bluuebunny/crossref_metadata_2025 huggingface dataset:
Precisely Picking Nanoparticles by a “Nano-Scalpel” for 360° Electron Tomography
Authors: Huang Xiaohui , Tang Yushu , Kübel Christian , Wang Di
Published: September 2022

Electron tomography (ET) has gained increasing attention for the 3D characterization of nanoparticles. However, the missing wedge problem due to a limited tilt angle range is still the main challenge for accurate reconstruction in most experimental TEM setups. Advanced algorithms could in-paint or compensate to some extent the missing wedge artifacts, but cannot recover the missing structural information completely. 360° ET provides an option to solve this problem by tilting a needle-shaped specimen over the full tilt range and thus filling the missing information. However, sample preparation especially for fine powders to perform full-range ET is still challenging, thus limiting its application. In this work, we propose a new universal sample preparation method that enables the transfer of selected individual nanoparticle or a few separated nanoparticles by cutting a piece of carbon film supporting the specimen particles and mounting them onto the full-range tomography holder tip with the help of an easily prepared sharp tungsten tip. This method is demonstrated by 360° ET of Pt@TiO2 hollow cage catalyst showing high quality reconstruction without missing wedge.
Alles Anorexie?
Authors: Schafroth Christian , Oestmann Andreas
Published: September 2022

Zusammenfassung. Wir berichten über eine 30-jährige Patientin mit Müdigkeit, Gewichtsverlust, Nausea, Erbrechen und Hyponatriämie. Die Abklärungen führten zur Diagnose eines Morbus Addison im Rahmen eines polyglandulären Autoimmunsyndroms Typ 2 mit Hashimoto-Thyreoiditis. Unter der Substitution mit Hydrocortison und Fludrocortison waren alle Symptome vollständig regredient.
Dark Tetrad, Acceptance of Sexual Violence, and	Sexism
Authors: Costa Rodrigo , Fávero Marisalva , Moreira Diana , Del Campo Amaia , Sousa-Gomes Valéria
Published: September 2022

Abstract. The Dark Tetrad is a cluster of four “dark” personality traits which are socially aversive, with distinct conceptual roots, but which are intercorrelated: narcissism, psychopathy, Machiavellianism, and sadism. Narcissism is associated with inflated self-esteem and feelings of grandiosity; psychopathy involves reduced empathy and a lack of remorse or guilt; Machiavellianism is characterized by a tendency for manipulation for own personal benefit; sadism involves feelings of pleasure with the pain or suffering of others. Sexism is the group of beliefs linked with the perceived superiority of men over women. Previous studies have found relationships between the Dark Tetrad and the tolerance of the use of sexual violence and between the former and sexism. Furthermore, sexism has been linked with the acceptance of sexual violence. This study aims to revise the literature exploring the link between each of the components of the Dark Tetrad and the legitimation of the use of sexual violence; it also aims to present the associations that have been found between the aforementioned variables and sexism and related concepts, in multiple studies. Based on the previous literature, suggestions for aims of future research in this field (i.e., Dark Tetrad, sexual violence, sexism) are made, more specifically exploring the relative effect of each of the components of the Dark Tetrad in the explanation of the legitimation of sexual violence, as well as exploring a possible, at least partial, mediation of sexism in the link between each of the “dark” traits and the acceptance of sexual violence.
A Question of Method and Subjective Beliefs
Authors: Grass Julia , Scherbaum Stefan , Strobel Anja
Published: September 2022

Abstract: Need for Cognition (NFC) describes the relatively stable intrinsic motivation to engage in cognitive endeavors. Recent research has revealed the importance of NFC for affective adjustment, especially in combination with self-control. We followed up on those findings by addressing methodological issues as well as processes that may underlie relations of NFC to self-control. Study 1 ( N = 102) examined whether NFC is associated with self-control independently of the measure or facet considered. Implicit willpower theories, that is, subjective beliefs concerning the limitation of self-control resources, were examined as a mediator for NFC predicting self-control. Higher NFC was associated with increased trait self-control but also with believing in unlimited self-control resources. The relation of NFC to willpower theories also mediated the prediction of trait self-control. Study 2 ( N = 188) replicated relations of NFC to self-control. We further pursued the explanatory approach from Study 1 and experimentally manipulated willpower theories to provide insight into their association with NFC. Willpower theories were related to NFC but had no mediating role in predicting self-control. The experimental manipulation had no impact on situation-specific NFC. Altogether, both studies provided first evidence that relations of NFC to self-control depend on the self-control measure and that willpower theories may be crucial for explaining the association with self-control.
Modeling Lithospheric Thickness Along the Conjugate South Atlantic Passive Margins Implies Asymmetric Rift Initiation
Authors: Haas Peter , Müller R. Dietmar , Ebbing Jörg , Finger Nils‐Peter , Kaban Mikhail K. , Heine Christian
Published: September 2022

The lithospheric architecture of passive margins is crucial for understanding the tectonic processes that caused the breakup of Gondwana. We highlight the evolution of the South Atlantic passive margins by a simple thermal lithosphere‐asthenosphere boundary (LAB) model based on onset and cessation of rifting, crustal thickness, and stretching factors. We simulate lithospheric thinning and select the LAB as the T = 1,330°C isotherm, which is calculated by 1D advection and diffusion. Stretching factors and margin geometry are adjusted to state‐of‐the‐art data sets, giving a thermal LAB model that is especially designed for the continental margins of the South Atlantic. Our LAB model shows distinct variations along the passive margins that are not imaged by global LAB models, indicating different rifting mechanisms. For example, we model up to 200 km deep lithosphere in the South American Santos Basin and shallow lithosphere less than 60 km in the Namibe Basin offshore Africa. These two conjugate basins reflect a strong asymmetry in LAB depth that resembles variations in margin width. In a Gondwana reconstruction, we discuss these patterns together with seismic velocity perturbations for the Central and Austral Segments of the margins. The shallow lithosphere in the Namibe Basin correlates with signatures of the Angola Dome, attributed to epeirogenic uplift in the Neogene, suggesting an additional component of post‐breakup lithospheric thinning.
Stable Isotopes and Bayesian Tracer Mixing Model Reveal Chemical Weathering and CO2 Release in the Jiulongjiang River Basin, Southeast China
Authors: Liu Jinke , Han Guilin , Zhang Qian , Liu Man , Li Xiaoqiang
Published: September 2022

Links between erosion, chemical weathering, and atmospheric CO2 can modulate the global climate over geologic times, but the role of chemical weathering on Earth's long‐term carbon cycle is still unclear. Although silicate weathering by carbonic acid could sequester CO2, the pyrite oxidation coupled to carbonate dissolution could provide a transient source of CO2 at the same time. Landscapes with low physical erosion rate cover the majority of exposed land area, however, the concomitant weathering of silicate, carbonate, and sulfide occurring in the low erosion rate terrains is not well understood. Here, we investigate these questions by examining the river water chemistry from a catchment characterized by complex lithology and low erosion rate. Using a Bayesian tracer mixing model, elemental and isotopic ratios, we quantitatively identify the proportion of cations from silicate and carbonate weathering as well as the acid sources during weathering. We propose that the sulfuric acid from pyrite oxidation boosts both silicate and carbonate weathering, and the coupling between pyrite oxidation and silicate weathering is more pronounced as the pyrite oxidation rates increases. In doing so we determine the effect of weathering on the CO2 balance in our study area, and find that the CO2 release from pyrite oxidation coupled to carbonate dissolution overwhelms the CO2 drawdown from silicate weathering on the time scale between marine carbonate precipitation and sulfate reduction (approximately 106–107 years). Our analysis indicates that the lithology and distribution of minerals play an important role on the chemical weathering in low erosion rate terrains.
Tropical Wetlands Emit More Methane Than Previously�Thought
Authors: Fritts Rachel
Published: September 2022

Climate models could be vastly underestimating methane emissions from the world’s tropical wetlands, according to observational surveys of wetlands in Zambia.
Simpler Presentations of Climate Change
Authors: Aber John , Ollinger Scott
Published: September 2022

The basics of climate change science have been known for a long time, and the predicted impact of a doubling of atmospheric carbon dioxide on global temperature hasn’t changed much in 100 years.
Light People: Professor Xi-Cheng Zhang
Authors: Wang Hui
Published: September 2022

Editorial

As 5 G ever becomes a part of everyday life and 6 G is also on the agenda, terahertz technology has gradually become known by the public, and is referred to as the “third eye” for human beings to understand the world.

Terahertz is considered one of the top ten technologies that will change the world due to its unique properties. In 2019, astronomers were able to observe a black hole for the first time, using a terahertz astronomical telescope. Terahertz is no longer far away from our lives, whether it is information, medicine, or food safety and other fields. It is everywhere, triggering major changes in people’s work and lifestyle.

Today’s guest of Light People is an internationally renowned scholar who has been engaged in terahertz research for many years, Professor Xi-Cheng Zhang works at the University of Rochester, one of the three major optics educational centers in the United States. As a pioneer in the field of terahertz technology, after years of practice, he has successfully generated terahertz waves using water, changing how we see water with THz wave forever.

Next, please follow the Light Science Editor into the terahertz world to learn about the latest and most cutting-edge science and technology and the “story” behind it.
Survival of veterans treated with enzalutamide and abiraterone for metastatic castrate resistant prostate cancer based on comorbid diseases
Authors: Schoen Martin W. , Carson Kenneth R. , Eisen Seth A. , Bennett Charles L. , Luo Suhong , Reimers Melissa A. , Knoche Eric M. , Whitmer Alison L. , Yan Yan , Drake Bettina F. , Sanfilippo Kristen M.
Published: September 2022

Background

Comorbid diseases influence patient outcomes, yet little is known about how comorbidities interact with treatments for metastatic castrate-resistant prostate cancer (mCRPC). No head-to-head trials have compared the efficacy of abiraterone and enzalutamide - oral androgen-receptor targeted agents (ARTAs) for mCRPC. In patients with comorbid disease, outcomes with ARTAs may differ due to disparate mechanisms of action, adverse events, and drug interactions.

Methods

Retrospective observational study of US veterans initiating treatment for mCRPC with abiraterone or enzalutamide between September 2014 and June 2017. Treatment duration and overall survival (OS) was compared based on age and comorbid diseases. The association between ARTA and OS was assessed using Cox proportional hazards and propensity-score matched modeling while adjusting for potential confounders. Sensitivity analyses were performed based on patient age, comorbidities, and subsequent treatments for mCRPC.

Results

Of 5822 veterans treated for mCRPC, 43.0% initially received enzalutamide and 57.0% abiraterone. Veterans initially treated with enzalutamide versus abiraterone were older (mean 75.8 vs. 75.0 years) with higher mean Charlson comorbidity index (4.4 vs. 4.1), and higher rates of cardiovascular disease or diabetes (74.2% vs. 70.6%). In the entire population, veterans initially treated with enzalutamide had longer median OS compared to those initially treated with abiraterone (24.2 vs. 22.1 months, p = 0.001). In veterans with cardiovascular disease or diabetes, median treatment duration with enzalutamide was longer (11.4 vs. 8.6 months, p < 0.001) with longer median OS compared to abiraterone (23.2 vs. 20.5 months, p < 0.001). In a propensity score matched cohort, enzalutamide was associated with decreased mortality compared to abiraterone (HR 0.90, 95% CI 0.84–0.96).

Conclusions

Veterans with cardiovascular disease or diabetes had longer treatment duration and OS with enzalutamide compared to abiraterone. Further study of ARTA selection may benefit men with metastatic castrate resistant prostate cancer and likely hormone sensitive prostate cancer, especially among patients with comorbid diseases.
Defining new reference intervals for serum free light chains in individuals with chronic kidney disease: Results of the iStopMM study
Authors: Long Thorir Einarsson , Indridason Olafur Skuli , Palsson Runolfur , Rognvaldsson Sæmundur , Love Thorvardur Jon , Thorsteinsdottir Sigrun , Sverrisdottir Ingigerdur Solveig , Vidarsson Brynjar , Onundarson Pall Torfi , Agnarsson Bjarni Agnar , Sigurdardottir Margret , Thorsteinsdottir Ingunn , Olafsson Isleifur , Thordardottir Asdis Rosa , Eythorsson Elias , Jonsson Asbjorn , Gislason Gauti , Olafsson Andri , Steingrimsdottir Hlif , Hultcrantz Malin , Durie Brian G. M. , Harding Stephen , Landgren Ola , Kristinsson Sigurdur Yngvi
Published: September 2022

Serum free light chain (FLC) concentration is greatly affected by kidney function. Using a large prospective population-based cohort, we aimed to establish a reference interval for FLCs in persons with chronic kidney disease (CKD). A total of 75422 participants of the iStopMM study were screened with serum FLC, serum protein electrophoresis and immunofixation. Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine. Central 99% reference intervals were determined, and 95% confidence intervals calculated. Included were 6461 (12%) participants with measured FLCs, eGFR < 60 mL/min/1.73 m2, not receiving renal replacement therapy, and without evidence of monoclonality. Using current reference intervals, 60% and 21% had kappa and lambda FLC values outside the normal range. The FLC ratio was outside standard reference interval (0.26–1.65) in 9% of participants and outside current kidney reference interval (0.37–3.10) in 0.7%. New reference intervals for FLC and FLC ratio were established. New reference intervals for the FLC ratio were 0.46–2.62, 0.48–3.38, and 0.54–3.30 for eGFR 45–59, 30–44, and < 30 mL/min/1.73 m2 groups, respectively. The crude prevalence of LC-MGUS in CKD patients was 0.5%. We conclude that current reference intervals for FLC and FLC ratio are inaccurate in CKD patients and propose new eGFR based reference intervals to be implemented.
Targeting of MCL-1 in breast cancer-associated fibroblasts reverses their myofibroblastic phenotype and pro-invasive properties
Authors: Bonneaud Thomas L. , Lefebvre Chloé C. , Nocquet Lisa , Basseville Agnes , Roul Julie , Weber Hugo , Campone Mario , Juin Philippe P. , Souazé Frédérique
Published: September 2022

Cancer-associated fibroblasts (CAF) are a major cellular component of epithelial tumors. In breast cancers in particular these stromal cells have numerous tumorigenic effects in part due to their acquisition of a myofibroblastic phenotype. Breast CAFs (bCAFs) typically express MCL-1. We show here that pharmacological inhibition or knock down of this regulator of mitochondrial integrity in primary bCAFs directly derived from human samples mitigates myofibroblastic features. This decreases expression of genes involved in actomyosin organization and contractility (associated with a cytoplasmic retention of the transcriptional regulator, yes-associated protein—YAP) and decreases bCAFs ability to promote cancer cells invasion in 3D coculture assays. Our findings underscore the usefulness of targeting MCL-1 in breast cancer ecosystems, not only to favor death of cancer cells but also to counteract the tumorigenic activation of fibroblasts with which they co-evolve. Mechanistically, pharmacological inhibition of MCL-1 with a specific BH3 mimetic promotes mitochondrial fragmentation in bCAFs. Inhibition of the mitochondrial fission activity of DRP-1, which interacts with MCL-1 upon BH3 mimetic treatment, allows the maintenance of the myofibroblastic phenotype of bCAFs.
The emerging roles of circular RNA-mediated autophagy in tumorigenesis and cancer progression
Authors: Yuan Yuan , Zhang Xiaojing , Fan Xinmin , Peng Yin , Jin Zhe
Published: September 2022

Circular RNA (circRNA) is characterized by a specific covalently closed ring structure. The back-splicing of precursor mRNA is the main way of circRNA generation, and various cis/trans-acting elements are involved in regulating the process. circRNAs exhibit multiple biological functions, including serving as sponges of microRNAs, interacting with proteins to regulate their stabilities and abilities, and acting as templates for protein translation. Autophagy participates in many physiological and pathological processes, especially it plays a vital role in tumorigenesis and carcinoma progression. Increasing numbers of evidences have revealed that circRNAs are implicated in regulating autophagy during tumor development. Until now, the roles of autophagy-associated circRNAs in carcinoma progression and their molecular mechanisms remain unclear. Here, the emerging regulatory roles and mechanisms of circRNAs in autophagy were summarized. Furtherly, the effects of autophagy-associated circRNAs on cancer development were described. We also prospected the potential of autophagy-associated circRNAs as novel therapeutic targets of tumors and as biomarkers for cancer diagnosis and prognosis.
Presenting clinical characteristics of open globe injuries in ocular trauma: baseline analysis of cases in the ASCOT national clinical trial
Authors: Cro Suzie , Partington Giles , Cornelius Victoria R. , Banerjee Philip J. , Zvobgo Tapiwa Margaret , Casswell Edward J. , Shahid Syed , Bunce Catey , Robertson Elizabeth , Murphy Caroline , Kelly Joanna , Charteris David G.
Published: September 2022

Background/Objectives

The Adjunctive Steroid Combination in Ocular Trauma (ASCOT) trial is a unique pragmatic, multi-centre, patient and assessor masked, randomised controlled trial. We evaluate the clinical characteristics and pathology of this large trial cohort of patients with open globe injuries undergoing vitreoretinal surgery, including the associations between patient characteristics and their baseline vision.

Subjects/Methods

We (i) summarise demographics, injury history and ocular history of the 280 participants recruited into the ASCOT trial using descriptive statistics; (ii) analyse the national and seasonal variation across England and Scotland in these participant characteristics; and (iii) explore the associations between participant demographic, trauma history, ocular history and presenting baseline visual acuity (measured using the Early Treatment Diabetic Retinopathy Study, ETDRS) using multivariable regression analyses.

Results

The majority of participants with open globe penetrating injuries were of white ethnicity (233, 84%), male (246, 88%), with a median age of 43 years (IQR 30–55 years). There was considerable variability in presenting visual acuity with 75% unable to read any letters on the ETDRS chart, whilst the median ETDRS letter score was 58 (IQR 24–80) for those who could read ≥1 letter. The most common causes of injury were workplace related (31%) or interpersonal violence (24%). Previous eye surgery, visual axis corneal scar, lens status, hyphaemia and vitreous haemorrhaging were found to be associated with presenting vision as measured by the ETDRS chart.

Conclusion

The ASCOT trial provides valuable insights into the spectrum of pathology of patients with open globe eye injuries undergoing vitreoretinal surgery. The identified causes of injury and clinical presentation of the cases will help in training and resource planning to deal with these often challenging surgical cases.

Trial registration

EudraCT No. 014-002193-37. HTA Project 12/35/64.
Characterisation of macular neovascularisation subtypes in age-related macular degeneration to optimise treatment outcomes
Authors: Mathis Thibaud , Holz Frank G. , Sivaprasad Sobha , Yoon Young Hee , Eter Nicole , Chen Lee-Jen , Koh Adrian , Cunha de Souza Eduardo , Staurenghi Giovanni
Published: September 2022

The aim of this review is to identify the common characteristics and prognoses of different subtypes of neovascular age-related macular degeneration (nAMD). We also propose recommendations on how to tailor treatments to the subtype of neovessels to optimise patient outcomes. The authors, selected members of the Vision Academy, met to discuss treatment outcomes in nAMD according to macular neovascularisation (MNV) subtypes, using evidence from a literature search conducted on the PubMed database (cut-off date: March 2019). This review article summarises the recommendations of the Vision Academy on how the characterisation of MNV subtypes can optimise treatment outcomes in nAMD. The identification of MNV subtypes has been facilitated by the advent of multimodal imaging. Findings from fluorescein angiography, indocyanine green angiography and spectral-domain optical coherence tomography collectively help refine and standardise the determination of the MNV subtype. To date, three subtypes have been described in the literature and have specific characteristics, as identified by imaging. Type 1 MNV is associated with better long-term outcomes but usually requires more intense anti-vascular endothelial growth factor dosing. Type 2 MNV typically responds quickly to treatment but is more prone to the development of fibrotic scars, which may be associated with poorer outcomes. Type 3 MNV tends to be highly sensitive to anti-vascular endothelial growth factor treatment but may be associated with a higher incidence of outer retinal atrophy, compared with other subtypes. Accurately assessing the MNV subtype provides information on prognosis and helps to optimise the management of patients with nAMD.
Ice mass loss sensitivity to the Antarctic ice sheet basal thermal state
Authors: Dawson Eliza J. , Schroeder Dustin M. , Chu Winnie , Mantelli Elisa , Seroussi Hélène
Published: September 2022

Sea-level rise projections rely on accurate predictions of ice mass loss from Antarctica. Climate change promotes greater mass loss by destabilizing ice shelves and accelerating the discharge of upstream grounded ice. Mass loss is further exacerbated by mechanisms such as the Marine Ice Sheet Instability and the Marine Ice Cliff Instability. However, the effect of basal thermal state changes of grounded ice remains largely unexplored. Here, we use numerical ice sheet modeling to investigate how warmer basal temperatures could affect the Antarctic ice sheet mass balance. We find increased mass loss in response to idealized basal thawing experiments run over 100 years. Most notably, frozen-bed patches could be tenuously sustaining the current ice configuration in parts of George V, Adélie, Enderby, and Kemp Land regions of East Antarctica. With less than 5 degrees of basal warming, these frozen patches may begin to thaw, producing new loci of mass loss.
The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils
Authors: Antonschmidt Leif , Matthes Dirk , Dervişoğlu Rıza , Frieg Benedikt , Dienemann Christian , Leonov Andrei , Nimerovsky Evgeny , Sant Vrinda , Ryazanov Sergey , Giese Armin , Schröder Gunnar F. , Becker Stefan , de Groot Bert L. , Griesinger Christian , Andreas Loren B.
Published: September 2022

Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well.
Flying electron spin control gates
Authors: Helgers Paul L. J. , Stotz James A. H. , Sanada Haruki , Kunihashi Yoji , Biermann Klaus , Santos Paulo V.
Published: September 2022

The control of "flying” (or moving) spin qubits is an important functionality for the manipulation and exchange of quantum information between remote locations on a chip. Typically, gates based on electric or magnetic fields provide the necessary perturbation for their control either globally or at well-defined locations. Here, we demonstrate the dynamic control of moving electron spins via contactless gates that move together with the spins. The concept is realized using electron spins trapped and transported by moving potential dots defined by a surface acoustic wave (SAW). The SAW strain at the electron trapping site, which is set by the SAW amplitude, acts as a contactless, tunable gate that controls the precession frequency of the flying spins via the spin-orbit interaction. We show that the degree of precession control in moving dots exceeds previously reported results for unconstrained transport by an order of magnitude and is well accounted for by a theoretical model for the strain contribution to the spin-orbit interaction. This flying spin gate permits the realization of an acoustically driven optical polarization modulator based on electron spin transport, a key element for on-chip spin information processing with a photonic interface.
Structure of an MHC I–tapasin–ERp57 editing complex defines chaperone promiscuity
Authors: Müller Ines Katharina , Winter Christian , Thomas Christoph , Spaapen Robbert M. , Trowitzsch Simon , Tampé Robert
Published: September 2022

Adaptive immunity depends on cell surface presentation of antigenic peptides by major histocompatibility complex class I (MHC I) molecules and on stringent ER quality control in the secretory pathway. The chaperone tapasin in conjunction with the oxidoreductase ERp57 is crucial for MHC I assembly and for shaping the epitope repertoire for high immunogenicity. However, how the tapasin–ERp57 complex engages MHC I clients has not yet been determined at atomic detail. Here, we present the 2.7-Å crystal structure of a tapasin–ERp57 heterodimer in complex with peptide-receptive MHC I. Our study unveils molecular details of client recognition by the multichaperone complex and highlights elements indispensable for peptide proofreading. The structure of this transient ER quality control complex provides the mechanistic basis for the selector function of tapasin and showcases how the numerous MHC I allomorphs are chaperoned during peptide loading and editing.
Streptococcus agalactiae cadD alleviates metal stress and promotes intracellular survival in macrophages and ascending infection during pregnancy
Authors: Korir Michelle L. , Doster Ryan S. , Lu Jacky , Guevara Miriam A. , Spicer Sabrina K. , Moore Rebecca E. , Francis Jamisha D. , Rogers Lisa M. , Haley Kathryn P. , Blackman Amondrea , Noble Kristen N. , Eastman Alison J. , Williams Janice A. , Damo Steven M. , Boyd Kelli L. , Townsend Steven D. , Henrique Serezani C. , Aronoff David M. , Manning Shannon D. , Gaddy Jennifer A.
Published: September 2022

Perinatal infection with Streptococcus agalactiae, or Group B Streptococcus (GBS), is associated with preterm birth, neonatal sepsis, and stillbirth. Here, we study the interactions of GBS with macrophages, essential sentinel immune cells that defend the gravid reproductive tract. Transcriptional analyses of GBS-macrophage co-cultures reveal enhanced expression of a gene encoding a putative metal resistance determinant, cadD. Deletion of cadD reduces GBS survival in macrophages, metal efflux, and resistance to metal toxicity. In a mouse model of ascending infection during pregnancy, the ΔcadD strain displays attenuated bacterial burden, inflammation, and cytokine production in gestational tissues. Furthermore, depletion of host macrophages alters cytokine expression and decreases GBS invasion in a cadD-dependent fashion. Our results indicate that GBS cadD plays an important role in metal detoxification, which promotes immune evasion and bacterial proliferation in the pregnant host.
Telomere-to-telomere genome sequence of the model mould pathogen Aspergillus fumigatus
Authors: Bowyer Paul , Currin Andrew , Delneri Daniela , Fraczek Marcin G.
Published: September 2022

The pathogenic fungus Aspergillus fumigatus is a major etiological agent of fungal invasive and chronic diseases affecting tens of millions of individuals worldwide. Draft genome sequences of two clinical isolates (Af293 and A1163) are commonly used as reference genomes for analyses of clinical and environmental strains. However, the reference sequences lack coverage of centromeres, an accurate sequence for ribosomal repeats, and a comprehensive annotation of chromosomal rearrangements such as translocations and inversions. Here, we used PacBio Single Molecule Real-Time (SMRT), Oxford Nanopore and Illumina HiSeq sequencing for de novo genome assembly and polishing of two laboratory reference strains of A. fumigatus, CEA10 (parental isolate of A1163) and its descendant A1160. We generated full length chromosome assemblies and a comprehensive telomere-to-telomere coverage for CEA10 and near complete assembly of A1160 including ribosomal repeats and the sequences of centromeres, which we discovered to be composed of long transposon elements. We envision these high-quality reference genomes will become fundamental resources to study A. fumigatus biology, pathogenicity and virulence, and to discover more effective treatments against diseases caused by this fungus.
Multiple parameters shape the 3D chromatin structure of single nuclei at the doc locus in Drosophila
Authors: Götz Markus , Messina Olivier , Espinola Sergio , Fiche Jean-Bernard , Nollmann Marcelo
Published: September 2022

The spatial organization of chromatin at the scale of topologically associating domains (TADs) and below displays large cell-to-cell variations. Up until now, how this heterogeneity in chromatin conformation is shaped by chromatin condensation, TAD insulation, and transcription has remained mostly elusive. Here, we used Hi-M, a multiplexed DNA-FISH imaging technique providing developmental timing and transcriptional status, to show that the emergence of TADs at the ensemble level partially segregates the conformational space explored by single nuclei during the early development of Drosophila embryos. Surprisingly, a substantial fraction of nuclei display strong insulation even before TADs emerge. Moreover, active transcription within a TAD leads to minor changes to the local inter- and intra-TAD chromatin conformation in single nuclei and only weakly affects insulation to the neighboring TAD. Overall, our results indicate that multiple parameters contribute to shaping the chromatin architecture of single nuclei at the TAD scale.
Structural basis for APE1 processing DNA damage in the nucleosome
Authors: Weaver Tyler M. , Hoitsma Nicole M. , Spencer Jonah J. , Gakhar Lokesh , Schnicker Nicholas J. , Freudenthal Bret D.
Published: September 2022

Genomic DNA is continually exposed to endogenous and exogenous factors that promote DNA damage. Eukaryotic genomic DNA is packaged into nucleosomes, which present a barrier to accessing and effectively repairing DNA damage. The mechanisms by which DNA repair proteins overcome this barrier to repair DNA damage in the nucleosome and protect genomic stability is unknown. Here, we determine how the base excision repair (BER) endonuclease AP-endonuclease 1 (APE1) recognizes and cleaves DNA damage in the nucleosome. Kinetic assays determine that APE1 cleaves solvent-exposed AP sites in the nucleosome with 3 − 6 orders of magnitude higher efficiency than occluded AP sites. A cryo-electron microscopy structure of APE1 bound to a nucleosome containing a solvent-exposed AP site reveal that APE1 uses a DNA sculpting mechanism for AP site recognition, where APE1 bends the nucleosomal DNA to access the AP site. Notably, additional biochemical and structural characterization of occluded AP sites identify contacts between the nucleosomal DNA and histone octamer that prevent efficient processing of the AP site by APE1. These findings provide a rationale for the position-dependent activity of BER proteins in the nucleosome and suggests the ability of BER proteins to sculpt nucleosomal DNA drives efficient BER in chromatin.
Decoupled Asian monsoon intensity and precipitation during glacial-interglacial transitions on the Chinese Loess Plateau
Authors: Zheng Yukun , Liu Hongyan , Yang Huan , Wang Hongya , Zhao Wenjie , Zhang Zeyu , Huang Miao , Liu Weihang
Published: September 2022

The discrepancies among the variations in global ice volume, cave stalagmite δ18O and rainfall reconstructed by cosmogenic 10Be tremendously restrain our understanding of the evolution of the East Asian summer monsoon (EASM). Here, we present a 430-ka EASM mean annual precipitation record on the Chinese Loess Plateau obtained using branched glycerol dialkyl glycerol tetraethers based on a deep learning neural network; this rainfall record corresponds well with cave-derived δ18O data from southern China but differs from precipitation reconstructed by 10Be. Both branched tetraether membrane lipids and cave δ18O may be affected by soil moisture and atmospheric temperature when glacial and interglacial conditions alternated and were thus decoupled from atmospheric precipitation; instead, they represent variations in the intensity of the EASM. Furthermore, we demonstrate that the brGDGT-DLNN method can significantly extend the temporal scale record of the EASM and is not restricted by geographic location compared with stalagmite records.
Optogenetic control of apical constriction induces synthetic morphogenesis in mammalian tissues
Authors: Martínez-Ara Guillermo , Taberner Núria , Takayama Mami , Sandaltzopoulou Elissavet , Villava Casandra E. , Bosch-Padrós Miquel , Takata Nozomu , Trepat Xavier , Eiraku Mototsugu , Ebisuya Miki
Published: September 2022

The emerging field of synthetic developmental biology proposes bottom-up approaches to examine the contribution of each cellular process to complex morphogenesis. However, the shortage of tools to manipulate three-dimensional (3D) shapes of mammalian tissues hinders the progress of the field. Here we report the development of OptoShroom3, an optogenetic tool that achieves fast spatiotemporal control of apical constriction in mammalian epithelia. Activation of OptoShroom3 through illumination in an epithelial Madin-Darby Canine Kidney (MDCK) cell sheet reduces the apical surface of the stimulated cells and causes displacements in the adjacent regions. Light-induced apical constriction provokes the folding of epithelial cell colonies on soft gels. Its application to murine and human neural organoids leads to thickening of neuroepithelia, apical lumen reduction in optic vesicles, and flattening in neuroectodermal tissues. These results show that spatiotemporal control of apical constriction can trigger several types of 3D deformation depending on the initial tissue context.
Cancer co-opts differentiation of B-cell precursors into macrophage-like cells
Authors: Chen Chen , Park Bongsoo , Ragonnaud Emeline , Bodogai Monica , Wang Xin , Zong Le , Lee Jung-Min , Beerman Isabel , Biragyn Arya
Published: September 2022

We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting, immunosuppressive B cells. Here, using various murine tumor models and samples from humans with breast and ovarian cancers, we provide evidence that cancers also co-opt differentiation of these B-cell precursors to generate macrophage-like cells (termed B-MF). We link the transdifferentiation to a small subset of CSF1R+ Pax5Low cells within BM pre-B and immature B cells responding to cancer-secreted M-CSF with downregulation of the transcription factor Pax5 via CSF1R signaling. Although the primary source of tumor-associated macrophages is monocytes, B-MFs are phenotypically and functionally distinguishable. Compared to monocyte-derived macrophages, B-MFs more efficiently phagocytize apoptotic cells, suppress proliferation of T cells and induce FoxP3+ regulatory T cells. In mouse tumor models, B-MFs promote shrinkage of the tumor-infiltrating IFNγ+ CD4 T cell pool and increase cancer progression and metastasis, suggesting that this cancer-induced transdifferentiation pathway is functionally relevant and hence could serve as an immunotherapeutic target.
Assembly of transmembrane pores from mirror-image peptides
Authors: Krishnan R Smrithi , Jana Kalyanashis , Shaji Amina H. , Nair Karthika S. , Das Anjali Devi , Vikraman Devika , Bajaj Harsha , Kleinekathöfer Ulrich , Mahendran Kozhinjampara R.
Published: September 2022

Tailored transmembrane alpha-helical pores with desired structural and functional versatility have promising applications in nanobiotechnology. Herein, we present a transmembrane pore DpPorA, based on the natural pore PorACj, built from D-amino acid α-helical peptides. Using single-channel current recordings, we show that DpPorA peptides self-assemble into uniform cation-selective pores in lipid membranes and exhibit properties distinct from their L-amino acid counterparts. DpPorA shows resistance to protease and acts as a functional nanopore sensor to detect cyclic sugars, polypeptides, and polymers. Fluorescence imaging reveals that DpPorA forms well-defined pores in giant unilamellar vesicles facilitating the transport of hydrophilic molecules. A second D-amino acid peptide based on the polysaccharide transporter Wza forms transient pores confirming sequence specificity in stable, functional pore formation. Finally, molecular dynamics simulations reveal the specific alpha-helical packing and surface charge conformation of the D-pores consistent with experimental observations. Our findings will aid the design of sophisticated pores for single-molecule sensing related technologies.
Platelet-rich plasma loaded nerve guidance conduit as implantable biocompatible materials for recurrent laryngeal nerve regeneration
Authors: Kim Ji Won , Kim Jeong Mi , Choi Mi Eun , Jeon Eun Jeong , Park Jin-Mi , Kim Young-Mo , Choi Seung-Ho , Eom Taesik , Shim Bong Sup , Choi Jeong-Seok
Published: September 2022

Vocal cord paralysis caused by recurrent laryngeal nerve (RLN) injury during thyroidectomy results in hoarseness, aspiration, and dyspnea. We evaluated the usefulness of nerve guidance conduits (NGCs) constructed from an asymmetric polycaprolactone (PCL)/Pluronic F127 porous membrane and filled with platelet-rich plasma (PRP) for functional RLN regeneration. We evaluated the proliferation and migration of Schwann cells (SCs) after PRP treatment in vitro. For the in vivo study, rabbits were divided into a non-loaded NGC group and a PRP-loaded NGC group. The left RLNs were resected and interposed with the NGCs. Functional and histological examinations of the vocal cords were performed. SC proliferation and migration increased in a PRP dose-dependent manner, with the PRP increasing the levels of neurotrophic factors, myelin-associated glycoprotein, and ERK. In vivo, the PRP group showed significantly better vocal cord mobility and less vocalis muscle atrophy than the non-loaded NGC group. Histologically, the ingrowth of nerve endings occurred more rapidly in the PRP group, and acetylcholinesterase, neurofilament, and S-100 expression in neural endings were significantly higher in the PRP group. Furthermore, transmission electron microscopy showed that myelinated axons were more tightly packed in the PRP group. This study shows that PRP-loaded NGCs provide a favorable environment for neural regeneration and suggests that this technique has therapeutic potential for promoting RLN recovery.
Deformation and seismicity decline before the 2021 Fagradalsfjall eruption
Authors: Sigmundsson Freysteinn , Parks Michelle , Hooper Andrew , Geirsson Halldór , Vogfjörd Kristín S. , Drouin Vincent , Ófeigsson Benedikt G. , Hreinsdóttir Sigrún , Hjaltadóttir Sigurlaug , Jónsdóttir Kristín , Einarsson Páll , Barsotti Sara , Horálek Josef , Ágústsdóttir Thorbjörg
Published: September 2022

Increased rates of deformation and seismicity are well-established precursors to volcanic eruptions, and their interpretation forms the basis for eruption warnings worldwide. Rates of ground displacement and the number of earthquakes escalate before many eruptions1–3, as magma forces its way towards the surface. However, the pre-eruptive patterns of deformation and seismicity vary widely. Here we show how an eruption beginning on 19 March 2021 at Fagradalsfjall, Iceland, was preceded by a period of tectonic stress release ending with a decline in deformation and seismicity over several days preceding the eruption onset. High rates of deformation and seismicity occurred from 24 February to mid-March in relation to gradual emplacement of an approximately 9-km-long magma-filled dyke, between the surface and 8 km depth (volume approximately 34 × 106 m3), as well as the triggering of strike-slip earthquakes up to magnitudeMW5.64. As stored tectonic stress was systematically released, there was less lateral migration of magma and a reduction in both the deformation rates and seismicity. Weaker crust near the surface may also have contributed to reduced seismicity, as the depth of active magma emplacement progressively shallowed. This demonstrates that the interaction between volcanoes and tectonic stress as well as crustal layering need to be fully considered when forecasting eruptions.
Tunable quantum criticalities in an isospin extended Hubbard model simulator
Authors: Li Qiao , Cheng Bin , Chen Moyu , Xie Bo , Xie Yongqin , Wang Pengfei , Chen Fanqiang , Liu Zenglin , Watanabe Kenji , Taniguchi Takashi , Liang Shi-Jun , Wang Da , Wang Chenjie , Wang Qiang-Hua , Liu Jianpeng , Miao Feng
Published: September 2022

Studying strong electron correlations has been an essential driving force for pushing the frontiers of condensed matter physics. In particular, in the vicinity of correlation-driven quantum phase transitions (QPTs), quantum critical fluctuations of multiple degrees of freedom facilitate exotic many-body states and quantum critical behaviours beyond Landau’s framework1. Recently, moiré heterostructures of van der Waals materials have been demonstrated as highly tunable quantum platforms for exploring fascinating, strongly correlated quantum physics2–22. Here we report the observation of tunable quantum criticalities in an experimental simulator of the extended Hubbard model with spin–valley isospins arising in chiral-stacked twisted double bilayer graphene (cTDBG). Scaling analysis shows a quantum two-stage criticality manifesting two distinct quantum critical points as the generalized Wigner crystal transits to a Fermi liquid by varying the displacement field, suggesting the emergence of a critical intermediate phase. The quantum two-stage criticality evolves into a quantum pseudo criticality as a high parallel magnetic field is applied. In such a pseudo criticality, we find that the quantum critical scaling is only valid above a critical temperature, indicating a weak first-order QPT therein. Our results demonstrate a highly tunable solid-state simulator with intricate interplay of multiple degrees of freedom for exploring exotic quantum critical states and behaviours.
Distinguishing externally from saccade-induced motion in visual cortex
Authors: Miura Satoru K. , Scanziani Massimo
Published: September 2022

Distinguishing sensory stimuli caused by changes in the environment from those caused by an animal’s own actions is a hallmark of sensory processing1. Saccades are rapid eye movements that shift the image on the retina. How visual systems differentiate motion of the image induced by saccades from actual motion in the environment is not fully understood2. Here we discovered that in mouse primary visual cortex (V1) the two types of motion evoke distinct activity patterns. This is because, during saccades, V1 combines the visual input with a strong non-visual input arriving from the thalamic pulvinar nucleus. The non-visual input triggers responses that are specific to the direction of the saccade and the visual input triggers responses that are specific to the direction of the shift of the stimulus on the retina, yet the preferred directions of these two responses are uncorrelated. Thus, the pulvinar input ensures differential V1 responses to external and self-generated motion. Integration of external sensory information with information about body movement may be a general mechanism for sensory cortices to distinguish between self-generated and external stimuli.
Brain-restricted mTOR inhibition with binary pharmacology
Authors: Zhang Ziyang , Fan Qiwen , Luo Xujun , Lou Kevin , Weiss William A. , Shokat Kevan M.
Published: September 2022

On-target–off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates1,2. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1 and the brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock, enabling the brain-restricted inhibition of their respective kinase targets.