bluuebunny/crossref_metadata_2025 huggingface dataset:
The Delivery of The Lamb
Authors: Trollope Anthony
Published: August 2021

IT is hoped that a certain quarter of lamb will not have been forgotten,—a quarter of lamb that was sent as a peace-offering from Exeter to Nuncombe Putney by the hands of Miss Stanbury’s Martha, not with purposes of corruption, not intended to buy back...
‘We Shall Be So Poor’
Authors: Trollope Anthony
Published: August 2021

MR. GLASCOCK at that moment was not only in Florence, but was occupying rooms in the very hotel in which the Rowleys were staying. Lady Rowley, when she heard that he was engaged to marry an American lady, became suddenly very sick at heart,— sick...
Casalunga
Authors: Trollope Anthony
Published: August 2021

SIR MARMADUKE had been told at the Florence post-office that he would no doubt be able to hear tidings of Trevelyan, and to learn his address, from the officials in the post-office at Siena. At Florence he had been introduced to some gentleman who was...
‘I Can Sleep on The Boards’
Authors: Trollope Anthony
Published: August 2021

THREE days after this there came another carriage to the bottom of the hill on which Casalunga stood, and a lady got out of it all alone. It was Emily Trevelyan, and she had come thither from Siena in quest of her husband and her...
Self-Sacrifice
Authors: Trollope Anthony
Published: August 2021

TREVELYAN, when his wife had left him, sat for hours in silence pondering over his own position and hers. He had taken his child to an upper room, in which was his own bed and the boy’s cot, and before he seated himself, he spread...
Cropper and Burgess
Authors: Trollope Anthony
Published: August 2021

WE must now go back to Exeter and look after Mr. Brooke Burgess and Miss Dorothy Stanbury. It is rather hard upon readers that they should be thus hurried from the completion of hymeneals at Florence to the preparations for other hymeneals in Devonshire; but...
‘I Wouldn’t Do It, If I Was You’
Authors: Trollope Anthony
Published: August 2021

MISS STANBURY at this time was known all through Exeter to be very much altered from the Miss Stanbury of old;—or even from the Miss Stanbury of two years since. The Miss Stanbury of old was a stalwart lady who would play her rubber of...
‘Say That You Forgive Me’
Authors: Trollope Anthony
Published: August 2021

ON the following day, again early in the morning, Mrs. Trevelyan and Stanbury were driven out to Casalunga. The country people along the road knew the carriage well, and the lady who occupied it, and would say that the English wife was going to see...
Trevelyan Back In England
Authors: Trollope Anthony
Published: August 2021

NORA, with Lady Milborough’s carriage, and Lady Milborough’s coach and footman, and with a cab ready for the luggage close behind the carriage, was waiting at the railway station when the party from Dover arrived. She soon saw Hugh upon the platform, and ran to...
Monkhams
Authors: Trollope Anthony
Published: August 2021

ON the 10th of August Nora Rowley left the cottage by the river-side at Twickenham, and went down to Monkhams. The reader need hardly be told that Hugh brought her up from Twickenham and sent her off in the railway carriage. They agreed that no...
Mrs. Brooke Burgess
Authors: Trollope Anthony
Published: August 2021

IT may be doubted whether there was a happier young woman in England than Dorothy Stanbury when that September came which was to make her the wife of Mr. Brooke Burgess, the new partner in the firm of Cropper and Burgess. Her early aspirations in...
Accretion environments of active galactic nuclei
Authors: Inoue Hajime
Published: August 2021

We study accretion environments of active galactic nuclei when a supermassive black hole wanders in a circumnuclear region and passes through an interstellar medium there. It is expected that Bondi–Hoyle–Lyttleton-type accretion of the interstellar matter takes place and an accretion stream of matter trapped by the black hole gravitational field appears from a tail shock region. Since the trapped matter is likely to have a certain amount of specific angular momentum, the accretion stream eventually forms an accretion ring around the black hole. According to recent studies, the accretion ring consists of a thick envelope and a thin core, and angular momenta are transferred from the inner side facing the black hole to the opposite side in the envelope and the core respectively. As a result, a thick accretion flow and a thick excretion flow extend from the envelope, and a thin accretion disk and a thin excretion disk extend from the core. The thin excretion disk is predicted to terminate at some distance, forming an excretion ring, while the thick excretion flow is considered to become a supersonic wind flowing to infinity. The thick excretion flow from the accretion ring is expected to interact with the accretion stream toward the accretion ring and to be collimated to bipolar cones. These pictures provide a likely guideline to interpreting the overall accretion environments suggested from observations.
The Wisdom of Crowds in FinTech: Evidence from Initial Coin Offerings
Authors: Lee Jongsub , Li Tao , Shin Donghwa
Published: August 2021

Certification by analysts on a FinTech platform that harnesses the “wisdom of crowds” is associated with successful initial coin offerings (ICOs). We show that favorable ratings by a group of analysts with diverse backgrounds positively predict fundraising success and long-run token performance. Analysts’ ratings also help detect potential fraud ex ante. We document that analysts have career concerns and are incentivized by the platform to issue informative ratings. Overall, our results suggest that a market-based certification process that relies on a diverse group of individuals is at play in financing blockchain startups. (JEL D82, G11, G24, G32, G34, L26).
Credit Default Swaps around the World
Authors: Bartram Söhnke M , Conrad Jennifer , Lee Jongsub , Subrahmanyam Marti G
Published: August 2021

We analyze the impact of the introduction of credit default swaps (CDSs) on real decision-making within the firm. Our structural model predicts that CDS introduction increases debt capacity more when uncertainty about the credit events that trigger CDS payment is lower. Using a sample of more than 56,000 firms across 51 countries, we find that CDSs increase leverage more in legal and market environments where uncertainty about CDS obligations is reduced and when property rights are weaker. Our results highlight the importance of legal uncertainty in the interpretation of the underlying trigger events of global credit derivatives.
Substance over form—when a loan is really a distribution
Authors: Bell-Connell Jeremy , Brandts-Giesen Henry
Published: August 2021

A recent judgment of the Court of Appeal of England and Wales1 provides a timely warning to trustees that characterising a payment to beneficiaries as a loan does not conclusively make it so, and that mischaracterising such transactions could place trustees in peril.
Column-Specific Distal Radius Fracture Fixation
Authors: Hoekzema Nathan A. , Brambila Maximino
Published: August 2021

Despite the popularity and success of volar fixed angle plating, variations in distal radius fracture presentation underscore the importance of understanding different surgical treatment options to maximize patient outcomes. The 3-column theory of wrist mechanics provided the foundation for using a column-specific fixation approach. Implant placement within the ulnar column can be challenging because of anatomical constraints. Some have described “safe zones” for implant position to decrease the potential for tendon impingement. A thorough understanding of the surrounding anatomy can allow fixation decisions based on fracture fragment location. Literature reports have shown excellent results when using fragment specific fixation constructs and similar outcomes when comparing these constructs with volar locked plating. Achieving optimal outcomes in surgically treated distal radius fractures requires the surgeon to be competent along a spectrum of surgical approaches and fixation constructs.
Prognostic value of platelet/lymphocyte ratio and CAMI-STEMI score for major adverse cardiac events in patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention
Authors: Wang Yaochen , Peng Zhongxing
Published: August 2021

The aim of this study was to investigate the predictive value of the platelet-to-lymphocyte ratio (PLR) and the China Acute Myocardial Infarction registry-ST segment elevation myocardial infarction (CAMI-STEMI) score for major adverse cardiovascular events (MACE) in ST-segment elevation myocardial infarction (STEMI) patients undergoing percutaneous coronary intervention (PCI) within 6 months.

We enrolled STEMI patients who received emergency PCI in the First Hospital of Lianyungang from January 2016 to December 2019. The clinical characteristics of the patients, the PLR, and the CAMI-STEMI score were recorded. The MACE included heart failure, nonfatal re-infarction, recurrent angina pain, re-hospitalization for cardiovascular-related illness, repeat PCI, coronary artery bypass grafting, and all-cause mortality. According to the incidence of MACE during the follow-up the patients were divided into the MACE group (96 cases, 24.8%) and the non-MACE group (291 cases, 75.2%).

The PLR, 147.62 (121.13–205.20) in MACE group, was 111.19 (90.23–146.42) in the non-MACE group in comparison, the PLR was higher in MACE group than that in non-MACE group (P < .01). Multivariate regression analysis showed that PLR (odds ratio (OR) = 1.007, 95% confidence interval (CI) 1.002–1.012, P < .01) and CAMI-STEMI score (OR = 1.575, 95% CI: 1.311–1.892, P < .01) were independent predictors of MACE. Besides, I-BIL was also an independent predictor of MACE (OR = 1.007, 95% CI: 1.011–1.146, P = .021). Reciever-operating characteristic curve showed that the area under curve of PLR was 0.704 (95%CI 0.644–0.763, P < .001). The cutoff value was 112.6, the sensitivity and specificity were 84.4% and 51.9%, respectively.

PLR and CAMI-STEMI scores were independent risk factors of MACE after PCI in STEMI patients.
Subtype maturation of spiral ganglion neurons
Authors: Sun Shuohao , Siebald Caroline , Müller Ulrich
Published: August 2021

Purpose of review

We review recent progress in the characterization of spiral ganglion neurons (SGNs), the afferent neurons that transmit sound information from mechanosensory hair cells in the inner ear to the central nervous system.

Recent findings

Single-cell ribonucleic acid sequencing studies of murine SGNs have demonstrated that SGNs consist of molecularly distinct subtypes. The molecularly defined SGN subtypes likely correspond to SGN subtypes previously identified on the basis of physiological properties, although this has not been experimentally demonstrated. Subtype maturation is completed postnatally in an activity-dependent manner and is impaired in several models of hearing loss.

The recent molecular studies open new avenues to rigorously test whether SGN subtypes are important for the encoding of different sound features and if they show differential vulnerability to genetic factors and environmental insults. This could have important implications for the development of therapeutic strategies to treat hearing loss.
The airway microbiome and pediatric asthma
Authors: Shah Rhia , Bunyavanich Supinda
Published: August 2021

Purpose of review

Asthma is the most common chronic disease of childhood. Investigations of the lower and upper airway microbiomes have significantly progressed over recent years, and their roles in pediatric asthma are becoming increasingly clear.

Recent findings

Early studies identified the existence of upper and lower airway microbiomes, including imbalances in both associated with pediatric asthma. The infant airway microbiome may offer predictive value for the development of asthma in later childhood, and it may also be influenced by external factors such as respiratory viral illness. The airway microbiome has also been associated with the clinical course of asthma, including rates of exacerbation and level of control. Advances in -omics sciences have enabled improved identification of the airway microbiome's relationships with host response and function in children with asthma. Investigations are now moving toward the application of the above findings to explore risk modification and treatment options.

The airway microbiome provides an intriguing window into pediatric asthma, offering insights into asthma diagnosis, clinical course, and perhaps treatment. Further investigation is needed to solidify these associations and translate research findings into clinical practice.
Longitudinal monitoring of SARS-CoV-2-specific immune responses
Authors: Rebholz Heike , Braun Ralf J. , Saha Titas , Harzer Oliver , Schneider Miriam , Ladage Dennis
Published: August 2021

The Lower Austrian Wachau region was an early COVID-19 hotspot of infection. As previously reported, in June 2020, after the first peak of infections, we determined that 8.5% and 9.0% of the participants in Weißenkirchen and surrounding communities in the Wachau region were positive for SARS-CoV-2-specific immunoglobulin G (IgG) and immunoglobulin A (IgA) antibodies, respectively. Here, we present novel data obtained eight months later (February 2021) from Weißenkirchen, after the second peak of infection, with 25.0% (138/552) and 23.6% (130/552) of participants that are positive for IgG and IgA, respectively. In participants with previous IgG/IgA positivity (June 2020), we observed a 24% reduction in IgG levels, whereas the IgA levels remained stable in February 2021. This subgroup was further analyzed for SARS-CoV-2-induced T cell activities. Although 76% (34/45) and 76% (34/45) of IgG positive and IgA positive participants, respectively, showed specific T cell activities, those were not significantly correlated with the levels of IgG or IgA. Thus, the analyses of antibodies cannot surrogate the measurement of T cell activities. For a comprehensive view on SARS-CoV-2-triggered immune responses, the measurement of different classes of antibodies should be complemented with the determination of T cell activities.
Cystatin C is glucocorticoid-responsive, directs recruitment of Trem2+ macrophages and predicts failure of cancer immunotherapy
Authors: Kleeman Sam O. , Demestichas Breanna , Mourikis Nicholas , Loiero Dominik , Ferrer Miriam , Bankier Sean , Riazat-Kesh Yosef J.R.A. , Lee Hassal , Chantzichristos Dimitrios , Regan Claire , Preall Jonathan , Sinha Sarthak , Rosin Nicole , Yipp Bryan , de Almeida Luiz G.N. , Biernaskie Jeff , Dufour Antoine , Tober-Lau Pinkus , Ruusalepp Arno , Bjorkegren Johan L. M. , Ralser Markus , Kurth Florian , Demechev Vadim , Heywood Todd , Gao Qing , Johannsson Gudmundur , Koelzer Viktor H. , Walker Brian R. , Meyer Hannah V. , Janowitz Tobias
Published: August 2021

Cystatin C (CyC) is a secreted cysteine protease inhibitor and its biological functions remain insufficiently characterized. Plasma CyC is elevated in many patients, especially when receiving glucocorticoid (GC) treatment. Endogenous GCs are essential for life and are appropriately upregulated in response to systemic stress. Here we empirically connect GCs with systemic regulation of CyC. We used genome-wide association and structural equation modeling to determine the genetics of the latent trait CyC production in UK Biobank. CyC production and a polygenic score (PGS) capturing germline predisposition to CyC production predicted elevated all-cause and cancer-specific mortality. We then demonstrated that CyC is a direct target of GC receptor, with GC-responsive CyC secretion exhibited by macrophages and cancer cells. Using isogenic CyC-knockout tumors, we discovered a markedly attenuated tumor growthin vivoand found abrogated recruitment of Trem2+ macrophages, which have been previously linked to failure of cancer immunotherapy. Finally, we showed that the CyC-production PGS predicted checkpoint immunotherapy failure in a combined clinical trial cohort of 685 metastatic cancer patients. Taken together, our results demonstrate that CyC may be a direct effector of GC-induced immunosuppression, acting through recruitment of Trem2+ macrophages, and therefore could be a target for combination cancer immunotherapy.
The Rapid Assessment of Aggregated Wastewater Samples for Genomic Surveillance of SARS-CoV-2 on a City-Wide Scale
Authors: Rouchka Eric C. , Chariker Julia L. , Saurabh Kumar , Waigel Sabine , Zacharias Wolfgang , Zhang Mei , Talley Daymond , Santisteban Ian , Puccio Madeline , Moyer Sarah , Holm Rochelle H. , Yeager Ray A. , Sokoloski Kevin , Fuqua Joshua , Bhatnagar Aruni , Smith Ted
Published: August 2021

Throughout the course of the ongoing SARS-CoV-2 pandemic there has been a need for approaches that enable rapid monitoring of public health using an unbiased and minimally invasive means. A major way this has been accomplished is through the regular assessment of wastewater samples by qRT-PCR to detect the prevalence of viral nucleic acid with respect to time and location. Further expansion of SARS-CoV-2 wastewater monitoring efforts to include the detection of variants of interest / concern through next-generation sequencing have enhanced the understanding of the SARS-CoV-2 outbreak. In this report we detail the results of a collaborative effort between public health and metropolitan wastewater management authorities and the University of Louisville to monitor the SARS-CoV-2 pandemic through the monitoring of aggregate wastewater samples over a period of 28 weeks. Our data indicates that wastewater monitoring of water quality treatment centers and smaller neighborhood-scale catchment areas is a viable means by which the prevalence and genetic variation of SARS-CoV-2 within a metropolitan community of approximately one million individuals may be monitored. Importantly, these efforts confirm that regional emergence and spread of variants of interest / concern may be detected as readily in aggregate wastewater samples as compared to the individual wastewater sheds.
The association between immunosuppressants use and COVID-19 adverse outcomes: National COVID-19 cohort in South Korea
Authors: Shin Hyun Joon , Chow Ronald , Noh Hyerim , Lee Jongseong , Lee Jihui , Choi Young-Geun
Published: August 2021

Purpose

There is uncertainty of the effect of immunosuppression, including corticosteroids, before COVID-19 infection on COVID-19 outcomes. The aim of this study was to investigate the relationship between prehospitalization immunosuppressants use (exposure), and COVID-19 patient outcomes.

Methods

We conducted a population-based retrospective cohort study using a nationwide healthcare claims database of South Korea as of May 15, 2020. Confirmed COVID-19 infection in hospitalized individuals aged 40 years or older were included for analysis. We defined exposure variable by using inpatient and outpatient prescription records of immunosuppressants from the database. Our primary outcome was a composite endpoint of all-cause death, intensive care unit (ICU) admission, and mechanical ventilation use. Inverse probability of treatment weighting (IPTW)-adjusted logistic regression analyses were used, to estimate odds ratio (OR) and 95% confidence intervals, comparing immunosuppressants users and non-users.

Results

We identified 4,349 patients, for which 1,356 were immunosuppressants users and 2,903 were non-users. Patients who used immunosuppressants were at increased odds of the primary outcome of all-cause death, ICU admission and mechanical ventilation use (IPTW OR 1.32; 95% CI: 1.06 – 1.63). Patients who used corticosteroids were at increased odds of the primary outcome (IPTW OR 1.33; 95% CI: 1.07 – 1.64).

Conclusion

We support the latest guidelines from the CDC, that people on immunosuppressants are at high risk of severe COVID-19 and immunocompromised people may need booster COVID-19 vaccinations.

Funding

YGC’s work was partially supported by 2020R1G1A1A01006229 awarded by the National Research Foundation of Korea.
Prevalence of cognitive impairment following chemotherapy treatment for breast cancer: A systematic review and meta-analysis
Authors: Whittaker Alexandra L , George Rebecca P , O’Malley Lucy
Published: August 2021

Breast cancer survival rates have markedly improved. Consequently, survivorship issues have received increased attention. One common sequela of treatment is chemotherapy- induced cognitive impairment (CICI). CICI causes a range of impairments that can have a significant negative impact on quality of life. Knowledge of the prevalence of this condition is required to inform survivorship plans, and ensure adequate resource allocation and support is available for sufferers.

Objective

To estimate the prevalence of cognitive impairment following chemotherapy treatment for breast cancer.

Methods

Medline, Scopus, CINAHL and PSYCHInfo were searched for eligible studies which included prevalence data on CICI, as ascertained though the use of self-report, or neuropsychological tests. Methodological quality of included studies was assessed. Findings were synthesised narratively, with meta-analyses being used to calculate pooled prevalence when impairment was assessed by neuropsychological tests.

Results and discussion

The review included 52 studies. Time-points considered ranged from the chemotherapy treatment period to greater than 10 years after treatment cessation. Summary prevalence figures (across time-points) using self-report, short cognitive screening tools and neuropsychological test batteries were 44%, 16% and 21-34% respectively (very low GRADE evidence).

Conclusion

Synthesised findings demonstrate that 1 in 3 breast cancer survivors may have clinically significant cognitive impairment. Prevalence is higher when self-report based on patient experience is considered. This review highlights a number of study design issues that may have contributed to the low certainty rating of the evidence. Future studies should take a more consistent approach to the criteria used to assess impairment. Larger studies are urgently needed.

Summary of Findings Table
Determinants shaping the nanoscale architecture of the mouse rod outer segment
Authors: Pöge Matthias , Mahamid Julia , Imanishi Sanae S. , Plitzko Jürgen M. , Palczewski Krzysztof , Baumeister Wolfgang
Published: August 2021

The unique membrane organization of the rod outer segment (ROS), the specialized sensory cilium of rod photoreceptor cells, provides the foundation for phototransduction, the initial step in vision. ROS architecture is characterized by a stack of identically shaped and tightly packed membrane disks loaded with the visual receptor rhodopsin. A wide range of genetic aberrations compromise ROS ultrastructure, impairing photoreceptor viability and function. Yet, the structural basis giving rise to the remarkable long-range order of ROS membrane stacks and the molecular mechanisms underlying genetically inherited diseases remain elusive. Here, cryo-electron tomography (cryo-ET) performed on native ROS at molecular resolution provides insights into key structural determinants of ROS membrane architecture.

Our data reveal the existence of two molecular connectors/spacers which likely contribute to the nanometer-scale precise stacking of the ROS disks. We further show that the extreme radius of curvature at the disk rims is enforced by a continuous supramolecular assembly composed of peripherin-2 (PRPH2) and rod outer segment membrane protein 1 (ROM1) tetramers. We suggest that, together these molecular assemblies constitute the structural basis of the highly specialized ROS functional architecture. Cryo-ET therefore provides novel quantitative and structural information on the molecular architecture in ROS and insights into possible mechanisms underlying pathologies of certain PRPH2 mutations leading to blindness.
Signatures of adaptive evolution in platyrrhine primate genomes
Authors: Byrne Hazel , Webster Timothy H. , Brosnan Sarah F. , Izar Patrícia , Lynch Jessica W.
Published: August 2021

The family Cebidae (capuchin and squirrel monkeys) form a remarkable platyrrhine clade exhibiting among the largest primate encephalisation quotients. Each cebid lineage is characterised by notable lineage-specific traits, with capuchins showing striking similarities to Hominidae including high sensorimotor intelligence with tool use, advanced cognitive abilities, and behavioural flexibility. Here, we take a comparative genomics approach, analysing five cebid branches including successive lineages, to infer a stepwise timeline for cebid adaptive evolution. We uncover candidate targets of selection across various periods of cebid evolution that may underlie the emergence of lineage-specific traits. Our analyses highlight shifting and sustained selective pressures on genes related to brain development, longevity, reproduction, and morphology, including evidence for cumulative and diversifying neurobiological adaptations over cebid evolutionary history. In addition to generating a new, high-quality reference genome assembly for robust capuchins, our results lend to a better understanding of the adaptive diversification of this distinctive primate clade.
Super-Resolution Electrochemical Impedance Imaging with a 100 × 100 CMOS Sensor Array
Authors: Hu Kangping , Arcadia Christopher E. , Rosenstein Jacob K.
Published: August 2021

This paper presents a 100 × 100 super-resolution integrated sensor array for microscale electrochemical impedance spectroscopy (EIS) imaging. The system is implemented in 180 nm CMOS with 10 μm × 10 μm pixels. Rather than treating each electrode independently, the sensor is designed to measure the mutual capacitance between programmable sets of pixels. Multiple spatially-resolved measurements can then be computationally combined to produce super-resolution impedance images. Experimental measurements of sub-cellular permittivity distributions within single algae cells demonstrate the potential of this new approach.
BH3 Profiling Identifies Selective BCL-2 Dependence of Adult Early T-cell Progenitor (ETP) Subtype of Acute Lymphoblastic Leukemia (ALL) Patients
Authors: Olesinski Elyse A. , Bhatia Karanpreet Singh , Garcia Jacqueline , Jain Nitin , Letai Anthony , Konopleva Marina , Bhatt Shruti
Published: August 2021

Early T-cell precursor (ETP) acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of T-ALL and is associated with poor survival outcomes with chemotherapy. We previously showed that maturation stage of thymocytes distinguishes pro-survival dependencies of pediatric ETP-ALL (BCL-2 dependent) from non-ETP-ALL (BCL-XL dependent). Comparable data in adults are lacking. Our present study focuses on characterizing functional dependencies of adult ETP-ALL and T-ALL on BCL-2 family proteins. Using BH3 profiling on primary tumors, we report that similar to pediatric ALL, adult ETP-ALL is primarily dependent on BCL-2; however, unlike pediatric ALL, adult non-ETP-ALL is co-dependent on both BCL-2 and BCL-XL for survival. By measuring direct mitochondrial permeabilization and cell viability assays, we validated that BH3 profiling predicted on-target cytotoxicity of venetoclax in adult ETP-ALL and navitoclax plus venetoclax in adult T-ALL. These findings provide pre-clinical evidence for venetoclax and navitoclax as potentially efficacious combination therapy for adults with T-ALL.

Statement of Significance

Adults with relapsed T-ALL have poor prognosis and represent an unmet need for novel treatments. We report that adult ETP-ALL is dependent on BCL-2 for survival, similar to pediatric ETP-ALL. However, adult non-ETP-ALL is heterogeneously dependent on both BCL-2 and BCL-XL. We characterize key dependencies on BCL-2 family proteins to direct BH3 mimetics therapy in T-ALL patients.
Shaping coral traits: plasticity more than filtering
Authors: Brambilla Viviana , Barbosa Miguel , Dehnert Inga , Madin Joshua , Maggioni Davide , Peddie Clare , Dornelas Maria
Published: August 2021

The structure of ecosystems is usually determined by the shape of the organisms that build it, commonly known as ecosystem engineers. Understanding to what extent plasticity and environmental filtering determine variation in ecosystem engineer physical structure is necessary to predict how ecosystem structure may change. Here, we explored coral survival and the plasticity of morphological traits that are critical for habitat provision in coral reefs. We conducted a reciprocal clonal transplant experiment in which branching corals from the genus Porites and Acropora were moved to and from a deep and a shallow site within a lagoon in the Maldives. Survival and trait analyses showed that transplant destination consistently induced the strongest changes, particularly among Acropora spp. The origin of the corals only marginally affected some of the traits. We also detected variation in the way individuals from the same species and site differentiate their shape, showing that traits linked to habitat provision are phenotypically plastic. The results suggest coral phenotypic plasticity plays a stronger role than environmental filtering, in determining zonation of coral morphologies, and consequently the habitats they provide for other taxa.
Isolation, ‘omics characterization and organotypic culture of alveolar type II pulmonary epithelial cells
Authors: Li Huaibiao , Schütte Moritz , Bober Magdalena , Kroll Torsten , Frappart Lucien , About Ghina Bou , Lin Yu-Chieh , Sorg Tania , Herault Yann , Wierling Christoph , Rinner Oliver , Lange Bodo MH , Ploubidou Aspasia
Published: August 2021

The alveolar type II (AT2) epithelial cell fraction includes the stem cells of the pulmonary alveoli, functioning in lung homeostasis and post-injury repair. AT2 cells have been characterized primarily in situ, in transgenic mouse models. We report a new methodology for their isolation, their “omics” characterization and stroma-cell-free organotypic culture. Our multi-omics analysis identified high expression of genes involved in oxidative phosphorylation and of AP-1 components, as well as new phosphorylation sites in AT2 biomarkers. Furthermore, we show that supplementation with KGF, FGF10 & HGF suffices for the in vitro proliferation of AT2 cells and formation of alveolar organoids, suggesting that AT2-based organotypic development depends on ligands of the c-Met and FGFR2 receptors. The reported methodology and in-depth molecular characterization provide new tools for the in vitro and in vivo functional analysis of pulmonary cells and of mouse models of lung disease.
Identification of Potential inhibitors for Hematopoietic Prostaglandin D2 Synthase: Computational Modeling and Molecular Dynamics Simulations
Authors: Beura Satyajit , Prabhakar Chetti
Published: August 2021

To design a new therapeutic agent for Hematopoietic Prostaglandin D2 synthase (hPGDS), a set of 60 molecules with different molecular scaffolds were (range of pIC50 values are from 8.301 to 3.932) considered to create a pharmacophore model. Further, identification of potential hPGDS inhibitors were carried out by using virtual screening with different databases (from 15,74,182 molecules). The Molecular screening was performed using different sequential methods right from Pharmacophore based virtual screening, molecular docking, MM-GBSAstudies, ADME property analysis and molecular dynamics simulations using Maestro11.9 software. Based on the best pharmacophore model (ADRR_1), the resultant set of 18,492 molecules were screened. The preliminarily screened molecules were subjected to molecular docking (PDB_ID: 2CVD) methods. A set of 27 molecules was screened from the resultant molecular docking outcomes (360 molecules) based on binding free energy (ΔGbind) and Lipinski’s rule of five. Out of 27 molecules, 4 were selected visual data analysis and further subjected to molecular dynamics (MD) simulation study. Outcomes of the present study conclude with three new proposed molecules (SP1, SP2 and SP10) which show a good range of interaction with human hPGDS enzyme in comparison to the marketed compounds i.e., HQL-79, TFC-007, HPGDS inhibitor I and TAS-204.
Stabilising microbial communities by looped mass transfer
Authors: Li Shuang , Abdulkadir Nafi’u , Schattenberg Florian , da Rocha Ulisses Nunes , Grimm Volker , Müller Susann , Liu Zishu
Published: August 2021

Creating structurally and functionally stable microbiomes would be greatly beneficial to biotechnology and human health but so far has proven challenging. Here, we propose a looped mass transfer design that keeps microbiomes constant over long periods of time. The effluent of five parallel reactors that began with the same inoculum, was mixed in a reactor that represented a regional pool. Part of this pool was transferred back to the five reactors. Community dynamics were monitored and visualized by quantitative microbial flow cytometry and selected taxonomic sequencing of whole communities and sorted subcommunities. The rescue effect, known from metacommunity theory, was the main stabilizing mechanism that led to the survival of subcommunities with zero netgrowth, especially at high mass transfer rates. The looped mass transfer approach promises to overcome notorious stochastic structural fluctuations in bioreactors and has the potential to design and stabilize communities that can perform desired functions.
Sensitivity to the slope of the amplitude spectrum is dependent on the spectral slopes of recently viewed environments: A visual adaptation study in modified reality
Authors: Richard Bruno , Shafto Patrick
Published: August 2021

Scenes contain many statistical regularities that could benefit visual processing if accounted for by the visual system. One such statistic is the orientation-averaged slope (α) of the amplitude spectrum of natural scenes. Human observers show different discrimination sensitivity to α: sensitivity is highest for α values between 1.0 and 1.2 and decreases as α is steepened or shallowed. The range of α for peak discrimination sensitivity is concordant with the average α of natural scenes, which may indicate that visual mechanisms are optimized to process information at α values commonly encountered in the environment. Here we explore the association between peak discrimination sensitivity and the most viewed αs in natural environments. Specifically, we verified whether discrimination sensitivity depends on the recently viewed environments. Observers were immersed, using a Head-Mounted Display, in an environment that was either unaltered or had its average α steepened or shallowed by 0.4. Discrimination thresholds were affected by the average shift in α, but this effect was most prominent following adaptation to a shallowed environment. We modeled these data with a Bayesian observer and explored whether a change in the prior or a change in the likelihood best explained the psychophysical effects. Change in discrimination thresholds following adaptation could be explained by a shift in the central tendency of the prior concordant with the shift of the environment, in addition to a change in the likelihood. Our findings suggest that expectations on the occurrence of α that result from a lifetime of exposure remain plastic and able to accommodate for the statistical structure of recently viewed environments.
Optimized Data-Independent Acquisition Approach for Proteomic Analysis at Single-Cell Level
Authors: Wang Yuefan , Lih Tung-Shing Mamie , Chen Lijun , Xu Yuanwei , Kuczler Morgan D. , Cao Liwei , Pienta Kenneth J. , Amend Sarah R. , Zhang Hui
Published: August 2021

Single-cell proteomic analysis provides valuable insights into cellular heterogeneity allowing the characterization of the cellular microenvironment which is difficult to accomplish in bulk proteomic analysis. Currently, single-cell proteomic studies utilize data-dependent acquisition (DDA) mass spectrometry (MS) coupled with a TMT labelled carrier channel. Due to the extremely imbalanced MS signals among the carrier channel and other TMT reporter ions, the quantification is compromised. Thus, data-independent acquisition (DIA)-MS should be considered as an alternative approach towards single-cell proteomic study since it generates reproducible quantitative data. However, there are limited reports on the optimal workflow for DIA-MS-based single-cell analysis. Herein, we report an optimized DIA workflow for single-cell proteomics using Orbitrap Lumos Tribrid instrument. We utilized a breast cancer cell line (MDA-MB-231) and induced drug resistant polyaneuploid cancer cells (PACCs) to evaluate our established workflow. We found that a short LC gradient was preferable for peptides extracted from single cell level with less than 2 ng sample amount. The total number of co-searching peptide precursors was also critical for protein and peptide identifications at nano- and sub-nano-gram levels. Post-translationally modified peptides could be identified from a nano-gram level of peptides. Using the optimized workflow, up to 1,500 protein groups were identified from a single PACC corresponding to 0.2 ng of peptides. Furthermore, about 200 peptides with phosphorylation, acetylation, and ubiquitination were identified from global DIA analysis of 100 cisplatin resistant PACCs (20 ng). Finally, we used this optimized DIA approach to compare the whole proteome of MDA-MB-231 parental cells and induced PACCs at a single-cell level. We found the single-cell level comparison could reflect real protein expression changes and identify the protein copy number. Our results demonstrate that the optimized DIA pipeline can serve as a reliable quantitative tool for single-cell as well as sub-nano-gram proteomic analysis.
A Lentiviral Envelope Signal Sequence is a Tetherin Antagonizing Protein
Authors: Morrison James H. , Poeschla Eric M.
Published: August 2021

Signal sequences are N-terminal peptides, generally less than 30 amino acids in length, that direct translocation of proteins into the endoplasmic reticulum and secretory pathway. The envelope glycoprotein (Env) of the nonprimate lentivirus Feline immunodeficiency virus (FIV) contains the longest signal sequence of all eukaryotic, prokaryotic and viral proteins (175 amino acids). The reason is unknown. Tetherin is a dual membrane-anchored host protein that inhibits the release of enveloped viruses from cells. Primate lentiviruses have evolved three antagonists: the small accessory proteins Vpu and Nef, and in the case of HIV-2, Env. Here we identify the FIV Env signal sequence (Fess) as the FIV tetherin antagonist. A short deletion in the central portion of Fess had no effect on viral replication in the absence of tetherin but severely impaired virion budding in its presence. Fess is necessary and sufficient, acting as an autonomous accessory protein with the rest of Env dispensable. In contrast to primate lentivirus tetherin antagonists, it functions by stringently blocking the incorporation of this restriction factor into viral particles rather than by degrading it or downregulating it from the plasma membrane.
The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy
Authors: Xuan Zhao , Yang Sisi , Hill Sarah E. , Clark Benjamin , Manning Laura , Colón-Ramos Daniel A.
Published: August 2021

In neurons, autophagy is temporally and spatially regulated to occur near presynaptic sites. How trafficking of autophagy proteins is regulated to support synaptic autophagy is not well understood. From forward genetic screens, we identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating trafficking of autophagy protein ATG-9 at synapses, and presynaptic autophagy. ATG-9 is a transmembrane protein that undergoes activity-dependent exo-endocytosis at synapses, and mutations in CLA-1L result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates. CLA-1L extends from the active zone to the periactive zone, and genetically interacts with periactive zone proteins required for clathrin-dependent endocytosis. We find that CLA-1L is specifically required for sorting of ATG-9 at synapses, likely via endosome-mediated endocytosis, and for activity-dependent presynaptic autophagy. Our findings provide mechanistic insights into how active zone proteins regulate key steps of ATG-9 exo-endocytosis, a process that could couple the activity state of the neuron and autophagy.

Highlights

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The long isoform of the active zone protein Clarinet (CLA-1L) regulates ATG-9 trafficking at synapses

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CLA-1L extends from the active zone to the periactive zone and cooperates with the periactive zone endocytic proteins EHS-1/EPS15 and ITSN-1/ intersectin 1 in ATG-9 trafficking during exo-endocytosis

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Mutations in CLA-1L, or in clathrin-associated adaptor molecules, result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates

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CLA-1L mutants which affect ATG-9 trafficking are also defective in activity-dependent presynaptic autophagy
Spatial and temporal expression of PORCN is highly dynamic in the developing mouse cochlea
Authors: Oliver Brianna L. , Young Caryl A. , Munnamalai Vidhya
Published: August 2021

The mammalian organ of Corti is a highly specialized sensory organ of the cochlea with a fine-grained pattern that is essential for auditory function. The sensory epithelium, the organ of Corti consists of a single row of inner hair cells and three rows of outer hair cells that are intercalated by support cells in a mosaic pattern. Previous studies show that the Wnt pathway regulates proliferation, promotes medial compartment formation in the cochlea, differentiation of the mechanosensory hair cells and axon guidance of Type II afferent neurons. WNT ligand expressions are highly dynamic throughout development but are insufficient to explain the roles of the Wnt pathway. We address a potential way for how WNTs specify the medial compartment by characterizing the expression of Porcupine (PORCN), an O-acyltransferase that is required for WNT secretion. We show PORCN expression across embryonic ages (E)12.5 - E14.5, E16.5, and postnatal day (P)1. Our results showed enriched PORCN in the medial domains during early stages of development, indicating that WNTs have a stronger influence on patterning of the medial compartment. PORCN was rapidly downregulated after E14.5, following the onset of sensory cell differentiation; residual expression remained in some hair cells and supporting cells. On E14.5 and E16.5, we also examined the spatial expression of Gsk3β, an inhibitor of canonical Wnt signaling to determine its potential role in radial patterning of the cochlea. Gsk3β was broadly expressed across the radial axis of the epithelium; therefore, unlikely to control WNT-mediated medial specification. In conclusion, the spatial expression of PORCN enriches WNT secretion from the medial domains of the cochlea to influence the specification of cell fates in the medial sensory domain.

Highlights

Wnt ligands are broadly expressed during cochlear development.

PORCN expression is highly dynamic during early cochlear development

PORCN becomes restricted to the medial domains along the longitudinal axis.

Wnt medial specification is regulated at the level of WNT ligand secretion.
Extracellular Vesicles Facilitate Large-Scale, Homogenizing Dynamic Exchange of Proteins and RNA Among Cultured Chinese Hamster Ovary (CHO) and Human Cells
Authors: Belliveau Jessica , Papoutsakis Eleftherios T.
Published: August 2021

Cells in culture are viewed as unique individuals in a large population communicating through extracellular molecules and, more recently extracellular vesicles (EVs). Our data here paints a different picture: the homogenizing effect of large-scale exchange of cellular material through EVs. We show that Chinese Hamster Ovary (CHO) cells dynamically produce and uptake EVs, to exchange proteins and RNAs at large-scale. To visualize the dynamic production and cellular uptake of EVs, we used correlative confocal microscopy and scanning electron microscopy, as well as flow cytometry to interrogate labeled cells. We employed cells expressing fluorescent proteins (GFP, miRFP703) and tagged cells with protein and RNA dyes. Flow cytometry was used to quantify the exchange of cellular RNA between cells through EVs. This EV-mediated dynamic exchange observed in CHO cultures was also observed in cultures of the human CHRF-288-11 cell line and of primary human hematopoietic stem and progenitor cells. This study demonstrates an underappreciated native cell communication and protein/RNA exchange mechanism mediated by EVs spanning cell type and lines, suggesting the proximity of cells in normal and tumor tissues may also result in prolific cellular exchange. This exchange would be expected to homogenize the cell-population cytoplasm and dynamically regulate cell proliferation and cellular state.
Organ protection by caloric restriction depends on activation of the de novo NAD+ synthesis pathway
Authors: Späth Martin Richard , Hoyer-Allo Karla Johanna Ruth , Johnsen Marc , Höhne Martin , Lucas Christina , Brodesser Susanne , Lackmann Jan-Wilm , Kiefer Katharina , Koehler Felix Carlo , Schiller Petra , Kubacki Torsten , Grundmann Franziska , Benzing Thomas , Schermer Bernhard , Burst Volker , Müller Roman-Ulrich
Published: August 2021

Therapeutic strategies to treat acute kidney injury (AKI) are lacking in clinical practice. Interestingly, preconditioning by hypoxia (HP) and caloric restriction (CR) is highly protective in rodent AKI models. However, the underlying molecular mechanisms of this process are unknown. A comparative transcriptome analysis of murine kidneys after HP and CR identified Kynureninase (KYNU) as a common downstream target. Using a newly generated KYNU-deficient mouse line, we show that KYNU strongly contributes to the protective effect of preconditioning. Metabolome, transcriptome and proteome analyses reveal the KYNU-dependent de novo nicotinamide adenine dinucleotide (NAD+) biosynthesis pathway as necessary for CR-associated maintenance of NAD+ levels. Importantly, the impact of CR on the de novo NAD+ biosynthesis pathway can be recapitulated in humans. These findings provide a valuable insight into the molecular mechanisms mediating protection upon preconditioning and point towards the de novo branch of NAD+ biosynthesis as a conserved target in nephroprotection.
Acoustic light-sheet microscopy
Authors: Wunderl S. , Ishijima A. , Susaki E. A. , Xu Z. , Song H. , Zha H. , Azuma T. , Sakuma I. , Fukuoka H. , Okada E. , Ueda H. R. , Takagi S. , Nakagawa K.
Published: August 2021

Light-sheet imaging of 3D objects with high spatial resolution remains an open challenge because of the trade-off between field-of-view (FOV) and axial resolution originating from the diffraction of light. We developed acoustic light-sheet microscopy (acoustic LSM), which actively manipulates the light propagation inside a large sample to obtain wide-field microscopic images deep inside a target. By accurately coupling a light-sheet illumination pulse into a planar acoustic pulse, the light-sheet can be continuously guided over large distances. We imaged a fluorescence-labeled transparent mouse brain for the FOVs of 19.3 × 12.4 mm2 and 9.7 × 5.9 mm2 with resolved microstructures and single cells deep inside the brain. Acoustic LSM creates new opportunities for the application of light-sheet in the field of industry to basic science.

One Sentence Summary

An acoustic-optical method overcomes a trade-off between field-of-view and axial resolution in light-sheet microscopy.