bluuebunny/crossref_metadata_2025 huggingface dataset:
Diagnostic Value of Quantitative Gray-Scale Analysis of Contrast-Enhanced Spectral Mammography for Benign and Malignant Breast Lesions
Authors: Lv Yongbin , Chi Xiaoxiao , Sun Bolin , Lin Shujuan , Xing Dong
Published: April 2020

Objective

The aim of the study was to quantitatively analyze the enhancement of breast lesions by contrast-enhanced spectral mammography to improve the differential diagnosis ability of contrast-enhanced spectral mammography.

Methods

A total of 283 patients with breast lesions admitted from August 2017 to May 2018 were retrospectively analyzed. Quantitative analysis of all enhancing lesions was performed to measure the gray values of the lesion region of interest (ROI), the area close to the lesion (ROI1), the area close to the chest wall (ROI2), and the chest wall (ROI3). Differences in gray values between different ROIs of benign and malignant lesions were compared. Taking the pathological results as the criterion standard, we used the receiver operating characteristic curve to evaluate the diagnostic efficacy of the ROI gray value and relative gray value (rROI) for the lesions.

Results

A total of 299 lesions were found in 283 patients, including 101 benign lesions and 198 malignant lesions. The ROI gray value, rROI1, rROI2, and rROI3 of malignant lesions were all significantly greater than those of benign lesions. The areas under the ROC curve of ROI, rROI1, rROI2, and rROI3 gray values of benign and malignant lesions were 0.795, 0.833, 0.812, and 0.741, respectively. The statistically significant difference in the area under the ROC curve was only found between rROI1 and ROI gray value and rROI1 had the greatest diagnostic value.

Conclusions

The gray value of malignant breast lesions was higher than that of benign lesions. The quantitative analysis of the gray value will help in the differential diagnosis of benign and malignant breast lesions.
Higher Mortality in Case of Small Left Atrium on Nongated Computed Tomography Pulmonary Angiography Is Associated With the Presence of Malignancy
Authors: Rozenbaum Zach , Granot Yoav , Halevi Carmel , Ziv-Baran Tomer , Berliner Shlomo , Aviram Galit
Published: April 2020

Purpose:

The purpose of this study was to evaluate the association between small left atria (LA) according to computed tomography pulmonary angiography (CTPA) and mortality among individuals without pulmonary embolism, and to examine which volumes begin to portend adverse outcomes.

Materials and Methods:

Left atrial volume indices (LAVIs) of 752 consecutive patients who underwent CTPA, in which pulmonary embolism were ruled out, were measured retrospectively using an automatic 4-chamber volumetric analysis software. Groups of 5 percentiles within the lower quartile were investigated, and the interquartile range (25th to 75th percentiles) was regarded as the control group.

Results:

Patients within the lower 25th LAVI percentiles (<33 mL/m2; n=188) were younger and had less cardiovascular morbidities, while malignancies were less common in the control group (LAVI: 33 to 54 mL/m2; n=376). Percentiles 5th to 25th did not demonstrate an independent association with mortality. After adjustment for baseline characteristics, the risk for 30-day and 1-year mortality was 5.6 (95% confidence interval: 2.1-14.8, P=0.001) and 6.1 (95% confidence interval: 2.4-15.1, P<0.001) times higher, respectively, among the lowest five LAVI percentiles (<24 mL/m2) compared with the control group. Among patients with small LA who died within 1 year, 83% had a diagnosis of malignancy. Albeit, only a minority (3%) of patients with malignancies had small LA.

Conclusions:

Individuals undergoing CTPA whose LAVI is within the lowest five percentiles have a markedly increased risk for short-term and long-term mortality. The risk can probably be attributed to an underlying malignancy. The feasibility of 4-chamber volumetric analysis while avoiding a time-consuming process due to the automatic properties enables the introduction of this feature to clinical practice.
Incisional hernia incidence following laparotomy for combat trauma: Investigating 15 years of US war surgery
Authors: Moas Victor , Eskridge Susan , Clouser Mary , Kurapaty Steven , Dyke Christopher , Souza Jason
Published: April 2020

BACKGROUND

While the incidence of incisional hernia (IH) following elective laparotomy has been well described, incidence following emergent laparotomy for combat trauma has been much less studied. This retrospective cohort investigates the latter to better describe the burden IH represents for the injured warfighter.

METHODS

Data were obtained from the Expeditionary Medical Encounter Database for service members who survived a combat-related injury between January 2002 and December 2016 and underwent abdominal surgery in the first 30 days after injury. Incisional hernia diagnosis at least 30 days after injury was determined from inpatient and outpatient records in the Military Health System's Medical Data Repository.

Means and SDs were reported for age and continuous Injury Severity Score, and frequency and percentages were reported for sex, branch of service, paygrade, mechanism of injury, Injury Severity Score, and maximum abdominal Abbreviated Injury Scale. Service members with and without a hernia diagnosis were compared using t test for continuous variables and χ2 or Fisher exact test (depending on cell size) for categorical variables.

Multivariate logistic regression models were used to examine relationships between IH diagnosis and the covariates previously mentioned. Data analysis was completed using SAS software version 9.4 (SAS Institute Inc., Cary, NC).

RESULTS

Of the 570 laparotomy patients, 109 (19.1%) developed IH. Of these, 58 (53%) were diagnosed within the first year after injury. An additional 21 (19%) were diagnosed within the following year, and 30 (28%) were diagnosed more than 2 years after injury. Presence of gastrointestinal injury, Abbreviated Injury Scale score of 4 and 5, and 5-year increments of age were positively associated with hernia formation.

CONCLUSION

The incidence of postlaparotomy IH in combat trauma is 19.1%, a considerable source of disability for injured warfighters. Further investigation into hernia-preventive closure strategies is warranted.

LEVEL OF EVIDENCE

Therapeutic study, level IV.
Enteric Conversion of Bladder-drained Pancreas as a Predictor of Outcomes in Almost 600 Recipients at a Single Center
Authors: Riad Samy M. , Keys Daniel O. , Jackson Scott , Vakil Viral , Berglund Danielle , Matas Arthur , Finger Erik B. , Kandaswamy Raja
Published: April 2020

Background.

Complications associated with bladder-drained pancreata necessitating enteric conversion are common. Data on the outcomes after enteric conversion are conflicting. We studied the association between enteric conversion and the pancreas graft rejection, loss, and mortality.

Methods.

At our center, 1117 pancreas transplants were performed between 2000 and 2016. We analyzed 593 recipients with bladder-drained pancreata, of which 523 received solitary transplants and 70 received simultaneous pancreas-kidney transplants. Kaplan-Meier function was used to estimate time to conversion by transplant type. Cox proportional hazards models were utilized to evaluate patient survival, death-censored graft survival, and acute rejection-free survival while treating conversion as a time-dependent covariate. Subsequently, we examined the association between timing of conversion and the same outcomes in the conversion cohort.

Results.

At 10 y posttransplant, 48.8% of the solitary pancreas recipients and 44.3% of simultaneous pancreas-kidney transplant recipients had undergone enteric conversion. The enteric conversion was associated with 85% increased risk of acute rejection (hazard ratio [HR] = 1.85; 95% confidence interval [CI] = 1.37-2.49; P < 0.001). However, the conversion was not associated with graft loss or mortality. In the conversion cohort, a longer interval from engraftment to conversion was associated with an 18% lower rejection rate (HR = 0.82; 95% CI = 0.708-0.960; P = 0.013) and a 22% better graft survival (HR = 0.78; 95% CI = 0.646-0.946; P = 0.01).

Conclusions.

Enteric conversion was associated with increased risk of rejection, but not increased risks of graft loss or mortality. The decision to convert should consider the increased rejection risk. A longer interval from engraftment to conversion appears favorable.
Is repeatability of metabolic rate influenced by social separation? A test with a teleost fish
Authors: Huang Yan , Fu Shijian , Cooke Steven J. , Xia Jigang
Published: April 2020

Metabolic rates are typically thought to have important influences on fitness and more broadly be relevant to the ecology and evolution of animals. Previous studies demonstrate that metabolic rates are repeatable to a certain extent under constant conditions, but how social conditions influence the repeatability of metabolic rate remains largely unknown. In this study, we investigated the repeatability of resting metabolic rate (RMR) in the highly social crucian carp (
Carassius auratus
) after being socially separated for different time periods relative to control fish that were not socially separated. We found that RMR was repeatable in fish in the control group, while the repeatability of RMR disappeared quickly (even within 7 days) when fish were exposed to social separation. This study is the first to our knowledge to examine the role of social separation for different time periods on the repeatability of intra-individual physiological variation in fish. We highlight that the inter-individual repeatability of metabolic rate can be substantial over time but was eliminated by social separation. The findings indicate that the repeatability of metabolic rate in fish is condition dependent, and that the change in repeatability of metabolic rate should not be overlooked when considering the ecological and evolutionary effects of environmental change.
Change in geomagnetic field intensity alters migration-associated traits in a migratory insect
Authors: Wan Guijun , Liu Ruiying , Li Chunxu , He Jinglan , Pan Weidong , Sword Gregory A. , Hu Gao , Chen Fajun
Published: April 2020

Geomagnetic field (GMF) intensity can be used by some animals to determine their position during migration. However, its role, if any, in mediating other migration-related phenotypes remains largely unknown. Here, we simulated variation in GMF intensity between two locations along the migration route of a nocturnal insect migrant, the brown planthopper
Nilaparvata lugens
, that varied by approximately 5 µT in field intensity. After one generation of exposure, we tested for changes in key morphological, behavioural and physiological traits related to migratory performance, including wing dimorphism, flight capacity and positive phototaxis. Our results showed that all three morphological and behavioural phenotypes responded to a small difference in magnetic field intensity. Consistent magnetic responses in the expression of the phototaxis-related
Drosophila-like cryptochrome 1
(
Cry1
) gene and levels of two primary energy substrates used during flight, triglyceride and trehalose, were also found. Our findings indicate changes in GMF intensity can alter the expression of phenotypes critical for insect migration and highlight the unique role of magnetoreception as a trait that may help migratory insects express potentially beneficial phenotypes in geographically variable environments.
Crowds in front of bottlenecks at entrances from the perspective of physics and social psychology
Authors: Adrian Juliane , Seyfried Armin , Sieben Anna
Published: April 2020

This article presents an interdisciplinary study of physical and social psychological effects on crowd dynamics based on a series of bottleneck experiments. Bottlenecks are of particular interest for applications such as crowd management and design of emergency routes because they limit the performance of a facility. In addition to previous work on the dynamics within the bottleneck, this study focuses on the dynamics in front of the bottleneck, more specifically, at entrances. The experimental set-up simulates an entrance scenario to a concert consisting of an entrance gate (serving as bottleneck) and a corridor formed by barriers. The parameters examined are the corridor width, degree of motivation and priming of the social norm of queuing. The analysis is based on head trajectories and questionnaires. We show that the density of persons per square metre depends on motivation and also increases continuously with increasing corridor width, meaning that a density reduction can be achieved by a reduction of space. In comparison to other corridor widths observed, the narrowest corridor is rated as being fairer, more comfortable and as showing less unfair behaviour. Pushing behaviour is seen as ambivalent: it is rated as unfair
and
listed as a strategy for faster access.
Freshwater snail feeding: lubrication-based particle collection on the water surface
Authors: Joo Soyoun , Jung Sunghwan , Lee Sungyon , Cowie Robert H. , Takagi Daisuke
Published: April 2020

The means by which aquatic animals such as freshwater snails collect food particles distributed on the water surface are of great interest for understanding life at the air–water interface. The apple snail
Pomacea canaliculata
stabilizes itself just below the air–water interface and manipulates its foot such that it forms a cone-shaped funnel into which an inhalant current is generated, thereby drawing food particles into the funnel to be ingested. We measured the velocity of this feeding current and tracked the trajectories of food particles around and on the snail. Our experiments indicated that the particles were collected via the free surface flow generated by the snail’s undulating foot. The findings were interpreted using a simple model based on lubrication theory, which considered several plausible mechanisms depending on the relative importance of hydrostatic pressure, capillary action and rhythmic surface undulation.
Identifying density-dependent interactions in collective cell behaviour
Authors: Browning Alexander P. , Jin Wang , Plank Michael J. , Simpson Matthew J.
Published: April 2020

Scratch assays are routinely used to study collective cell behaviour
in vitro
. Typical experimental protocols do not vary the initial density of cells, and typical mathematical modelling approaches describe cell motility and proliferation based on assumptions of linear diffusion and logistic growth. Jin
et al.
(Jin
et al
. 2016
J. Theor. Biol.
390
, 136–145 (
doi:10.1016/j.jtbi.2015.10.040
)) find that the behaviour of cells in scratch assays is density-dependent, and show that standard modelling approaches cannot simultaneously describe data initiated across a range of initial densities. To address this limitation, we calibrate an individual-based model to scratch assay data across a large range of initial densities. Our model allows proliferation, motility, and a direction bias to depend on interactions between neighbouring cells. By considering a hierarchy of models where we systematically and sequentially remove interactions, we perform model selection analysis to identify the minimum interactions required for the model to simultaneously describe data across all initial densities. The calibrated model is able to match the experimental data across all densities using a single parameter distribution, and captures details about the spatial structure of cells. Our results provide strong evidence to suggest that motility is density-dependent in these experiments. On the other hand, we do not see the effect of crowding on proliferation in these experiments. These results are significant as they are precisely the opposite of the assumptions in standard continuum models, such as the Fisher–Kolmogorov equation and its generalizations.
Assessing corrosion resistance of two-dimensional nanomaterial-based coatings on stainless steel substrates
Authors: Mujib Shakir Bin , Mukherjee Santanu , Ren Zhongkan , Singh Gurpreet
Published: April 2020

Two-dimensional (2D) materials have elicited considerable interest in the past decade due to a diverse array of novel properties ranging from high surface to mass ratios, a wide range of band gaps (insulating boron nitride (BN) to semiconducting transition metal dichalcogenides), high mechanical strength and chemical stability. Given the superior chemo-thermo-mechanical properties, 2D materials may provide transformative solution to a familiar yet persistent problem of significant socio-economic burden: the corrosion of stainless steel (SS). With this broader perspective, we investigate corrosion resistance properties of SS-coated with 2D nanomaterials; molybdenum disulfide (MoS2), BN, bulk graphite in 3.5 wt% aqueous NaCl solution. The nanosheets were prepared by a novel liquid phase exfoliation technique and the coatings were made by a paint brush to achieve uniformity. Open circuit potential (OCP) and potentiodynamic plots indicate the best corrosion resistance is provided by the MoS2coatings. Superior performance of the coating is attributed to low electronic conductivity, large flake size and uniform coverage of SS substrate, which probably impeded the corrosive ions from the solution from diffusing through the coating.
A dynamical model of oncotripsy by mechanical cell fatigue: selective cancer cell ablation by low-intensity pulsed ultrasound
Authors: Schibber E. F. , Mittelstein D. R. , Gharib M. , Shapiro M. G. , Lee P. P. , Ortiz M.
Published: April 2020

The method of
oncotripsy
, first proposed in Heyden & Ortiz (Heyden & Ortiz 2016
J. Mech. Phys. Solids
92
, 164–175 (
doi:10.1016/j.jmps.2016.04.016
)), exploits aberrations in the material properties and morphology of cancerous cells in order to ablate them selectively by means of tuned low-intensity pulsed ultrasound. We propose the dynamical model of oncotripsy that follows as an application of cell dynamics, statistical mechanical theory of network elasticity and ‘birth–death’ kinetics to describe the processes of damage and repair of the cytoskeleton. We also develop a reduced dynamical model that approximates the three-dimensional dynamics of the cell and facilitates parametric studies, including sensitivity analysis and process optimization. We show that the dynamical model predicts—and provides a conceptual basis for understanding—the oncotripsy effect and other trends in the data of Mittelstein
et al.
(Mittelstein
et al.
2019
Appl. Phys. Lett.
116
, 013701 (
doi:10.1063/1.5128627
)), for cells in suspension, including the dependence of cell-death curves on cell and process parameters.
Physician-patient relationship at HUEH: is it a “relationship to” or a “relationship between”
Authors: Jean Paul Axler , Leonard Yves Gardy , Saint Louis Rebecca , Camille Jackyvens , Delicat Hans Peter K. , Castra Roubytherson , Jean Ricardi , Delma Rubens , Decan Yvelo , Civil Marc Felix
Published: April 2020

To discover the relationship model in force between doctor and patient at the Haitian State University Hospital of Haïti (HUEH), a semi-directed survey was conducted among fifty patients. The qualitative analysis of the various interviews showed that patients were generally satisfied with their relationship with doctors. However, opinions are not sharing on their level information whether it is their illness or their therapeutic management; the results also showed that doctors had poor empathy. Hence our conclusion there is an unethical relationship in this institution, where doctors and patients coexist mainly in a “to” relationship and less so in a “between” relationship.
Between-centre differences for COVID-19 ICU mortality from early data in England
Authors: Qian Zhaozhi , Alaa Ahmed M. , van der Schaar Mihaela , Ercole Ari
Published: April 2020

The high numbers of COVID-19 patients developing severe respiratory failure has placed exceptional demands on ICU capacity around the world. Understanding the determinants of ICU mortality is important for surge planning and shared decision making. We used early data from the COVID-19 Hospitalisation in England Surveillance System (from the start of data collection 8th February -22nd May 2020) to look for factors associated with ICU outcome in the hope that information from such timely analysis may be actionable before the outbreak peak. Immunosuppressive disease, chronic cardiorespiratory/renal disease and age were key determinants of ICU mortality in a proportional hazards mixed effects model. However variation in site-stratified random effects were comparable in magnitude suggesting substantial between-centre variability in mortality. Notwithstanding possible ascertainment and lead-time effects, these early results motivate comparative effectiveness research to understand the origin of such differences and optimise surge ICU provision.
Particle Based Model for Airborne Disease Transmission
Authors: Dillon Michael B , Dillon Charles F
Published: April 2020

Executive Summary

Prior literature documents cases of airborne infectious disease transmission at distances ranging from ≥ 2 m to inter-continental in scale. Physics- and biology- based models describe the key aspects of these airborne disease transmission events, but important gaps remain. This report extends current approaches by developing a new, single-particle based theory that (a) assesses the likelihood of rare airborne infections (where individuals inhale either one or no infectious particles) and (b) explicitly accounts for the variability in airborne exposures and population susceptibilities within a geographic region of interest. For these hazards, airborne particle fate and transport is independent of particulate concentration, and so results for complex releases can be determined from the results of many single-particle releases.

This work is intended to provide context for both (a) the initial stages of a disease outbreak and (b) larger scale (≥ 2 m) disease spread, including distant disease “sparks” (low probability, unexpected disease transmission events that infect remote, susceptible populations). The physics of airborne particulate dispersion inherently constrains airborne disease transmission. As such, this work suggests results that,a priori, may be applicable to many airborne diseases.

Model Predictions

Modeling predictions of the single-particle transmission kernel suggest that outdoor airborne disease transmission events may occur episodically as the infection probabilities can vary over many orders of magnitude depending on the distance downwind; specific virus, prion, or microorganism; and meteorological conditions.

Model results suggest that, under the right conditions, an indoor infected person could spread disease to a similar, or greater, number of people downwind than in the building they occupy. However, the downwind, per-person infection probability is predicted to be lower than the within-building, per-person infection probability. This finding is limited to airborne transmission considerations.

This work suggests a new relative disease probability metric for airborne transmitted diseases. This metric, which is distinct from the traditional relative risk metric, is applicable when the rate at which the infectious agent losses infectivity in the atmosphere is ≲ 1 h-1.
Association of Digestive Symptoms and Hospitalization in Patients with SARS-CoV-2 Infection
Authors: Cholankeril George , Podboy Alexander , Aivaliotis Vasiliki Irene , Pham Edward A. , Spencer Sean , Kim Donghee , Hsing Ann , Ahmed Aijaz
Published: April 2020

Background

High rates of concurrent gastrointestinal manifestations have been noted in patients with COVID-19, however the association between these digestive manifestations and need for hospitalization has not been established.

Methods

Following expedited approval from our Institutional Review Board, we analyzed retrospectively collected data from consecutive patients with confirmed COVID-19 based on a positive polymerase chain reaction testing at our institution from March 03, 2020 to April 7, 2020. Baseline demographic, clinical, laboratory and patient-reported symptom data were collected at presentation in the emergency room. Multivariable logistic regression analyses were performed to evaluate the association between hospitalization and presence of gastrointestinal symptoms.

Results

During this study period, we identified 207 consecutive patients with confirmed COVID-19. 34.5% noted concurrent gastrointestinal symptoms; of which 90% of gastrointestinal symptoms were mild. In a multivariate regression model controlled for demographics and disease severity, an increased risk for hospitalization was noted in patients with any gastrointestinal symptom (adjusted OR 4.84 95% CI: 1.68-13.94]. Diarrhea was associated with a seven-fold higher likelihood for hospitalization (adjusted OR=7.58, 95% CI: 2.49-20.02, P <0.001) and nausea or vomiting had a four times higher odds. (adjusted OR 4.39, 95% CI: 1.61-11.4, P = 0.005).

Conclusion

We demonstrate that a significant portion of COVID19 patients have concurrent mild gastrointestinal symptoms and that the presence of these digestive symptoms is associated with a need for hospitalization. With the current focus on streamlining triaging efforts, first responders and frontline providers should consider assessing for digestive symptoms in their initial clinical evaluation and decision-making.
Molecular Characterization of Depression Trait and State
Authors: Shukla Rammohan , Newton Dwight F. , Sumitomo Akiko , Zare Habil , Mccullumsmith Robert , Lewis David A. , Tomoda Toshifumi , Sibille Etienne
Published: April 2020

Major Depressive disorder (MDD) is a chronic and recurrent brain disorder characterized by episode and remission phases, and poor therapeutic responses. The molecular correlates of MDD have been investigated in case-control settings, but the biological changes associated with trait (regardless of episode/remission) or state (illness phases) remains largely unknown, hence preventing therapeutic opportunities. To address this gap, we generated transcriptome profiles in the subgenual anterior cingulate cortex of MDD subjects who died during a single or recurrent episode or when in remission. We show that biological changes associated with MDD trait (inflammation, immune activation, reduced bioenergetics) are distinct from those associated with MDD phases or state (neuronal structure and function, neurotransmission). On the cell-type level, gene variability in subsets of GABAergic interneurons positive for corticotropin-releasing hormone, somatostatin or vasoactive-intestinal peptide was associated with MDD phases. Applying a probabilistic Bayesian network approach, we next show that gene modules enriched for immune system activation, cytokine response and oxidative stress, may exert causal roles across MDD phases. Finally, using a database of drug-induced transcriptome perturbations, we show that MDD-induced changes in putative causal pathways are antagonized by families of drugs associated with clinical response, including dopaminergic and monoaminergic ligands, and uncover potential novel therapeutic targets. Collectively, these integrative transcriptome analyses provide novel insight into cellular and molecular pathologies associated with trait and state MDD, and a method of drug discovery focused on disease-causing pathways.

One Sentence Summary

Integrating transcriptomic with various in-silico analyses identified cellular, molecular and putative biological causal pathways in trait and state depression
Embedded Enzyme Nanoclusters Depolymerize Polyesters via Chain-End Mediated Processive Degradation
Authors: DelRe Christopher , Kwon Junpyo , Kang Philjun , Ma Le , Hall Aaron , Ruan Zhiyuan , Zolkin Kyle , Li Tim , Ritchie Robert O. , Xu Ting
Published: April 2020

Many bioactive elements, long perceived as non-viable for material development, are now emerging as viable building blocks to encode material lifecycle and to ensure our harmonious existence with nature. Yet, there is a significant knowledge gap on how bio-elements interface with synthetic counterparts and function outside of their native environments. Here, we show that when enzymes are dispersed as nanoclusters confined within macromolecular matrices, their reaction kinetics, pathway, and substrate selectivity can be modulated to achieve programmable polymer degradation down to repolymerizable small molecules. Specifically, when enzyme nanoclusters are dispersed in trace amount (~0.02wt%) in polyesters, i.e. poly(caprolactone) (PCL) and poly(lactic acid) (PLA), chain-end mediated processive depolymerization can be realized, leading to scalable bioactive plastics for efficient sorting, such as recovery of precious metal filler from flexible electronics. Present studies demonstrate that when the enzyme is confined at dimensions similar to that of polymer chains, their behaviors are governed by the polymer conformation, segmental dynamic and thermal history, highlighting the importance to consider bioactive plastics differently from solution enzymology.
Interspecies differences in proteome turnover kinetics are correlated with lifespans and energetic demands
Authors: Swovick Kyle , Firsanov Denis , Welle Kevin A. , Hryhorenko Jennifer R. , Wise John P. , George Craig , Sformo Todd L. , Seluanov Andrei , Gorbunova Vera , Ghaemmaghami Sina
Published: April 2020

Cells continually degrade and replace damaged and old proteins. However, the high energetic demand of protein turnover generates reactive oxygen species (ROS) that compromise the long-term health of the proteome. Thus, the relationship between aging, protein turnover and energetic demand remains unclear. Here, we used a proteomic approach to measure rates of protein turnover within primary fibroblasts isolated from a number of species with diverse lifespans including the longest-lives rodent, the naked mole rat and the longest-lived mammal, the bowhead whale. We show that organismal lifespan is negatively correlated with turnover rates of highly abundant proteins. In comparison to mice, cells from long-lived naked mole rats have slower rates of protein turnover, lower levels of ATP production and reduced ROS levels. Despite having slower rates of protein turnover, naked mole rat cells tolerate protein misfolding stress more effectively than mouse cells. We suggest that in lieu of rapid constitutive turnover, long-lived species may have evolved more energetically efficient mechanisms for selective detection and clearance of damaged proteins.
Episodic memories: how do the hippocampus and the entorhinal ring attractors cooperate to create them?
Authors: Kovács Krisztián A.
Published: April 2020

The brain is capable of registering a constellation of events, encountered only once, as an episodic memory that can last for a lifetime. As evidenced by the clinical case of the patient HM, memories preserving their episodic nature still depend on the hippocampal formation, several years after being created, while semantic memories are thought to reside in neocortical areas. The neurobiological substrate of one-time learning and life-long storing in the brain, that must exist at the cellular and circuit level, is still undiscovered. The breakthrough is delayed by the fact that studies jointly investigating the rodent hippocampus and entorhinal cortex are mostly targeted at understanding the spatial aspect of learning. Here we present the concept of an entorhinal cortical module, termed EPISODE module, that could explain how the representations of different elements constituting episodic memories can be linked together. The new model that we propose here reconciles the structural and functional observations made in the entorhinal cortex and explains how the downstream hippocampal processing organizes the representations into meaningful sequences.
Antibiotic-dependent relationships between nasal microbiome and secreted proteome in chronic rhinosinusitis and nasal polyps
Authors: Kim Yi-Sook , Han Dohyun , Mo Ji-Hun , Kim Yong-Min , Kim Dae Woo , Choi Hyo-Guen , Park Jong-Wan , Shin Hyun-Woo
Published: April 2020

Background

Antibiotics are commonly prescribed to treat chronic rhinosinusitis (CRS); however, the effects of antibiotics on the microbiome and secreted proteome remain unknown in regard to CRS.

Objective

We analyzed the effects of antibiotics on the nasal microbiome and secreted proteome in the context of CRS using multi-omic analysis.

Methods

Nasal secretions were collected from 29 control, 30 CRS patients without nasal polyps (CRSsNP), and 40 CRS patients with nasal polyps (CRSwNP). A total of 99 subjects were divided into two groups that included subjects who had taken antibiotics 3 months prior to sampling (ABX) and those who had not (NABX). We performed 16S rDNA sequence analyses and Orbitrap mass spectrometry-based proteomic analyses in data-independent acquisition (DIA) on the nasal secretions. Spearman correlation was used to assess the correlations between the nasal microbiome and secreted proteome.

Results

We observed a strong association between the nasal microbiome and secreted proteome according to disease status. Antibiotic use reduced differences in the microbial community and secreted proteome according to disease status. Interestingly, in nasal polyp (NP) patients, antibiotics exhibited strong effects not only on the nasal microbiome and the secreted proteome but also on their associations. Additionally, their correlations were strengthened in subjects who had taken antibiotics.

Conclusion

Integrative analyses revealed that the correlations between the microbiome and the secreted proteome could be altered and strengthened in subjects who used antibiotics. These findings provide novel insight into the effects of antibiotics on the nasal environment and the host responses in CRS.
The Injury Response to DNA Damage Promotes Anti-Tumor Immunity
Authors: Sriram Ganapathy , Milling Lauren , Chen Jung-Kuei , Abraham Wuhbet , Handly Erika D. , Irvine Darrell J. , Yaffe Michael B.
Published: April 2020

Inhibition of immune checkpoints has shown promising results in the treatment of certain tumor types. However, the majority of cancers do not respond to immune checkpoint inhibition (ICI) treatment, indicating the need to identify additional modalities that enhance the response to immune checkpoint blockade. In this study, we identified a tumor-tailored approach usingex-vivoDNA damaging chemotherapy-treated tumor cells as a live injured cell adjuvant. Using an optimizedex vivosystem for dendritic cell-mediated T-cell IFN-γ induction in response to DNA-damaged tumor cells, we identified specific dose-dependent treatments with etoposide and mitoxantrone that markedly enhance IFN-γ production by T-cells. Unexpectedly, the immune-enhancing effects of DNA damage failed to correlate with known markers of immunogenic cell death or with the extent of apoptosis or necroptosis. Furthermore, dead tumor cells alone were not sufficient to promote DC cross-presentation and induce IFN-γ in T-cells. Instead, the enhanced immunogenicity resided in the fraction of injured cells that remained alive, and required signaling through the RIPK1, NF-kB and p38MAPK pathways. Directin vivotranslation of these findings was accomplished by intra-tumoral injection ofex vivoetoposide-treated tumor cells as an injured cell adjuvant, in combination with systemic anti-PD1/CTLA4 antibodies. This resulted in increased intra-tumoral CD103+dendritic cells and circulating tumor antigen-specific CD8+T-cells, leading to enhanced anti-tumor immune responses and improved survival. The effect was abrogated in BATF3-deficient mice indicating that BATF3+DCs are required for appropriate T-cell stimulation by live but injured DNA-damaged tumor cells. Notably, injection of the free DNA-damaging drug directly into the tumor failed to elicit such an enhanced anti-tumor response as a consequence of simultaneous damage to dendritic cells and T-cells. Finally, the DNA damage induced injured cell adjuvant and systemic ICI combination, but not ICI alone, induced complete tumor regression in a subset of mice who were then able to reject tumor re-challenge, indicating induction of a long-lasting anti-tumor immunological memory by the injured cell adjuvant treatmentin vivo.
Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice
Authors: Aryal Sameer , Longo Francesco , Klann Eric
Published: April 2020

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene-specificity of altered mRNA translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA-Seq on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in ribosome footprint abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state, and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.
In vitroEvolution of Antibody Affinity via Insertional Mutagenesis Scanning of an Entire Antibody Variable Region
Authors: Skamaki Kalliopi , Emond Stephane , Chodorge Matthieu , Andrews John , Rees D. Gareth , Cannon Daniel , Popovic Bojana , Buchanan Andrew , Minter Ralph , Hollfelder Florian
Published: April 2020

We report the first systematic combinatorial exploration of affinity enhancement of antibodies by insertions and deletions (InDels). Transposon-based introduction of InDels via the method TRIAD was used to generate large libraries with random in-frame InDels across the entire scFv gene that were further recombined and screened by ribosome display. Knowledge of potential insertion points from TRIAD libraries formed the basis of exploration of length and sequence diversity of novel insertions by insertional-scanning mutagenesis (ISM). An overall 256-fold affinity improvement of an anti-IL-13 antibody BAK1 as a result of InDel mutagenesis and combination with known point mutations validates this approach and suggests that the results of this InDel approach and conventional exploration of point mutations can synergize to generate antibodies with higher affinity.

Significance

Insertion/deletion (InDel) mutations play key roles in genome and protein evolution. Despite their prominence in evolutionary history, the potential of InDels for changing function in protein engineering by directed evolution remains unexplored. Instead point mutagenesis is widely used. Here we create antibody libraries containing InDels and demonstrate that affinity maturation can be achieved in this way, establishing an alternative to the point mutation strategies employed in all previous in vitro selections. These InDels mirror the observation of considerable length variation in loops of natural antibodies originating from the same germline genes and be combined with point mutations, making both natural sources of functional innovation available for artificial evolution in the test tube.
Flood-induced interspecific interactions in spring-fed tributary as an ecosystem function of heterogeneous river networks
Authors: Sakai Masaru , Wakiya Ryoshiro , Hoshi Gosuke
Published: April 2020

Understanding the migratory community dynamics of river networks is important for maintaining lotic system integrity. River animals migrate to their preferred habitats in spatiotemporally heterogeneous river environments. Spring-fed habitats are uniquely characterized by stable temperature and flow regimes, which create suitable spawning habitats for the chum salmonOncorhynchus keta. O. ketaexhibits “run up” to its birthplace for spawning, especially during floods. Because the eggs deposited by this anadromous fish are nutritious and actively consumed by freshwater animals, the location and timing ofO. ketaspawning events affect the spatiotemporal accumulation of mobile consumers. In this study, we examined changes in temporal population density in spawningO. ketaand a mobile consumer (juvenileO. masou masou) in a lowland, spring-fed tributary in northern Japan during a 48.5-mm autumn rainfall event. In both species, population density increased, and then decreased, after the rainfall event. InO. keta, these changes were closely associated with rainfall intensity, whereas inO. masou masouthe peak was delayed until 3 days after the rainfall event. A comparison of the gut contents ofO. masou masousampled from a spring-fed tributary and an adjacent non-spring-fed tributary indicated greater consumption ofO. ketaeggs in the spring-fed tributary. These results suggested that preferential migration ofO. ketainto spring-fed tributaries for spawning induces subsequent accumulation of juvenileO. masou masou, in turn increasingO. ketaegg consumption. These findings improve our understanding of community dynamics during floods in a heterogeneous river network environment.
Rapid and sensitive direct detection and identification of poliovirus from stool and environmental surveillance samples using nanopore sequencing
Authors: Shaw Alexander G. , Majumdar Manasi , Troman Catherine , O’Toole Áine , Benny Blossom , Abraham Dilip , Praharaj Ira , Kang Gagandeep , Sharif Salmaan , Masroor Alam Muhammad , Shaukat Shahzad , Angez Mehar , Khurshid Adnan , Mahmood Nayab , Arshad Yasir , Rehman Lubna , Mujtaba Ghulam , Akthar Ribqa , Salman Muhammad , Klapsa Dimitra , Hajarha Yara , Asghar Humayun , Bandyopadhyay Ananda , Rambaut Andrew , Martin Javier , Grassly Nicholas
Published: April 2020

Global poliovirus surveillance involves virus isolation from stool and environmental samples, intratypic differential (ITD) by PCR and sequencing of the VP1 region to distinguish vaccine (Sabin), vaccine-derived and wild-type polioviruses and ensure an appropriate response. This cell-culture algorithm takes 2-3 weeks on average between sample receipt and sequencing. Direct detection of viral RNA using PCR allows faster detection but has traditionally faced challenges related to poor sensitivity and difficulties in sequencing common samples containing poliovirus and enterovirus mixtures. We present a nested PCR and nanopore sequencing protocol that allows rapid (<3 days) and sensitive direct detection and sequencing of polioviruses in stool and environmental samples. We developed barcoded primers and a real-time analysis platform that generate accurate VP1 consensus sequences from multiplexed samples. The sensitivity and specificity compared with cell-culture were 90.9% (95% Confidence Interval: 75.7-98.1%) and 99.2% (95.5-100.0%) for wild-type 1 poliovirus, 92.5% (79.6-98.4%) and 98.7% (95.4-99.8%) for vaccine and vaccine-derived serotype 2 poliovirus, and 88.3% (81.2-93.5%) and 93.2% (88.6-96.3%) for Sabin 1 and 3 poliovirus alone or in mixtures when tested on 155 stool samples in Pakistan. Variant analysis of sequencing reads also allowed identification of polioviruses and enteroviruses in artificial mixtures and was able to distinguish complex mixtures of polioviruses in environmental samples. The median identity of consensus nanopore sequences with Sanger or Illumina sequences from the same samples was >99.9%. This novel method shows promise as a faster and safer alternative to cell-culture for the detection and real-time sequencing of polioviruses in stool and environmental samples.
Mycobacteriumphage Butters-encoded proteins contribute to host defense against viral attack
Authors: Mageeney Catherine M. , Mohammed Hamidu T. , Dies Marta , Anbari Samira , Cudkevich Netta , Chen Yanyan , Buceta Javier , Ware Vassie C.
Published: April 2020

A diverse set of prophage-mediated mechanisms protecting bacterial hosts from infection has been recently uncovered within Cluster N mycobacteriophages. In that context, we unveil a novel defense mechanism in Cluster N prophage Butters. By using bioinformatics analyses, phage plating efficiency experiments, microscopy, and immunoprecipitation assays, we show that Butters genes located in the central region of the genome play a key role in the defense against heterotypic viral attack. Our study suggests that a two component system articulated by interactions between protein products of genes30and31confers defense against heterotypic phage infection by PurpleHaze or Alma, but is insufficient to confer defense against attack by the heterotypic phage Island3. Therefore, based on heterotypic phage plating efficiencies on the Butters lysogen, additional prophage genes required for defense are implicated.

IMPORTANCE

Many sequenced bacterial genomes including pathogenic bacteria contain prophages. Some prophages encode defense systems that protect their bacterial host against heterotypic viral attack. Understanding the mechanisms undergirding these defense systems will be critical to development of phage therapy that circumvents these defenses. Additionally, such knowledge will help engineer phage-resistant bacteria of industrial importance.
Spatial Transcriptional Mapping of the Human Nephrogenic Program
Authors: Lindström Nils O. , Sealfon Rachel , Chen Xi , Parvez Riana , Ransick Andrew , De Sena Brandine Guilherme , Guo Jinjin , Hill Bill , Tran Tracy , Kim Albert D. , Zhou Jian , Tadych Alicja , Watters Aaron , Wong Aaron , Lovero Elizabeth , Grubbs Brendan H. , Thornton Matthew E. , McMahon Jill A. , Smith Andrew D. , Ruffins Seth W. , Armit Chris , Troyanskaya Olga G. , McMahon Andrew P.
Published: April 2020

Congenital abnormalities of the kidney and urinary tract are amongst the most common birth defects affecting 3% of newborns. The human kidney develops over a 30-week period in which a nephron progenitor pool gives rise to around a million nephrons. To establish a framework for human nephrogenesis, we spatially resolved a stereotypical process by which equipotent nephron progenitors generate a nephron anlagen, then applied data-driven approaches to construct three-dimensional protein maps on anatomical models of the nephrogenic program. Single cell RNA sequencing identified novel progenitor states which were spatially mapped to the nephron anatomy enabling the generation of functional gene-networks predicting interactions within and between nephron cell-types. Network mining identified known developmental disease genes and predicts new targets of interest. The spatially resolved nephrogenic program made available through the Human Nephrogenesis Atlas (https://sckidney.flatironinstitute.org/) will facilitate an understanding of kidney development and disease, and enhance efforts to generate new kidney structures.