bluuebunny/crossref_metadata_2025 huggingface dataset:
Design and automation at the end of modernity: the teachings of the pandemic
Authors: Carpo Mario
Published: June 2022

Many in the design community have long claimed that digital mass-customization is cheaper, faster, smarter and more environmentally sustainable than the mechanical mass-production of standardized industrial products; and that the electronic transmission of information is cheaper, faster, smarter, and more environmentally sustainable than the mechanical transportation of people and goods. The global pandemic has tragically proven that a computational alternative to the modern, mechanical way of making, working, and living, now exists, and it is viable. When we had to shut down corporate offices, global megafactories, suburban shopping malls, and intercontinental airports, we did. We did because we had to; but also because today's technology already allows us to do so.
Brainwashing
Authors: Introvigne Massimo
Published: June 2022

The events of January 6, 2021 gave new currency to the idea of brainwashing. Some claimed that Trump's followers had been brainwashed, while others insisted that a 'deep state' had brainwashed most Americans into accepting a rigged election. Scholars who explain that brainwashing theories have long been rejected by most academics and courts of law find it difficult to be heard. Brainwashing nevertheless remains a convenient explanation of how seemingly normal citizens convert to unusual religious or political ideologies. This Element traces its origins to the idea that conversion to deviant beliefs is due to black magic. A more scientific hypnosis later replaced magic and the Cold War introduced the supposedly infallible technique of brainwashing. From the 1960s, new religious movements, more commonly called cults, were accused of using brainwashing. Most scholars of religion reject the theory as pseudoscience, but the controversy continues to this day.
A Hail of a Night in Mexico
Authors: Basilio Humberto
Published: June 2022

When a severe hailstorm hit Mexico’s capital last week, citizens began to wonder whether climate change could be the cause. But is that the right question to ask?
On the Step Type of Continuous Propagating Positive Leader in Laboratory‐Scale Long Spark Discharges
Authors: Huang Shengxin , Chen Weijiang , Fu Zhong , Xiang Nianwen , Ding Yujian , Cheng Dengfeng , Gu Jianwei , Pei Zhehao
Published: June 2022

Positive leader steps are currently not well understood. Many recent findings challenge the previous understanding of the positive leader steps occurring in continuous leader development. In this work, we investigate the stepping propagation of positive leaders in laboratory spark discharge by using a high‐speed video camera and a synchronized electrical parameter measurement system. Two types of steps were distinguished in the positive leader continuous development process based on the current pulse features. One type of step exhibits a bell‐shaped current pulse, while the other type of step exhibits a steep current rise. The former type vanishes when the rising rate of the ambient electric field increases, whereas the latter type, which could be led by a separate luminous structure, does not.
Lithospheric Structure of the South India Precambrian Terrains From Surface Wave Tomography
Authors: Mullick N. , Rai S. S. , Saha G.
Published: June 2022

We have developed a 3‐D shear velocity (Vsv) model of Precambrian terrains of South India with a lateral resolution of 55 km to a depth of 250 km by inversion of fundamental mode Rayleigh wave phase velocity dispersion data in the period of 30–140s, combined with a well‐constrained crustal velocity model from an earlier study. The dispersion data were computed from 748 earthquakes recorded at 85 homogeneously distributed seismographs. Our velocity model shows 150–200 km thick lithosphere in most of the Archean Dharwar craton where Vsv is >4.7 km/s in the depth of 50–100 km and progressively decreases to 4.6 km/s at 120–150 km followed by a constant velocity of 4.5 km/s beyond 150–200 km depth. It correlates well with the results of the petrological studies of kimberlite xenoliths. An extraordinary high shear velocity (up to 4.8 km/s) and thick lithosphere (150 km) are observed beneath the Proterozoic Carbonatite complex, located at the south‐eastern edge of the Dharwar craton. We infer compositional modification of lower lithosphere at the south‐western margin of the Dharwar craton and lithospheric erosion at the Granulite terrain both possibly due to interaction with the Marion mantle plume at ∼90 Ma. The region is underlain by a 2%–3% lower velocity channel at ∼180–220 km depth in the asthenosphere, uncorrelated with the overlying lithosphere, possibly due to relative motion between them. It may be attributed to deep Earth‐processes such as asthenospheric upwelling.
A Dual Regime of Mesoscale Convective Systems in the East Asian Monsoon Annual Cycle
Authors: Cheng Tat Fan , Dong Qizhen , Dai Lun , Lu Mengqian
Published: June 2022

Eastern China is perennially hit by mesoscale convective systems (MCSs), yet it remains an open question as to whether and how their general properties change throughout the annual cycle. By leveraging high‐resolution satellite observations and a hybrid tracking algorithm, we present a 20‐year (2001–2020) climatology of MCSs over eastern China during eight subseasonal‐to‐seasonal (S2S) monsoon stages. MCSs contribute up to 50% of the stage‐total precipitation and over 60% of the rainband‐zone precipitation during the Pre‐Meiyu and Meiyu episodes, and their contributions remain non‐trivial during the transition seasons. We discover two contrasting regimes of MCSs that alternate immediately upon the Pre‐Meiyu and the Fall onsets. The wintertime regime features fast‐propagating shallow systems initiated at night in a strongly sheared and dry environment. The summertime regime, instead, features an outbreak of MCSs in the south, where the systems often initiate in the afternoon and propagate 2–3 times slower than the cold‐season ones. Based on multivariate clustering analysis, the nighttime MCSs that dictate the winter stages often initiate over a deep nocturnal boundary layer with moist rear inflows upgliding above it. In contrast, the afternoon‐initiated MCSs under the summertime regime feature a pronounced convective available potential energy (CAPE) "tongue" and upslope flows in their southeast quadrant. The southwesterly moist ascending flows are likely to shallow the convective inhibition at the tip of the CAPE tongue and facilitate the intense updrafts of the MCSs. Findings here may offer insights into S2S weather prediction and facilitate agricultural and water management throughout the year.
Enhanced Oxidation of SO2 by H2O2 During Haze Events: Constraints From Sulfur Isotopes
Authors: Han Xiaokun , Lang Yunchao , Guo Qingjun , Li Xiaodong , Ding Hu , Li Siliang
Published: June 2022

Sulfate aerosols play a critical role in atmospheric chemistry and climate change. However, the mechanism of sulfate formation during haze events remains highly uncertain. In this study, sulfur isotopic compositions of SO2 and sulfate in PM2.5 samples collected in Tianjin, China as well as a Rayleigh distillation model are used to constrain SO2 oxidation pathways. The sulfur isotopic fractionation (ε) between SO2 and sulfate displays a seasonal change with low values in summer (−0.1 ± 1.0‰, n = 16) and high values in winter (2.1 ± 1.2‰, n = 16). Although an influence of temperature effect to this seasonal trend cannot be ignored, the relation between ε values and SO2 oxidation ratios indicates that the seasonality is mainly attributed to the changes in relative contributions of oxidation pathways. In addition, an elevated ε value has been observed during the first stage of haze event, suggesting that the relative contribution of H2O2 pathway to sulfate formation is higher in haze days than that in normal days. Our results highlight the important role of SO2 oxidation by H2O2 in the first stage of haze event.
Low quality of life in men with chronic prostatitis-like symptoms
Authors: Sugimoto Mikio , Hijikata Yasukazu , Tohi Yoichiro , Kuroda Hideya , Takei Mineo , Matsuki Takakazu , Kamitani Tsukasa , Kakehi Yoshiyuki , Yamamoto Yosuke , Fukuhara Shunichi
Published: June 2022

Background

Chronic prostatitis (CP) can impair health-related quality of life (QOL), but the full impact of CP, including the impact of CP-like symptoms in men who have no CP diagnosis (CPS), is unknown. We estimated the impact of diagnosed CP (DCP) and CPS on Health-related QOL.

Methods

From a representative nationwide survey of men aged 20–84 in Japan, we determined the prevalence of DCP and also of CPS. For CPS, we used Nickel’s criteria, which were used previously to estimate the prevalence of CP and are based on the NIH Chronic Prostatitis Symptom Index. To test the robustness of Nickel’s criteria, we used two other definitions of CPS (two sensitivity analyses). We measured QOL with the Short-Form 12-Item Health Survey. We compared the participants’ QOL scores with the national-norm scores, and with the scores of men who had benign prostatic hyperplasia (BPH).

Results

Among the 5 010 participants, 1.4% had DCP and 3.7% had CPS. The sensitivity analyses resulted in CPS prevalence estimates of 3.1% and 4.5%. CPS was particularly common in younger participants (5.7% of those in their 30 s had CPS). QOL was very low among men with CP: In most areas (domains) of QOL, their scores were more than 0.5 standard deviation below the national-norm mean. Their mental-health scores were lower than those of men with BPH. The lowest scores among all 8 QOL domains were in role-functioning.

Conclusions

CP is common, but it is underdiagnosed, particularly in younger men. Whether diagnosed or only suspected, CP’s impact on QOL is large. Because CP is common, and because it substantially impairs individuals’ QOL and can also reduce societal productivity, it requires more attention. Specifically, needed now is a simple tool for urologists and for primary care providers, to identify men, particularly young men, whose QOL is impaired by CP.
Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials
Authors: Shi Yuncong , Zhang Huanji , Huang Suli , Yin Li , Wang Feng , Luo Pei , Huang Hui
Published: June 2022

Epigenetics is closely related to cardiovascular diseases. Genome-wide linkage and association analyses and candidate gene approaches illustrate the multigenic complexity of cardiovascular disease. Several epigenetic mechanisms, such as DNA methylation, histone modification, and noncoding RNA, which are of importance for cardiovascular disease development and regression. Targeting epigenetic key enzymes, especially the DNA methyltransferases, histone methyltransferases, histone acetylases, histone deacetylases and their regulated target genes, could represent an attractive new route for the diagnosis and treatment of cardiovascular diseases. Herein, we summarize the knowledge on epigenetic history and essential regulatory mechanisms in cardiovascular diseases. Furthermore, we discuss the preclinical studies and drugs that are targeted these epigenetic key enzymes for cardiovascular diseases therapy. Finally, we conclude the clinical trials that are going to target some of these processes.
ATF6 prevents DNA damage and cell death in colon cancer cells undergoing ER stress
Authors: Benedetti Rossella , Romeo Maria Anele , Arena Andrea , Gilardini Montani Maria Saveria , Di Renzo Livia , D’Orazi Gabriella , Cirone Mara
Published: June 2022

Colon cancer represents one of the most common and aggressive cancers in its advanced state. Among the most innovative anti-cancer approaches, the manipulation of UPR is a promising one, effective also against cancers carrying dysfunctional p53. Interestingly, it is emerging that UPR cross-talks with DDR and that targeting the interplay between these two adaptive responses may be exploited to overcome the resistance to the single DDR- and UPR-targeting treatments. Previous studies have highlighted the role of IRE1 alpha and PERK UPR sensors on DDR, while the impact of ATF6 on this process remains under-investigated. This study shows for the first time that ATF6 sustains the expression level of BRCA-1 and protects colon cancer cells from the cytotoxic effect of ER stressors DPE and Thapsigargin. At molecular level, ATF6 activates mTOR to sustain the expression of HSP90, of which BRCA-1 is a client protein. Therefore, pharmacological or genetic inhibition of ATF6 promoted BRCA-1 degradation and increased DNA damage and cell death, particularly in combination with Adriamycin. All together this study suggests that targeting ATF6 may not only potentiate the cytotoxic effect of drugs triggering ER stress but may render colon cancer cells more sensitive to Adriamycin and possibly to other DNA damaging agents used to treat colon cancer.
Effective high-throughput RT-qPCR screening for SARS-CoV-2 infections in children
Authors: Dewald Felix , Suárez Isabelle , Johnen Ronja , Grossbach Jan , Moran-Tovar Roberto , Steger Gertrud , Joachim Alexander , Rubio Gibran Horemheb , Fries Mira , Behr Florian , Kley Joao , Lingnau Andreas , Kretschmer Alina , Gude Carina , Baeza-Flores Guadelupe , del Valle David Laveaga , Roblero-Hernandez Alberto , Magana-Cerino Jesus , Hernandez Adriana Torres , Ruiz-Quinones Jesus , Schega Konstantin , Linne Viktoria , Junker Lena , Wunsch Marie , Heger Eva , Knops Elena , Di Cristanziano Veronica , Meyer Meike , Hünseler Christoph , Weber Lutz T. , Lüers Jan-Christoffer , Quade Gustav , Wisplinghoff Hilmar , Tiemann Carsten , Zotz Rainer , Jomaa Hassan , Pranada Arthur , Herzum Ileana , Cullen Paul , Schmitz Franz-Josef , Philipsen Paul , Kirchner Georg , Knabbe Cornelius , Hellmich Martin , Buess Michael , Wolff Anna , Kossow Annelene , Niessen Johannes , Jeworutzki Sebastian , Schräpler Jörg-Peter , Lässig Michael , Dötsch Jörg , Fätkenheuer Gerd , Kaiser Rolf , Beyer Andreas , Rybniker Jan , Klein Florian
Published: June 2022

Systematic SARS-CoV-2 testing is a valuable tool for infection control and surveillance. However, broad application of high sensitive RT-qPCR testing in children is often hampered due to unpleasant sample collection, limited RT-qPCR capacities and high costs. Here, we developed a high-throughput approach (‘Lolli-Method’) for SARS-CoV-2 detection in children, combining non-invasive sample collection with an RT-qPCR-pool testing strategy. SARS-CoV-2 infections were diagnosed with sensitivities of 100% and 93.9% when viral loads were >106 copies/ml and >103 copies/ml in corresponding Naso-/Oropharyngeal-swabs, respectively. For effective application of the Lolli-Method in schools and daycare facilities, SEIR-modeling indicated a preferred frequency of two tests per week. The developed test strategy was implemented in 3,700 schools and 698 daycare facilities in Germany, screening over 800,000 individuals twice per week. In a period of 3 months, 6,364 pool-RT-qPCRs tested positive (0.64%), ranging from 0.05% to 2.61% per week. Notably, infections correlated with local SARS-CoV-2 incidences and with a school social deprivation index. Moreover, in comparison with the alpha variant, statistical modeling revealed a 36.8% increase for multiple (≥2 children) infections per class following infections with the delta variant. We conclude that the Lolli-Method is a powerful tool for SARS-CoV-2 surveillance and can support infection control in schools and daycare facilities.
The force required to remove tubulin from the microtubule lattice by pulling on its α-tubulin C-terminal tail
Authors: Kuo Yin-Wei , Mahamdeh Mohammed , Tuna Yazgan , Howard Jonathon
Published: June 2022

Severing enzymes and molecular motors extract tubulin from the walls of microtubules by exerting mechanical force on subunits buried in the lattice. However, how much force is needed to remove tubulin from microtubules is not known, nor is the pathway by which subunits are removed. Using a site-specific functionalization method, we applied forces to the C-terminus of α-tubulin with an optical tweezer and found that a force of ~30 pN is required to extract tubulin from the microtubule wall. Additionally, we discovered that partial unfolding is an intermediate step in tubulin removal. The unfolding and extraction forces are similar to those generated by AAA-unfoldases. Lastly, we show that three kinesin-1 motor proteins can also extract tubulin from the microtubule lattice. Our results provide the first experimental investigation of how tubulin responds to mechanical forces exerted on its α-tubulin C-terminal tail and have implications for the mechanisms of severing enzymes and microtubule stability.
Wiskott-Aldrich syndrome protein forms nuclear condensates and regulates alternative splicing
Authors: Yuan Baolei , Zhou Xuan , Suzuki Keiichiro , Ramos-Mandujano Gerardo , Wang Mengge , Tehseen Muhammad , Cortés-Medina Lorena V. , Moresco James J. , Dunn Sarah , Hernandez-Benitez Reyna , Hishida Tomoaki , Kim Na Young , Andijani Manal M. , Bi Chongwei , Ku Manching , Takahashi Yuta , Xu Jinna , Qiu Jinsong , Huang Ling , Benner Christopher , Aizawa Emi , Qu Jing , Liu Guang-Hui , Li Zhongwei , Yi Fei , Ghosheh Yanal , Shao Changwei , Shokhirev Maxim , Comoli Patrizia , Frassoni Francesco , Yates John R. , Fu Xiang-Dong , Esteban Concepcion Rodriguez , Hamdan Samir , Izpisua Belmonte Juan Carlos , Li Mo
Published: June 2022

The diverse functions of WASP, the deficiency of which causes Wiskott-Aldrich syndrome (WAS), remain poorly defined. We generated three isogenic WAS models using patient induced pluripotent stem cells and genome editing. These models recapitulated WAS phenotypes and revealed that WASP deficiency causes an upregulation of numerous RNA splicing factors and widespread altered splicing. Loss of WASP binding to splicing factor gene promoters frequently leads to aberrant epigenetic activation. WASP interacts with dozens of nuclear speckle constituents and constrains SRSF2 mobility. Using an optogenetic system, we showed that WASP forms phase-separated condensates that encompasses SRSF2, nascent RNA and active Pol II. The role of WASP in gene body condensates is corroborated by ChIPseq and RIPseq. Together our data reveal that WASP is a nexus regulator of RNA splicing that controls the transcription of splicing factors epigenetically and the dynamics of the splicing machinery through liquid-liquid phase separation.
Self-sustained electricity generator driven by the compatible integration of ambient moisture adsorption and evaporation
Authors: Tan Jin , Fang Sunmiao , Zhang Zhuhua , Yin Jun , Li Luxian , Wang Xiang , Guo Wanlin
Published: June 2022

Generating sustainable electricity from ambient humidity and natural evaporation has attracted tremendous interest recently as it requires no extra mechanical energy input and is deployable across all weather and geography conditions. Here, we present a device prototype for enhanced power generation from ambient humidity. This prototype uses both heterogenous materials assembled from a LiCl-loaded cellulon paper to facilitate moisture adsorption and a carbon-black-loaded cellulon paper to promote water evaporation. Exposing such a centimeter-sized device to ambient humidity can produce voltages of around 0.78 V and a current of around 7.5 μA, both of which can be sustained for more than 10 days. The enhanced electric output and durability are due to the continuous water flow that is directed by evaporation through numerous, negatively charged channels within the cellulon papers. The voltage and current exhibit an excellent scaling behavior upon device integration to sufficiently power commercial devices including even cell phones. The results open a promising prospect of sustainable electricity generation based on a synergy between spontaneous moisture adsorption and water evaporation.
Echolocation-related reversal of information flow in a cortical vocalization network
Authors: García-Rosales Francisco , López-Jury Luciana , González-Palomares Eugenia , Wetekam Johannes , Cabral-Calderín Yuranny , Kiai Ava , Kössl Manfred , Hechavarría Julio C.
Published: June 2022

The mammalian frontal and auditory cortices are important for vocal behavior. Here, using local-field potential recordings, we demonstrate that the timing and spatial patterns of oscillations in the fronto-auditory network of vocalizing bats (Carollia perspicillata) predict the purpose of vocalization: echolocation or communication. Transfer entropy analyses revealed predominant top-down (frontal-to-auditory cortex) information flow during spontaneous activity and pre-vocal periods. The dynamics of information flow depend on the behavioral role of the vocalization and on the timing relative to vocal onset. We observed the emergence of predominant bottom-up (auditory-to-frontal) information transfer during the post-vocal period specific to echolocation pulse emission, leading to self-directed acoustic feedback. Electrical stimulation of frontal areas selectively enhanced responses to sounds in auditory cortex. These results reveal unique changes in information flow across sensory and frontal cortices, potentially driven by the purpose of the vocalization in a highly vocal mammalian model.
Spin relaxation in a single-electron graphene quantum dot
Authors: Banszerus L. , Hecker K. , Möller S. , Icking E. , Watanabe K. , Taniguchi T. , Volk C. , Stampfer C.
Published: June 2022

The relaxation time of a single-electron spin is an important parameter for solid-state spin qubits, as it directly limits the lifetime of the encoded information. Thanks to the low spin-orbit interaction and low hyperfine coupling, graphene and bilayer graphene (BLG) have long been considered promising platforms for spin qubits. Only recently, it has become possible to control single-electrons in BLG quantum dots (QDs) and to understand their spin-valley texture, while the relaxation dynamics have remained mostly unexplored. Here, we report spin relaxation times (T1) of single-electron states in BLG QDs. Using pulsed-gate spectroscopy, we extract relaxation times exceeding 200 μs at a magnetic field of 1.9 T. The T1 values show a strong dependence on the spin splitting, promising even longer T1 at lower magnetic fields, where our measurements are limited by the signal-to-noise ratio. The relaxation times are more than two orders of magnitude larger than those previously reported for carbon-based QDs, suggesting that graphene is a potentially promising host material for scalable spin qubits.
Detection of SARS-CoV-2 intra-host recombination during superinfection with Alpha and Epsilon variants in New York City
Authors: Wertheim Joel O. , Wang Jade C. , Leelawong Mindy , Martin Darren P. , Havens Jennifer L. , Chowdhury Moinuddin A. , Pekar Jonathan E. , Amin Helly , Arroyo Anthony , Awandare Gordon A. , Chow Hoi Yan , Gonzalez Edimarlyn , Luoma Elizabeth , Morang’a Collins M. , Nekrutenko Anton , Shank Stephen D. , Silver Stefan , Quashie Peter K. , Rakeman Jennifer L. , Ruiz Victoria , Torian Lucia V. , Vasylyeva Tetyana I. , Kosakovsky Pond Sergei L. , Hughes Scott
Published: June 2022

Recombination is an evolutionary process by which many pathogens generate diversity and acquire novel functions. Although a common occurrence during coronavirus replication, detection of recombination is only feasible when genetically distinct viruses contemporaneously infect the same host. Here, we identify an instance of SARS-CoV-2 superinfection, whereby an individual was infected with two distinct viral variants: Alpha (B.1.1.7) and Epsilon (B.1.429). This superinfection was first noted when an Alpha genome sequence failed to exhibit the classic S gene target failure behavior used to track this variant. Full genome sequencing from four independent extracts reveals that Alpha variant alleles comprise around 75% of the genomes, whereas the Epsilon variant alleles comprise around 20% of the sample. Further investigation reveals the presence of numerous recombinant haplotypes spanning the genome, specifically in the spike, nucleocapsid, and ORF 8 coding regions. These findings support the potential for recombination to reshape SARS-CoV-2 genetic diversity.
Microtubule disassembly by caspases is an important rate-limiting step of cell extrusion
Authors: Villars Alexis , Matamoro-Vidal Alexis , Levillayer Florence , Levayer Romain
Published: June 2022

The expulsion of dying epithelial cells requires well-orchestrated remodelling steps to maintain tissue sealing. This process, named cell extrusion, has been mostly analysed through the study of actomyosin regulation. Yet, the mechanistic relationship between caspase activation and cell extrusion is still poorly understood. Using theDrosophilapupal notum, a single layer epithelium where extrusions are caspase-dependent, we showed that the initiation of cell extrusion and apical constriction are surprisingly not associated with the modulation of actomyosin concentration and dynamics. Instead, cell apical constriction is initiated by the disassembly of a medio-apical mesh of microtubules which is driven by effector caspases. Importantly, the depletion of microtubules is sufficient to bypass the requirement of caspases for cell extrusion, while microtubule stabilisation strongly impairs cell extrusion. This study shows that microtubules disassembly by caspases is a key rate-limiting step of extrusion, and outlines a more general function of microtubules in epithelial cell shape stabilisation.
Ru(II) photocages enable precise control over enzyme activity with red light
Authors: Havrylyuk Dmytro , Hachey Austin C. , Fenton Alexander , Heidary David K. , Glazer Edith C.
Published: June 2022

The cytochrome P450 family of enzymes (CYPs) are important targets for medicinal chemistry. Recently, CYP1B1 has emerged as a key player in chemotherapy resistance in the treatment of cancer. This enzyme is overexpressed in a variety of tumors, and is correlated with poor treatment outcomes; thus, it is desirable to develop CYP1B1 inhibitors to restore chemotherapy efficacy. However, possible off-target effects, such as inhibition of liver CYPs responsible for first pass metabolism, make selective inhibition a high priority to avoid possible drug-drug interactions and toxicity. Here we describe the creation of light-triggered CYP1B1 inhibitors as “prodrugs”, and achieve >6000-fold improvement in potency upon activation with low energy (660 nm) light. These systems provide a selectivity index of 4,000–100,000 over other off-target CYPs. One key to the design was the development of coordinating CYP1B1 inhibitors, which suppress enzyme activity at pM concentrations in live cells. The metal binding group enforces inhibitor orientation in the active site by anchoring to the iron. The second essential component was the biologically compatible Ru(II) scaffold that cages the inhibitors before photochemical release. These Ru(II) photocages are anticipated to provide similar selectivity and control for any coordinating CYP inhibitors.
Targeting fungal membrane homeostasis with imidazopyrazoindoles impairs azole resistance and biofilm formation
Authors: Revie Nicole M. , Iyer Kali R. , Maxson Michelle E. , Zhang Jiabao , Yan Su , Fernandes Caroline M. , Meyer Kirsten J. , Chen Xuefei , Skulska Iwona , Fogal Meea , Sanchez Hiram , Hossain Saif , Li Sheena , Yashiroda Yoko , Hirano Hiroyuki , Yoshida Minoru , Osada Hiroyuki , Boone Charles , Shapiro Rebecca S. , Andes David R. , Wright Gerard D. , Nodwell Justin R. , Del Poeta Maurizio , Burke Martin D. , Whitesell Luke , Robbins Nicole , Cowen Leah E.
Published: June 2022

Fungal infections cause more than 1.5 million deaths annually. With an increase in immune-deficient susceptible populations and the emergence of antifungal drug resistance, there is an urgent need for novel strategies to combat these life-threatening infections. Here, we use a combinatorial screening approach to identify an imidazopyrazoindole, NPD827, that synergizes with fluconazole against azole-sensitive and -resistant isolates of Candida albicans. NPD827 interacts with sterols, resulting in profound effects on fungal membrane homeostasis and induction of membrane-associated stress responses. The compound impairs virulence in a Caenorhabditis elegans model of candidiasis, blocks C. albicans filamentation in vitro, and prevents biofilm formation in a rat model of catheter infection by C. albicans. Collectively, this work identifies an imidazopyrazoindole scaffold with a non-protein-targeted mode of action that re-sensitizes the leading human fungal pathogen, C. albicans, to azole antifungals.
Defect-induced monopole injection and manipulation in artificial spin ice
Authors: Puttock Robert , Andersen Ingrid M. , Gatel Christophe , Park Bumsu , Rosamond Mark C. , Snoeck Etienne , Kazakova Olga
Published: June 2022

Lithographically defined arrays of nanomagnets are well placed for application in areas such as probabilistic computing or reconfigurable magnonics due to their emergent collective dynamics and writable magnetic order. Among them are artificial spin ice (ASI), which are arrays of binary in-plane macrospins exhibiting geometric frustration at the vertex interfaces. Macrospin flips in the arrays create topologically protected magnetic charges, or emergent monopoles, which are bound to an antimonopole to conserve charge. In the absence of controllable pinning, it is difficult to manipulate individual monopoles in the array without also influencing other monopole excitations or the counter-monopole charge. Here, we tailor the local magnetic order of a classic ASI lattice by introducing a ferromagnetic defect with shape anisotropy into the array. This creates monopole injection sites at nucleation fields below the critical lattice switching field. Once formed, the high energy monopoles are fixed to the defect site and may controllably propagate through the lattice under stimulation. Defect programing of bound monopoles within the array allows fine control of the pathways of inverted macrospins. Such control is a necessary prerequisite for the realization of functional devices, e. g. reconfigurable waveguide in nanomagnonic applications.
Mucin induces CRISPR-Cas defense in an opportunistic pathogen
Authors: de Freitas Almeida Gabriel Magno , Hoikkala Ville , Ravantti Janne , Rantanen Noora , Sundberg Lotta-Riina
Published: June 2022

Parasitism by bacteriophages has led to the evolution of a variety of defense mechanisms in their host bacteria. However, it is unclear what factors lead to specific defenses being deployed upon phage infection. To explore this question, we co-evolved the bacterial fish pathogen Flavobacterium columnare and its virulent phage V156 in presence and absence of a eukaryotic host signal (mucin) for sixteen weeks. The presence of mucin leads to a dramatic increase in CRISPR spacer acquisition, especially in low nutrient conditions where over 60% of colonies obtain at least one new spacer. Additionally, we show that the presence of a competitor bacterium further increases CRISPR spacer acquisition in F. columnare. These results suggest that ecological factors are important in determining defense strategies against phages, and that the phage-bacterium interactions on mucosal surfaces may select for the diversification of bacterial immune systems.
Identification and characterization of a new ensemble of cometary organic molecules
Authors: Hänni N. , Altwegg K. , Combi M. , Fuselier S. A. , De Keyser J. , Rubin M. , Wampfler S. F.
Published: June 2022

In-situ study of comet 1P/Halley during its 1986 apparition revealed a surprising abundance of organic coma species. It remained unclear, whether or not these species originated from polymeric matter. Now, high-resolution mass-spectrometric data collected at comet 67P/Churyumov-Gerasimenko by ESA’s Rosetta mission unveil the chemical structure of complex cometary organics. Here, we identify an ensemble of individual molecules with masses up to 140 Da while demonstrating inconsistency of the data with relevant amounts of polymeric matter. The ensemble has an average composition of C1H1.56O0.134N0.046S0.017, identical to meteoritic soluble organic matter, and includes a plethora of chain-based, cyclic, and aromatic hydrocarbons at an approximate ratio of 6:3:1. Its compositional and structural properties, except for the H/C ratio, resemble those of other Solar System reservoirs of organics—from organic material in the Saturnian ring rain to meteoritic soluble and insoluble organic matter –, which is compatible with a shared prestellar history.
Occult polyclonality of preclinical pancreatic cancer models drives in vitro evolution
Authors: Monberg Maria E. , Geiger Heather , Lee Jaewon J. , Sharma Roshan , Semaan Alexander , Bernard Vincent , Wong Justin , Wang Fang , Liang Shaoheng , Swartzlander Daniel B. , Stephens Bret M. , Katz Matthew H. G. , Chen Ken , Robine Nicolas , Guerrero Paola A. , Maitra Anirban
Published: June 2022

Heterogeneity is a hallmark of cancer. The advent of single-cell technologies has helped uncover heterogeneity in a high-throughput manner in different cancers across varied contexts. Here we apply single-cell sequencing technologies to reveal inherent heterogeneity in assumptively monoclonal pancreatic cancer (PDAC) cell lines and patient-derived organoids (PDOs). Our findings reveal a high degree of both genomic and transcriptomic polyclonality in monolayer PDAC cell lines, custodial variation induced by growing apparently identical cell lines in different laboratories, and transcriptomic shifts in transitioning from 2D to 3D spheroid growth models. Our findings also call into question the validity of widely available immortalized, non-transformed pancreatic lines as contemporaneous “control” lines in experiments. We confirm these findings using a variety of independent assays, including but not limited to whole exome sequencing, single-cell copy number variation sequencing (scCNVseq), single-nuclei assay for transposase-accessible chromatin with sequencing, fluorescence in-situ hybridization, and single-cell RNA sequencing (scRNAseq). We map scRNA expression data to unique genomic clones identified by orthogonally-gathered scCNVseq data of these same PDAC cell lines. Further, while PDOs are known to reflect the cognate in vivo biology of the parental tumor, we identify transcriptomic shifts during ex vivo passage that might hamper their predictive abilities over time. The impact of these findings on rigor and reproducibility of experimental data generated using established preclinical PDAC models between and across laboratories is uncertain, but a matter of concern.
Assembly dynamics of FtsZ and DamX during infection-related filamentation and division in uropathogenic E. coli
Authors: Söderström Bill , Pittorino Matthew J. , Daley Daniel O. , Duggin Iain G.
Published: June 2022

During infection of bladder epithelial cells, uropathogenic Escherichia coli (UPEC) can stop dividing and grow into highly filamentous forms. Here, we find that some filaments of E. coli UTI89 released from infected cells grow very rapidly and by more than 100 μm before initiating division, whereas others do not survive, suggesting that infection-related filamentation (IRF) is a stress response that promotes bacterial dispersal. IRF is accompanied by unstable, dynamic repositioning of FtsZ division rings. In contrast, DamX, which is associated with normal cell division and is also essential for IRF, is distributed uniformly around the cell envelope during filamentation. When filaments initiate division to regenerate rod cells, DamX condenses into stable rings prior to division. The DamX rings maintain consistent thickness during constriction and remain at the septum until after membrane fusion. Deletion of damX affects vegetative cell division in UTI89 (but not in the model E. coli K-12), and, during infection, blocks filamentation and reduces bacterial cell integrity. IRF therefore involves DamX distribution throughout the membrane and prevention of FtsZ ring stabilization, leading to cell division arrest. DamX then reassembles into stable division rings for filament division, promoting dispersal and survival during infection.
Emergent properties as by-products of prebiotic evolution of aminoacylation ribozymes
Authors: Janzen Evan , Shen Yuning , Vázquez-Salazar Alberto , Liu Ziwei , Blanco Celia , Kenchel Josh , Chen Irene A.
Published: June 2022

Systems of catalytic RNAs presumably gave rise to important evolutionary innovations, such as the genetic code. Such systems may exhibit particular tolerance to errors (error minimization) as well as coding specificity. While often assumed to result from natural selection, error minimization may instead be an emergent by-product. In an RNA world, a system of self-aminoacylating ribozymes could enforce the mapping of amino acids to anticodons. We measured the activity of thousands of ribozyme mutants on alternative substrates (activated analogs for tryptophan, phenylalanine, leucine, isoleucine, valine, and methionine). Related ribozymes exhibited shared preferences for substrates, indicating that adoption of additional amino acids by existing ribozymes would itself lead to error minimization. Furthermore, ribozyme activity was positively correlated with specificity, indicating that selection for increased activity would also lead to increased specificity. These results demonstrate that by-products of ribozyme evolution could lead to adaptive value in specificity and error tolerance.
Age and sex-specific risks of myocarditis and pericarditis following Covid-19 messenger RNA vaccines
Authors: Le Vu Stéphane , Bertrand Marion , Jabagi Marie-Joelle , Botton Jérémie , Drouin Jérôme , Baricault Bérangère , Weill Alain , Dray-Spira Rosemary , Zureik Mahmoud
Published: June 2022

Cases of myocarditis and pericarditis have been reported following the receipt of Covid-19 mRNA vaccines. As vaccination campaigns are still to be extended, we aimed to provide a comprehensive assessment of the association, by vaccine and across sex and age groups. Using nationwide hospital discharge and vaccine data, we analysed all 1612 cases of myocarditis and 1613 cases of pericarditis that occurred in France in the period from May 12, 2021 to October 31, 2021. We perform matched case-control studies and find increased risks of myocarditis and pericarditis during the first week following vaccination, and particularly after the second dose, with adjusted odds ratios of myocarditis of 8.1 (95% confidence interval [CI], 6.7 to 9.9) for the BNT162b2 and 30 (95% CI, 21 to 43) for the mRNA-1273 vaccine. The largest associations are observed for myocarditis following mRNA-1273 vaccination in persons aged 18 to 24 years. Estimates of excess cases attributable to vaccination also reveal a substantial burden of both myocarditis and pericarditis across other age groups and in both males and females.
COVID-19 disease severity in US Veterans infected during Omicron and Delta variant predominant periods
Authors: Mayr Florian B. , Talisa Victor B. , Castro Alexander D. , Shaikh Obaid S. , Omer Saad B. , Butt Adeel A.
Published: June 2022

The SARS-CoV-2 Omicron variant is thought to cause less severe disease among the general population, but disease severity among at-risk populations is unknown. We performed a retrospective analysis using a matched cohort of United States veterans to compare the disease severity of subjects infected during Omicron and Delta predominant periods within 14 days of initial diagnosis. We identified 22,841 matched pairs for both periods. During the Omicron period, 20,681 (90.5%) veterans had mild, 1308 (5.7%) moderate, and 852 (3.7%) severe disease. During the Delta predominant period, 19,356 (84.7%) had mild, 1467 (6.4%) moderate, and 2018 (8.8%) severe disease. Moderate or severe disease was less likely during the Omicron period and more common among older subjects and those with more comorbidities. Here we show that infection with the Omicron variant is associated with less severe disease than the Delta variant in a high-risk older veteran population, and vaccinations provide protection against severe or critical disease.
FANCM promotes class I interfering crossovers and suppresses class II non-interfering crossovers in wheat meiosis
Authors: Desjardins Stuart D. , Simmonds James , Guterman Inna , Kanyuka Kostya , Burridge Amanda J. , Tock Andrew J. , Sanchez-Moran Eugenio , Franklin F. Chris H. , Henderson Ian R. , Edwards Keith J. , Uauy Cristobal , Higgins James D.
Published: June 2022

FANCM suppresses crossovers in plants by unwinding recombination intermediates. In wheat, crossovers are skewed toward the chromosome ends, thus limiting generation of novel allelic combinations. Here, we observe that FANCM maintains the obligate crossover in tetraploid and hexaploid wheat, thus ensuring that every chromosome pair exhibits at least one crossover, by localizing class I crossover protein HEI10 at pachytene. FANCM also suppresses class II crossovers that increased 2.6-fold in fancm msh5 quadruple mutants. These data are consistent with a role for FANCM in second-end capture of class I designated crossover sites, whilst FANCM is also required to promote formation of non-crossovers. In hexaploid wheat, genetic mapping reveals that crossovers increase by 31% in fancm compared to wild type, indicating that fancm could be an effective tool to accelerate breeding. Crossover rate differences in fancm correlate with wild type crossover distributions, suggesting that chromatin may influence the recombination landscape in similar ways in both wild type and fancm.
Existing function in primary visual cortex is not perturbed by new skill acquisition of a non-matched sensory task
Authors: Jeon Brian B. , Fuchs Thomas , Chase Steven M. , Kuhlman Sandra J.
Published: June 2022

Acquisition of new skills has the potential to disturb existing network function. To directly assess whether previously acquired cortical function is altered during learning, mice were trained in an abstract task in which selected activity patterns were rewarded using an optical brain-computer interface device coupled to primary visual cortex (V1) neurons. Excitatory neurons were longitudinally recorded using 2-photon calcium imaging. Despite significant changes in local neural activity during task performance, tuning properties and stimulus encoding assessed outside of the trained context were not perturbed. Similarly, stimulus tuning was stable in neurons that remained responsive following a different, visual discrimination training task. However, visual discrimination training increased the rate of representational drift. Our results indicate that while some forms of perceptual learning may modify the contribution of individual neurons to stimulus encoding, new skill learning is not inherently disruptive to the quality of stimulus representation in adult V1.
Large Scale Genome-Centric Metagenomic Data from the Gut Microbiome of Food-Producing Animals and Humans
Authors: Lemos Leandro Nascimento , de Carvalho Fabíola Marques , Santos Fernanda Fernandes , Valiatti Tiago Barcelos , Corsi Dandara Cassu , de Oliveira Silveira Alessandro Conrado , Gerber Alexandra , Guimarães Ana Paula C. , de Oliveira Souza Cintya , Brasiliense Danielle Murici , Maia Castelo-Branco Débora de Souza Collares , Anzai Eleine Kuroki , Bessa-Neto Francisco Ozório , de Melo Gláucia Morgana , de Souza Gleyce Hellen , Ferraz Lúcio Fábio Caldas , de Nazaré Miranda Bahia Márcia , Mattos Márcia Soares , da Silva Ramon Giovani Brandão , Veiga Ruanita , Simionatto Simone , Monteiro Walter Aparecido Pimentel , de Oliveira Lima William Alencar , Kiffer Carlos Roberto Veiga , Cayô Rodrigo , Gales Ana Cristina , de Vasconcelos Ana Tereza Ribeiro
Published: June 2022

The One Health concept is a global strategy to study the relationship between human and animal health and the transfer of pathogenic and non-pathogenic species between these systems. However, to the best of our knowledge, no data based on One Health genome-centric metagenomics are available in public repositories. Here, we present a dataset based on a pilot-study of 2,915 metagenome-assembled genomes (MAGs) of 107 samples from the human (N = 34), cattle (N = 28), swine (N = 15) and poultry (N = 30) gut microbiomes. Samples were collected from the five Brazilian geographical regions. Of the draft genomes, 1,273 were high-quality drafts (≥90% of completeness and ≤5% of contamination), and 1,642 were medium-quality drafts (≥50% of completeness and ≤10% of contamination). Taxonomic predictions were based on the alignment and concatenation of single-marker genes, and the most representative phyla were Bacteroidota, Firmicutes, and Proteobacteria. Many of these species represent potential pathogens that have already been described or potential new families, genera, and species with potential biotechnological applications. Analyses of this dataset will highlight discoveries about the ecology and functional role of pathogens and uncultivated Archaea and Bacteria from food-producing animals and humans. Furthermore, it also represents an opportunity to describe new species from underrepresented taxonomic groups.
Optimizing process-based models to predict current and future soil organic carbon stocks at high-resolution
Authors: Pierson Derek , Lohse Kathleen A. , Wieder William R. , Patton Nicholas R. , Facer Jeremy , de Graaff Marie-Anne , Georgiou Katerina , Seyfried Mark S. , Flerchinger Gerald , Will Ryan
Published: June 2022

From hillslope to small catchment scales (< 50 km2), soil carbon management and mitigation policies rely on estimates and projections of soil organic carbon (SOC) stocks. Here we apply a process-based modeling approach that parameterizes the MIcrobial-MIneral Carbon Stabilization (MIMICS) model with SOC measurements and remotely sensed environmental data from the Reynolds Creek Experimental Watershed in SW Idaho, USA. Calibrating model parameters reduced error between simulated and observed SOC stocks by 25%, relative to the initial parameter estimates and better captured local gradients in climate and productivity. The calibrated parameter ensemble was used to produce spatially continuous, high-resolution (10 m2) estimates of stocks and associated uncertainties of litter, microbial biomass, particulate, and protected SOC pools across the complex landscape. Subsequent projections of SOC response to idealized environmental disturbances illustrate the spatial complexity of potential SOC vulnerabilities across the watershed. Parametric uncertainty generated physicochemically protected soil C stocks that varied by a mean factor of 4.4 × across individual locations in the watershed and a − 14.9 to + 20.4% range in potential SOC stock response to idealized disturbances, illustrating the need for additional measurements of soil carbon fractions and their turnover time to improve confidence in the MIMICS simulations of SOC dynamics.