekly all-cause mortality. The STMF online vizualisation tool provides an opportunity to perform a quick assessment of the excess weekly mortality in one or several countries by means of an interactive graphical interface.
Metabolic rewiring is associated with HPV-specific profiles in cervical cancer cell lines
Authors: Pappa Kalliopi I. , Daskalakis George , Anagnou Nicholas P.
Published: September 2021

Both HPV-positive and HPV-negative cervical cancers are associated with aberrant metabolism, although the oncogenic drivers remain elusive. Here we show the assessment of the metabolomic profiles of four distinct cervical cell lines, a normal and three cancer cell lines, one HPV-negative (C33A) and two HPV-positive (SiHa HPV16+, HeLa HPV18+), employing an ultra performance liquid chromatography and a high resolution mass spectrometry. Out of the total 462 metabolites, 248 to 326 exhibited statistically significant differences, while Random Forests analysis identified unique molecules for each cell line. The two HPV+ cell lines exhibited features of Warburg metabolism, consistent with the role of the HPV E6 protein. SiHa and HeLa cells displayed purine salvage pathway activity, while C33A cells revealed synthesis of cytidine, via a novel mechanism. These data document a highly dynamic HPV-specific rewiring of metabolic pathways occurring in cervical cancer. Therefore, this approach can eventually provide novel mechanistic insights into cervical carcinogenesis.
Ruminants reveal Eocene Asiatic palaeobiogeographical provinces as the origin of diachronous mammalian Oligocene dispersals into Europe
Authors: Mennecart Bastien , Aiglstorfer Manuela , Li Yikun , Li Chunxiao , Wang ShiQi
Published: September 2021

Faunal provincialism between the North and South parts of Eastern Asia is shown to have been in place since the late Eocene. This provincialism structured the mammalian dispersals across Eurasia for millions of years and provides insights into both palaeonvironments and palaeoclimate zonation. In addition, this study reveals the oldest record of a crown ruminant (Iberomeryx from Shinao, China). Ecologically, as well as economically, ruminant artiodactyls are one of the most important large mammal groups today. The revision of the ruminants from the Shinao Formation, from the Caijiachong marls and Xiaerhete, resulted in two new taxa and shows that the different provinces were populated by distinct taxa living in different environments, dominated by the monsoon in the South and drier conditions in the North. Evaluating this result in a Eurasian context demonstrates that the dispersals from Asia to Europe was complex. These results confirm that there were at least two dispersal events, distinct in space and time: the Grande-Coupure from Northern and Central Asia along the North ca. 34 Mya and the Bachitherium dispersal event from the Southern province along a southerly route ca. 31 Mya.