bluuebunny/crossref_metadata_2025 huggingface dataset:
GBS-SBG - GBS Serotyping by Genome Sequencing
Authors: Tiruvayipati Suma , Tang Wen Ying , Barkham Timothy M. S. , Chen Swaine L.
Published: December 2021

Group B

Streptococcus

(GBS;

Streptococcus agalactiae

) is the most common cause of neonatal meningitis and a rising cause of sepsis in adults. Recently, it has also been shown to cause foodborne disease. As with many other bacteria, the polysaccharide capsule of GBS is antigenic, enabling its use for strain serotyping. Recent advances in DNA sequencing have made sequence-based typing attractive (as has been implemented for several other bacteria, including

Escherichia coli

,

Klebsiella pneumoniae

species complex,

Streptococcus pyogenes

, and others). For GBS, existing WGS-based serotyping systems do not provide complete coverage of all known GBS serotypes (specifically including subtypes of serotype III), and none are simultaneously compatible with the two most common data types, raw short reads and assembled sequences. Here, we create a serotyping database (GBS-SBG, GBS Serotyping by Genome Sequencing), with associated scripts and running instructions, that can be used to call all currently described GBS serotypes, including subtypes of serotype III, using both direct short-read- and assembly-based typing. We achieved higher concordance using GBS-SBG on a previously reported data set of 790 strains. We further validated GBS-SBG on a new set of 572 strains, achieving 99.8% concordance with PCR-based molecular serotyping using either short-read- or assembly-based typing. The GBS-SBG package is publicly available and will hopefully accelerate and simplify serotyping by sequencing for GBS.
Epidemiology and population structure of Haemophilus influenzae causing invasive disease
Authors: Carrera-Salinas Anna , González-Díaz Aida , Calatayud Laura , Mercado-Maza Julieta , Puig Carmen , Berbel Dàmaris , Càmara Jordi , Tubau Fe , Grau Imma , Domínguez M. Ángeles , Ardanuy Carmen , Martí Sara
Published: December 2021

This study provides an update on invasive

Haemophilus influenzae

disease in Bellvitge University Hospital (2014–2019), reporting its evolution from a previous period (2008–2013) and analysing the non-typeable

H. influenzae

(NTHi) population structure using a clade-related classification. Clinical data, antimicrobial susceptibility and serotyping were studied and compared with those of the previous period. Population structure was assessed by multilocus sequence typing (MLST), SNP-based phylogenetic analysis and clade-related classification. The incidence of invasive

H. influenzae

disease remained constant between the two periods (average 2.07 cases per 100 000 population), while the 30 day mortality rate decreased (20.7–14.7 %, respectively). Immunosuppressive therapy (40 %) and malignancy (36 %) were the most frequent comorbidities. Ampicillin and fluoroquinolone resistance rates had increased between the two periods (10–17.6 % and 0–4.4 %, respectively). NTHi was the main cause of invasive disease in both periods (84.3 and 85.3 %), followed by serotype f (12.9 and 8.8 %). NTHi displayed high genetic diversity. However, two clusters of 13 (n=20) and 5 sequence types (STs) (n=10) associated with clade V included NTHi strains of the most prevalent STs (ST3 and ST103), many of which showed increased frequency over time. Moreover, ST103 and ST160 from clade V were associated with β-lactam resistance. Invasive

H. influenzae

disease is uncommon, but can be severe, especially in the elderly with comorbidities. NTHi remains the main cause of invasive disease, with ST103 and ST160 (clade V) responsible for increasing β-lactam resistance over time.
Orchestrating a heist: uptake and storage of metals by apicomplexan parasites
Authors: Sloan Megan A. , Aghabi Dana , Harding Clare R.
Published: December 2021

The acquisition and storage of metals has been a preoccupation of life for millennia. Transition metals, in particular iron, copper and zinc, have vital roles within cells. However, metals also make dangerous cargos; inappropriate uptake or storage of transition metals leads to cell death. This paradox has led to cells developing elegant and frequently redundant mechanisms for fine-tuning local metal concentrations. In the context of infection, pathogens must overcome further hurdles, as hosts act to weaponize metal availability to prevent pathogen colonization and spread. Here, we detail the methods used by the Apicomplexa, a large family of eukaryotic parasites, to obtain and store essential metals.
Impact of growth media and pressure on the diversity and antimicrobial activity of isolates from two species of hexactinellid sponge
Authors: Koch Matthew J. , Hesketh-Best Poppy J. , Smerdon Gary , Warburton Philip J. , Howell Kerry , Upton Mathew
Published: December 2021

Access to deep-sea sponges brings with it the potential to discover novel antimicrobial candidates, as well as novel cold- and pressure-adapted bacteria with further potential clinical or industrial applications. In this study, we implemented a combination of different growth media, increased pressure and high-throughput techniques to optimize recovery of isolates from two deep-sea hexactinellid sponges, Pheronema carpenteri and Hertwigia sp., in the first culture-based microbial analysis of these two sponges. Using 16S rRNA gene sequencing for isolate identification, we found a similar number of cultivable taxa from each sponge species, as well as improved recovery of morphotypes from P. carpenteri at 22–25 °C compared to other temperatures, which allows a greater potential for screening for novel antimicrobial compounds. Bacteria recovered under conditions of increased pressure were from the phyla

Proteobacteria

,

Actinobacteria

and

Firmicutes

, except at 4 %O2/5 bar, when the phylum

Firmicutes

was not observed. Cultured isolates from both sponge species displayed antimicrobial activity against Micrococcus luteus, Staphylococcus aureus and

Escherichia coli

.
Incidence of COVID-19 reinfection: an analysis of outpatient-based data in the United States of America
Authors: Azam Mahalul , Pribadi Feddy Setio , Rahadian Arief , Saefurrohim Muhammad Zakki , Dharmawan Yudhy , Fibriana Arulita Ika , Lestarini Ima Arum , Aljunid Syed Mohamed
Published: December 2021

Objectives

COVID-19 reinfection cases are evidence of antibody waning in recovered individuals. Previous studies had reported cases of COVID-19 reinfection both in hospital-based and community-based data. However, limited studies reported COVID-19 reinfection in large community-based data. The present study aimed to provide the incidence of COVID-19 reinfection based on secondary data in the U.S.

Study design

Cross-sectional study

Methods

A cross-sectional study was conducted using secondary data provided by COVID-19 Research Database, i.e., Healthjump. Reinfection were defined as diagnosed COVID-19 (U07.1= confirmed virus identified) twice with ≥90 days interval between diagnosis. Age, gender, and region data were also explored. A Chi-square test continued by a binary logistic regression was conducted to determine the association between parameters. Data collecting and processing were done in the Amazon workspace.

Results

The study revealed 3,778 reinfection cases of 116,932 COVID-19 infected cases (3.23%). Reinfection cases were more common in females (3.35%) than males (3.23%). Elderly subjects were the highest incidence (5.13%), followed by adult (4.14%), young adults (2.35%), and children (1.09%). Proportion in the region of living northeast was the highest (3.68%), compared to the south (3.49%), west (2.59%), and midwest (2.48%).

Conclusion

The incidence of COVID-19 reinfection was 3.23%, suggesting our concern with COVID-19 management and future research to understand COVID-19 reinfection better. The incident is more likely to occur in female and elderly patients.
A qualitative mathematical model of immunocompetence with applications to SARS-CoV-2 immunity
Authors: Burgos-Salcedo Javier
Published: December 2021

A qualitative mathematical model of the notion of immunocompetence is developed, based on the formalism of Memory Evolutive Systems (MES), from which, immunocompetence is defined as an emergent structure of a higher order arising from the signal networks that are established between effector cells and molecules of the immune response in the presence of a given antigen. In addition, a possible mechanism of functorial nature is proposed, which may explain how immunocompetence is achieved in an organism endowed with innate and adaptive components of its immune system. Finally, a practical method to measure the immunocompetence status is established, using elements of the theory of small random graphs and taking into account the characteristics of the immune networks, established through transcriptional studies, of patients with severe COVID-19 and healthy patients, assuming that both types of patients were vaccinated with an effective biological against SARS-CoV-2.
Evaluation of transplacental transfer of mRNA vaccine products and functional antibodies during pregnancy and early infancy
Authors: Prahl Mary , Golan Yarden , Cassidy Arianna G. , Matsui Yusuke , Li Lin , Alvarenga Bonny , Chen Hao , Jigmeddagva Unurzul , Lin Christine Y. , Gonzalez Veronica J. , Chidboy Megan A. , Warrier Lakshmi , Buarpung Sirirak , Murtha Amy P. , Flaherman Valerie J. , Greene Warner C. , Wu Alan H.B. , Lynch Kara L. , Rajan Jayant , Gaw Stephanie L.
Published: December 2021

Studies are needed to evaluate the safety and effectiveness of mRNA SARS-CoV-2 vaccination during pregnancy, and the levels of protection provided to their newborns through placental transfer of antibodies. We evaluated the transplacental transfer of mRNA vaccine products and functional anti-SARS-CoV-2 antibodies during pregnancy and early infancy in a cohort of 20 individuals vaccinated during pregnancy. We found no evidence of mRNA vaccine products in maternal blood, placenta tissue, or cord blood at delivery. However, we found time-dependent efficient transfer of IgG and neutralizing antibodies to the neonate that persisted during early infancy. Additionally, using phage immunoprecipitation sequencing, we found a vaccine-specific signature of SARS-CoV-2 Spike protein epitope binding that is transplacentally transferred during pregnancy. In conclusion, products of mRNA vaccines are not transferred to the fetus during pregnancy, however timing of vaccination during pregnancy is critical to ensure transplacental transfer of protective antibodies during early infancy.
Theta and gamma hippocampal–neocortical oscillations during the episodic-like memory test: impairment in epileptogenic rats
Authors: Malkov Anton , Shevkova Ludmila , Latyshkova Aleksandra , Kitchigina Valentina
Published: December 2021

Cortical oscillations in different frequency bands have been shown to be intimately involved in exploration of environment and cognition. Here, the local field potentials in the hippocampus, the medial prefrontal cortex (mPFC), and the medial entorhinal cortex (mEC) were recorded simultaneously in rats during the execution of the episodic-like memory task. The power of hippocampal theta (~4-10 Hz), slow gamma (~25-50 Hz), and fast gamma oscillations (~55-100 Hz) was analyzed in all structures examined. Particular attention was paid to the theta coherence between three mentioned structures. The modulation of the power of gamma rhythms by the phase of theta cycle during the execution of the episodic-like memory test by rats was also closely studied. Healthy rats and rats one month after kainate-induced status epilepticus (SE) were examined. Paroxysmal activity in the hippocampus (high amplitude interictal spikes), excessive excitability of animals, and the death of hippocampal and dentate granular cells in rats with kainate-evoked SE were observed, which indicated the development of seizure focus in the hippocampus (epileptogenesis). One month after SE, the rats exhibited a specific impairment of episodic memory for the what-where-when triad: unlike healthy rats, epileptogenic SE animals did not identify the objects during the test. This impairment was associated with the changes in the characteristics of theta and gamma rhythms and specific violation of theta coherence and theta/gamma coupling in these structures in comparison with the healthy animals. We believe that these disturbances in the cortical areas play a role in episodic memory dysfunction in kainate-treated animals. These findings can shed light on the mechanisms of cognitive deficit during epileptogenesis.
Characterization of the significant decline in humoral immune response six months post-SARS-CoV-2 mRNA vaccination: A systematic review
Authors: Notarte Kin Israel , Guerrero-Arguero Israel , Velasco Jacqueline Veronica , Ver Abbygail Therese , de Oliveira Maria Helena Santos , Catahay Jesus Alfonso , Khan Md. Siddiqur Rahman , Pastrana Adriel , Juszczyk Grzegorz , Torrelles Jordi B. , Lippi Giuseppe , Martinez-Sobrido Luis , Henry Brandon Michael
Published: December 2021

Accumulating evidence shows a progressive decline in the efficacy of coronavirus disease 2019 (COVID-19) mRNA vaccines such as Pfizer-BioNTech (mRNA BNT161b2) and Moderna (mRNA-1273) in preventing breakthrough infections due to diminishing humoral immunity over time. Thus, this review characterizes the kinetics of anti-SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) antibodies after the second dose of a primary cycle of COVID-19 mRNA vaccination. A systematic search of literature was performed and a total of 18 studies (N=15,980) were identified and reviewed. The percent difference of means of reported antibody titers were then calculated to determine the decline in humoral response after the peak levels post-vaccination. Findings revealed that the peak humoral response was reached at 21-28 days after the second dose, after which serum levels progressively diminished at 4-6 months post-vaccination. Additionally, results showed that regardless of age, sex, serostatus and presence of comorbidities, longitudinal data reporting antibody measurement exhibited a decline of both anti-receptor binding domain (RBD) IgG and anti-spike IgG, ranging from 94-95% at 90-180 days and 55-85% at 140-160 days, respectively, after the peak antibody response. This suggests that the rate of antibody decline may be independent of patient-related factors and peak antibody titers but mainly a function of time and antibody class/molecular target. Hence, this study highlights the necessity of more efficient vaccination strategies to provide booster administration in attenuating the effects of waning immunity, especially in the appearance of new variants of concerns (VoCs).
A single latent channel is sufficient for biomedical image segmentation
Authors: Kist Andreas M. , Schützenberger Anne , Dürr Stephan , Semmler Marion
Published: December 2021

Glottis segmentation is a crucial step to quantify endoscopic footage in laryngeal high-speed videoendoscopy. Recent advances in using deep neural networks for glottis segmentation allow a fully automatic workflow. However, exact knowledge of integral parts of these segmentation deep neural networks remains unknown. Here, we show using systematic ablations that a single latent channel as bottleneck layer is sufficient for glottal area segmentation. We further show that the latent space is an abstraction of the glottal area segmentation relying on three spatially defined pixel subtypes. We provide evidence that the latent space is highly correlated with the glottal area waveform, can be encoded with four bits, and decoded using lean decoders while maintaining a high reconstruction accuracy. Our findings suggest that glottis segmentation is a task that can be highly optimized to gain very efficient and clinical applicable deep neural networks. In future, we believe that online deep learning-assisted monitoring is a game changer in laryngeal examinations.
Test-retest reproducibility of in vivo magnetization transfer ratio and saturation index in mice at 9.4 Tesla
Authors: Rahman Naila , Ramnarine Jordan , Xu Kathy , Brown Arthur , Baron Corey A.
Published: December 2021

Background

Magnetization transfer saturation (MTsat) imaging was developed to reduce T1 dependence and improve specificity to myelin compared to the widely used MT ratio (MTR), while maintaining a feasible scan time. Knowledge of MTsat reproducibility is necessary to apply MTsat in preclinical neuroimaging.

Purpose

To assess the test-retest reproducibility of MTR and MTsat in the mouse brain at 9.4 T and calculate sample sizes required to detect various effect sizes.

Study Type

Prospective

Animal Model

C57Bl/6 Mouse Model (6 females and 6 males, aged 12 – 14 weeks)

Field Strength/Sequence

Magnetization Transfer Imaging at 9.4 T

Assessment

All mice were scanned at two timepoints (5 days apart). MTR and MTsat maps were analyzed using mean region-of-interest (ROI), and whole brain voxel-wise analysis.

Statistical Tests

Bland-Altman plots assessed biases between test and retest measurements. Test-retest reproducibility was evaluated via between and within-subject coefficients of variation (CV). Sample sizes required were calculated (at a 95 % significance level and power of 80 %), given various minimum detectable effect sizes, using both between and within-subject approaches.

Results

Bland-Altman plots showed negligible biases between test and retest sessions. ROI-based and voxel-wise CVs revealed high reproducibility for both MTR (ROI: CVs < 8 %) and MTsat (ROI: CVs < 10 %). With a sample size of 6, changes on the order of 15% can be detected in MTR and MTsat, both between and within subjects, while smaller changes (6 – 8 %) require sample sizes of 10 – 15 for MTR, and 15 – 20 for MTsat.

Data Conclusion

MTsat exhibits comparable reproducibility to MTR, while providing sensitivity to myelin with less T1 dependence than MTR. Our findings suggest both MTR and MTsat can detect moderate changes, common in pathologies, with feasible preclinical sample sizes.
Evaluating denoising strategies in resting-state fMRI in traumatic brain injury (EpiBioS4Rx)
Authors: Weiler Marina , Casseb Raphael F. , de Campos Brunno M. , Crone Julia S. , Lutkenhoff Evan S. , Vespa Paul M. , Monti Martin M. ,   for the EpiBioS4Rx Study Group
Published: December 2021

Objective

Resting-state functional MRI is increasingly used in the clinical setting and is now included in some diagnostic guidelines for severe brain injury patients. However, to ensure high-quality data, one should mitigate fMRI-related noise typical of this population. Therefore, we aimed to evaluate the ability of different preprocessing strategies to mitigate noise-related signal (i.e., in-scanner movement and physiological noise) in functional connectivity of traumatic brain injury patients.

Methods

We applied nine commonly used denoising strategies, combined into 17 pipelines, to 88 traumatic brain injury patients from the Epilepsy Bioinformatics Study for Anti-epileptogenic Therapy clinical trial (EpiBioS4Rx). Pipelines were evaluated by three quality control metrics across three exclusion regimes based on the participant’s head movement profile.

Results

While no pipeline eliminated noise effects on functional connectivity, some pipelines exhibited relatively high effectiveness depending on the exclusion regime. Once high-motion participants were excluded, the choice of denoising pipeline becomes secondary - although this strategy leads to substantial data loss. Pipelines combining spike regression with physiological regressors were the best performers, whereas pipelines that used automated data driven methods performed comparatively worse.

Conclusion

In this study, we report the first large-scale evaluation of denoising pipelines aimed at reducing noise-related functional connectivity in a clinical population known to be highly susceptible to in-scanner motion and significant anatomical abnormalities. If resting-state functional magnetic resonance is to be a successful clinical technique, it is crucial that procedures mitigating the effect of noise be systematically evaluated in the most challenging populations, such as traumatic brain injury datasets.
Discrete Protein Metric (DPM): A new image similarity metric to calculate accuracy of deep learning-generated cell focal adhesion predictions
Authors: Contreras Miguel , Bachman William , Long David S.
Published: December 2021

Understanding cell behaviors can provide new knowledge on the development of different pathologies. Focal adhesion (FA) sites are important sub-cellular structures that are involved in these processes. To better facilitate the study of FA sites, deep learning (DL) can be used to predict FA site morphology based on limited datasets (e.g., cell membrane images). However, calculating the accuracy score of these predictions can be challenging due to the discrete/point pattern like nature of FA sites. In the present work, a new image similarity metric, discrete protein metric (DPM), was developed to calculate FA prediction accuracy. This metric measures differences in distribution (d), shape/size (s), and angle (a) of FA sites between the predicted image and its ground truth image. Performance of the DPM was evaluated by comparing it to three other commonly used image similarity metrics: Pearson correlation coefficient (PCC), feature similarity index (FSIM), and Intersection over Union (IoU). A sensitivity analysis was performed by comparing changes in each metric value due to quantifiable changes in FA site location, number, aspect ratio, area, or orientation. Furthermore, accuracy score of DL-generated predictions was calculated using all four metrics to compare their ability to capture variation across samples. Results showed better sensitivity and range of variation for DPM compared to the other metrics tested. Most importantly, DPM had the ability to determine which FA predictions were quantitatively more accurate and consistent with qualitative assessments. The proposed DPM hence provides a method to validate DL-generated FA predictions and can be extended to evaluating other predicted or segmented discrete structures of biomedical relevance.
Developing A Deep Learning Natural Language Processing Algorithm For Automated Reporting Of Adverse Drug Reactions
Authors: McMaster Christopher , Chan Julia , Liew David FL , Su Elizabeth , Frauman Albert G , Chapman Wendy W , Pires Douglas EV
Published: December 2021

The detection of adverse drug reactions (ADRs) is critical to our understanding of the safety and risk-benefit profile of medications. With an incidence that has not changed over the last 30 years, ADRs are a significant source of patient morbidity, responsible for 5-10% of acute care hospital admissions worldwide. Spontaneous reporting of ADRs has long been the standard method of reporting, however this approach is known to have high rates of under-reporting, a problem that limits pharmacovigilance efforts. Automated ADR reporting presents an alternative pathway to increase reporting rates, although this may be limited by over-reporting of other drug-related adverse events.

We developed a deep learning natural language processing algorithm to identify ADRs in discharge summaries at a single academic hospital centre. Our model was developed in two stages: first, a pre-trained model (DeBERTa) was further pre-trained on 1.1 million unlabelled clinical documents; secondly, this model was fine-tuned to detect ADR mentions in a corpus of 861 annotated discharge summaries. This model was compared to a version without the pre-training step, and a model finetuned from the ClinicalBERT model, which has demonstrated state-of-the-art performance on other pharmacovigilance tasks. To ensure that our algorithm could differentiate ADRs from other drug-related adverse events, the annotated corpus was enriched for both validated ADR reports and confounding drug-related adverse events using. The final model demonstrated good performance with a ROC-AUC of 0.955 (95% CI 0.946 - 0.963) for the task of identifying discharge summaries containing ADR mentions, significantly outperforming the two comparator models.
Machine learning based preoperative analytics for the prediction of anastomotic insufficiency in colorectal surgery: a single-centre pilot study
Authors: Taha-Mehlitz Stephanie , Wentzler Larissa , Angehrn Fiorenzo , Hendie Ahmad , Ochs Vincent , Staartjes Victor E. , Flüe Markus von , Taha Anas , Steinemann Daniel
Published: December 2021

Introduction

Anastomotic insufficiency (AI) is a relatively common but grave complication after colorectal surgery. This study aims to determine whether AI can be predicted from simple preoperative data using machine learning (ML) algorithms.

Methods and analysis

In this retrospective analysis, patients undergoing colorectal surgery with creation of a bowel anastomosis from the University Hospital of Basel were included. Data was split into a training set (80%) and a test set (20%). The group of patients with AI was oversampled to a ratio of 50:50 in the training set and missing values were imputed. Known predictors of AI were included as inputs: age, BMI, smoking status, the Charlson Comorbidity Index, the American Society of Anesthesiologists score, type of operation, indication, haemoglobin and albumin levels, and renal function.

Results

Of the 593 included patients, 88 experienced AI. At internal validation on unseen patients from the test set, area under the curve (AUC) was 0.61 (95% confidence interval [CI]: 0.44-0.79), calibration slope was 0.16 (95% CI: −0.06-0.39) and calibration intercept was 0.06 (95% CI: 0.02-0.11). We observed a specificity of 0.67 (95% CI: 0.58-0.76), sensitivity of 0.36 (95% CI: 0.08-0.67), and accuracy of 0.64 (95% CI: 0.55-0.72).

Conclusion

By using 10 patient-related risk factors associated with AI, we demonstrate the feasibility of ML-based prediction of AI after colorectal surgery. Nevertheless, it is crucial to include multicenter data and higher sample sizes to develop a robust and generalisable model, which will subsequently allow for deployment of the algorithm in a web-based application.

Strengths and limitations of this study

To the best of our knowledge, this is the first study to establish a risk prediction model for anastomotic insufficiency in a perioperative setting in colon surgery.

Data from all patients that underwent colon surgery within 8 years at University Hospital Basel were included.

We evaluated the feasibility of developing a machine learning model that predicts the outcome by using well-known risk factors for anastomotic insufficiency.

Although our model showed promising results, it is crucial to validate our findings externally before clinical practice implications are possible.
Reliability of transcranial magnetic stimulation evoked potentials to detect the effects of theta-burst stimulation of the prefrontal cortex
Authors: Moffa Adriano H. , Nikolin Stevan , Martin Donel , Loo Colleen , Boonstra Tjeerd W.
Published: December 2021

Background

Transcranial magnetic stimulation (TMS) with simultaneous electroencephalography (EEG) is a novel method for assessing cortical properties outside the motor region. Theta burst stimulation (TBS), a form of repetitive TMS, can non-invasively modulate cortical excitability and has been increasingly used to treat psychiatric disorders by targetting the dorsolateral prefrontal cortex (DLPFC). The TMS-evoked potentials (TEPs) analysis has been used to evaluate cortical excitability changes after TBS. However, it remains unclear whether TEPs can detect the neuromodulatory effects of TBS.

Objectives

To confirm the reliability of TEP components within and between sessions and to measure changes in neural excitability induced by intermittent (iTBS) and continuous TBS (cTBS) applied to the left DLPFC.

Methods

Test-retest reliability of TEPs and TBS-induced changes in cortical excitability were assessed in twenty-four healthy participants by stimulating the DLPFC in five separate sessions, once with sham and twice with iTBS and cTBS. EEG responses were recorded of 100 single TMS pulses before and after TBS, and the reproducibility measures were quantified with the concordance correlation coefficient (CCC).

Results

The N100 and P200 components presented substantial reliability within the baseline block (CCCs>0.8) and moderate concordance between sessions (CCCmax≈0.7). Both N40 and P60 TEP amplitudes showed little concordance between sessions. Changes in TEP amplitudes after iTBS were marginally reliable for N100 (CCCmax=0.52), P200 (CCCmax=0.47) and P60 (CCCmax=0.40), presenting only fair levels of concordance at specific time points.

Conclusions

The present findings show that only the N100 and P200 components had good concordance between sessions. The reliability of earlier components may have been affected by TMS-evoked artefacts. The poor reliability to detect changes in neural excitability induced by TBS indicates that TEPs do not provide a precise estimate of the changes in excitability in the DLPFC or, alternatively, that TBS did not induce consistent changes in neural excitability.
Prolonged XPO1 inhibition is essential for optimal anti-leukemic activity in NPM1-mutated AML
Authors: Pianigiani Giulia , Gagliardi Andrea , Mezzasoma Federica , Rocchio Francesca , Tini Valentina , Bigerna Barbara , Sportoletti Paolo , Caruso Simona , Marra Andrea , Spinozzi Giulio , Shacham Sharon , Landesman Yosef , Quintarelli Concetta , Locatelli Franco , Martelli Maria Paola , Falini Brunangelo , Brunetti Lorenzo
Published: December 2021

NPM1 encodes for a nucleolar multifunctional protein and is the most frequently mutated gene in adult acute myeloid leukemia (AML). NPM1 mutations cause the aberrant accumulation of mutant NPM1 (NPM1c) in the cytoplasm of leukemic cells, that is mediated by the nuclear exporter Exportin-1 (XPO1). Recent work has demonstrated that the interaction between NPM1c and XPO1 promotes high homeobox (HOX) genes expression, which is critical for maintaining the leukemic state of NPM1-mutated cells. However, the XPO1 inhibitor Selinexor administered once or twice/week in early-phase clinical trials did not translate into clinical benefit for NPM1-mutated AML patients. Here, we demonstrate that this dosing strategy results in only temporary disruption of the XPO1-NPM1c interaction and transient HOX genes downregulation, limiting the efficacy of Selinexor in the context of NPM1-mutated AML. Since second-generation XPO1 inhibitors can be administered more frequently, we compared intermittent (twice/week) versus prolonged (5 days/week) XPO1 inhibition in NPM1-mutated AML models. Integrating in vitro and in vivo data, we show that only prolonged XPO1 inhibition results in stable HOX downregulation, cell differentiation and remarkable anti-leukemic activity. This study lays the groundwork for the accurate design of clinical trials with second-generation XPO1 inhibitors in NPM1-mutated AML.
Peptide Aggregation Induced Immunogenic Rupture (PAIIR)
Authors: Gunay Gokhan , Hamsici Seren , Lang Gillian A. , Lang Mark L. , Kovats Susan , Acar Handan
Published: December 2021

Under the influence of stress and membrane damage, cells undergo immunogenic cell death (ICD), which involves the release of damage associated molecular patterns (DAMPs), natural adjuvants for enhancing an immune response. In the presence of an antigen, released DAMPs can determine the type and magnitude of the immune response, and therefore the longevity and efficacy of an antigen-specific immunity. In the last decade, the immune response effect of ICD has been shown, yet there is no tool that can induce controlled ICD with predictable results, regardless of the cell type. We designed a peptide-based tool, called [II], for controlled damage to cell membrane to induce ICD and DAMPs release. Herein we describe a series of experiments that determine that the mechanism of action of [II] includes a caspase-dependent ICD and subsequent release of immune stimulating DAMPs, on various cell types. Moreover, we tested the hypothesis that controlled DAMP release via [II] in vivo was associated with enhancement of antigen-specific adaptive immunity with influenza hemagglutinin (HA) subunit vaccine. HA and [II] showed significantly higher HA specific IgG1 and IgG2a antibodies, compared to HA-only immunized mice, while the peptide itself did not elicit antibodies. In this paper, we demonstrate the first peptide-aggregation induced immunogenic rupture (PAIIR) approach as vaccine adjuvants for increasing both humoral and cellular immunity. In consideration of its ability to enhance IgG2a responses that are associated with heterosubtypic influenza virus protection, PAIIR is a promising adjuvant to promote universal protection upon influenza HA vaccination.
Sensitizing solid tumors to CAR-mediated cytotoxicity using synthetic antigens
Authors: Gamboa Lena , Zamat Ali H. , Vanover Daryll , Thiveaud Chloé A. , Peck Hannah E. , Phuengkham Hathaichanok , Sivakumar Anirudh , Harris Adrian M. , Dahotre Shreyas N. , Su Fang-Yi , Santangelo Philip J. , Kwong Gabriel A.
Published: December 2021

CAR T cell immunotherapy relies on CAR targeting of tumor-associated antigens, yet heterogenous antigen expression, interpatient variation, and off-tumor expression by healthy cells remain barriers. Here, we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by viral vectors. Using the RSV-F camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of αVHH CAR T cells to mice bearing VHH expressing tumors reduced tumor burden in multiple syngeneic mouse models of cancer, improved survival, induced epitope spread, and protected against tumor rechallenge. Our work supportsin situdelivery of synthetic antigens to treat antigen low or negative tumors with CAR T cells.
Plasma neutralization properties of the SARS-CoV-2 Omicron variant
Authors: Schmidt Fabian , Muecksch Frauke , Weisblum Yiska , Silva Justin Da , Bednarski Eva , Cho Alice , Wang Zijun , Gaebler Christian , Caskey Marina , Nussenzweig Michel C. , Hatziioannou Theodora , Bieniasz Paul D.
Published: December 2021

BACKGROUND

The Omicron SARS-CoV-2 variant has spread internationally and is responsible for rapidly increasing case numbers. The emergence of divergent variants in the context of a heterogeneous and evolving neutralizing antibody response in host populations might compromise protection afforded by vaccines or prior infection.

METHODS

We measured neutralizing antibody titers in 169 longitudinally collected plasma samples using pseudotypes bearing the Wuhan-hu-1 or the Omicron variant or a laboratory-designed neutralization-resistant SARS-CoV-2 spike (PMS20). Plasmas were obtained from convalescents who did or did not subsequently receive an mRNA vaccine, or naive individuals who received 3-doses of mRNA or 1-dose Ad26 vaccines. Samples were collected approximately 1, 5-6 and 12 months after initial vaccination or infection.

RESULTS

Like PMS20, the Omicron spike protein was substantially resistant to neutralization compared to Wuhan-hu-1. In convalescent plasma the median deficit in neutralizing activity against PMS20 or Omicron was 30- to 60-fold. Plasmas from recipients of 2 mRNA vaccine doses were 30- to 180- fold less potent against PMS20 and Omicron than Wuhan-hu-1. Notably, previously infected or two-mRNA dose vaccinated individuals who received additional mRNA vaccine dose(s) had 38 to 154-fold and 35 to 214-fold increases in neutralizing activity against Omicron and PMS20 respectively.

CONCLUSIONS

Omicron exhibits similar distribution of sequence changes and neutralization resistance as does a laboratory-designed neutralization-resistant spike protein, suggesting natural evolutionary pressure to evade the human antibody response. Currently available mRNA vaccine boosters, that may promote antibody affinity maturation, significantly ameliorate SARS-CoV-2 neutralizing antibody titers.
Landscape of Epithelial Mesenchymal Plasticity as an emergent property of coordinated teams in regulatory networks
Authors: Hari Kishore , Ullanat Varun , Balasubramanian Archana , Gopalan Aditi , Jolly Mohit Kumar
Published: December 2021

Elucidating the design principles of regulatory networks driving cellular decision-making has fundamental implications in mapping and eventually controlling cell-fate decisions. Despite being complex, these regulatory networks often only give rise to a few phenotypes. Previously, we identified two “teams” of nodes in a small cell lung cancer regulatory network that constrained the phenotypic repertoire and aligned strongly with the dominant phenotypes obtained from network simulations (Chauhan et al., 2021). However, it remained elusive whether these “teams” exist in other networks, and how do they shape the phenotypic landscape. Here, we demonstrate that five different networks of varying sizes governing epithelial-mesenchymal plasticity comprised of two “teams” of players – one comprised of canonical drivers of epithelial phenotype and the other containing the mesenchymal inducers. These “teams” are specific to the topology of these regulatory networks and orchestrate a bimodal phenotypic landscape with the epithelial and mesenchymal phenotypes being more frequent and dynamically robust to perturbations, relative to the intermediary/hybrid epithelial/ mesenchymal ones. Our analysis reveals that network topology alone can contain information about corresponding phenotypic distributions, thus obviating the need to simulate them. We propose “teams” of nodes as a network design principle that can drive cell-fate canalization in diverse decision-making processes.
Characterization of individual HIV-1 budding event using ultra-fast atomic force microscopy reveals a multiplexed role for VPS4
Authors: Harel Shimon , Altaras Yarin , Nachmias Dikla , Rotem-Dai Noa , Segal Inbar , Elia Natalie , Rousso Itay
Published: December 2021

The assembly and budding of newly formed human immunodeficiency virus-1 (HIV-1) particles occur at the plasma membrane of infected cells. Whereas the molecular basis for viral budding has been studied extensively, investigation of its spatiotemporal characteristics has been limited by the small dimensions (< 100 nm) of HIV particles and the fast kinetics of the process (a few minutes from bud formation to virion release). Here we applied ultra-fast atomic force microscopy to achieve real-time visualization of individual HIV-1 budding events from wildtype (WT) cell lines as well as from mutated lines lacking vacuolar protein sorting-4 (VPS4) or visceral adipose tissue-1 protein (VTA1). Using single-particle analysis, we show that HIV-1 bud formation follows two kinetic pathways (fast and slow) with each composed of three distinct phases (growth, stationary, decay). Notably, approximately 30% of events did not result in viral release and were characterized by the formation of short (rather than tall) particles that slowly decayed back into the cell membrane. These non-productive events became more abundant in VPS4 knockout cell lines. Strikingly, the absence of VPS4B, rather than VPS4A, increased the production of short viral particles, suggesting a role for VPS4B in earlier stages of HIV-1 budding than traditionally thought.
NFE2L1-mediated proteasome function protects from ferroptosis
Authors: Kotschi Stefan , Jung Anna , Willemsen Nienke , Ofoghi Anahita , Proneth Bettina , Conrad Marcus , Bartelt Alexander
Published: December 2021

Objective

Ferroptosis continues to emerge as a novel modality of cell death with important therapeutic implications for a variety of diseases, most notably cancer and degenerative diseases. While susceptibility, initiation, and execution of ferroptosis have been linked to reprogramming of cellular lipid metabolism, imbalances in iron-redox homeostasis, and aberrant mitochondrial respiration, the detailed mechanisms of ferroptosis are still insufficiently well understood.

Methods and Results

Here we show that diminished proteasome function is a new mechanistic feature of ferroptosis. The transcription factor nuclear factor erythroid-2, like-1 (NFE2L1) protects from ferroptosis by sustaining proteasomal activity. In cellular systems, loss of NFE2L1 reduced cellular viability after the induction of both chemically and genetically induced ferroptosis, which was linked to the regulation of proteasomal activity under these conditions. Importantly, this was reproduced in a Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) patient-derived cell line carrying mutated glutathione peroxidase-4 (GPX4), a critical regulator of ferroptosis. Also, reduced proteasomal activity was associated with ferroptosis in Gpx4-deficient mice. In a mouse model for genetic Nfe2l1 deficiency, we observed brown adipose tissue (BAT) involution, hyperubiquitination of ferroptosis regulators, including the GPX4 pathway, and other hallmarks of ferroptosis.

Conclusion

Our data highlight the relevance of the NFE2L1-proteasome pathway in ferroptosis. Manipulation of NFE2L1 activity might enhance ferroptosis-inducing cancer therapies as well as protect from aberrant ferroptosis in neurodegeneration, general metabolism, and beyond.

Graphical abstract

Highlights

Proteasome function is diminished during ferroptosis

NFE2L1-mediated proteasomal activity protects from ferroptosis

The ubiquitination of the GPX4-glutathione pathway is implicated in Nfe2l1 deficiency

NFE2L1 deficiency in brown fat is associated with hallmarks of ferroptosis
A Dual-reporter Platform for Screening Tumor-targeted Extracellular Vesicles
Authors: Kanada Masamitsu , Linenfelser Lauren , Cox Elyssa , Gilad Assaf A.
Published: December 2021

Extracellular vesicle (EV)-mediated transfer of biomolecules plays an essential role in intercellular communication and may improve targeted drug delivery. In the past decade, various approaches to EV surface modification for targeting specific cells or tissues have been proposed, including genetic engineering of parental cells or postproduction EV engineering. However, due to technical limitations, targeting moieties of engineered EVs have not been thoroughly characterized. Here, we report the bioluminescence resonance energy transfer (BRET) EV reporter, PalmReNL-based dual-reporter platform for characterizing the cellular uptake of tumor homing peptide (THP)-engineered EVs, targeting PDL1, uPAR, or EGFR proteins expressed in MDA-MB-231 breast cancer cells, simultaneously by bioluminescence measurement and fluorescence microscopy. Bioluminescence analysis of cellular EV uptake revealed the highest binding efficiency of uPAR-targeted EVs, whereas PDL1-targeted EVs showed slower cellular uptake. EVs engineered with two known EGFR-binding peptides via lipid nanoprobes did not increase cellular uptake, indicating that designs of EGFR-binding peptide conjugation to the EV surface are critical for functional EV engineering. Fluorescence analysis of cellular EV uptake allowed us to track individual PalmReNL-EVs bearing THPs in recipient cells. These results demonstrate that the PalmReNL-based EV assay platform can be a foundation for high-throughput screening of tumor-targeted EVs.
Can return on investment in knowledge management initiatives in organizations be measured?
Authors: Nakash Maayan , Bouhnik Dan
Published: December 2021

Purpose

This paper focuses on the meanings attributed to the measurement of return on investment (ROI) in knowledge management (KM) initiatives in knowledge-intensive organizations. At the heart of this exploratory research is the introduction of a unique coherent perspective of discipline experts regarding the ROI metric, as part of their perception of assessing effectiveness in this field.

Design/methodology/approach

The research begins with in-depth semi-structured personal interviews and continues with focus groups, as part of a qualitative research paradigm. The data were analyzed using a thematic analysis method, based on the grounded theory approach.

Findings

The findings provide empirical evidence regarding the significant challenges associated with the objective assessment of KM performance, which is deeply rooted in numerical-financial values. Despite the high status of ROI in the business environment, the authors find that decision-makers surprisingly avoid evaluating ROI for the most important resource of the organization, notwithstanding the immeasurable hopes that depend on this performance measure and the expectation of establishing the profitability of investment in organizational KM.

Originality/value

The uniqueness of this research is the adoption of the skeptical-critical research approach. For the first time, the authors interrogate the suitability and relevance of the general model of the ROI metric as a means of proving the value and contribution of well-managed knowledge to organizations. The authors call for adoption of a new integrative perspective for evaluating effectiveness, which will reflect the holistic set of KM in organizations.
Construction sustainability of container-modular-housing in coastal regions towards resilient community
Authors: Haque Md. Obidul , Aman Jayedi , Mohammad Fahim
Published: December 2021

Purpose

This paper addresses housing problems of coastal areas in Bangladesh and investigates container-modular-housing (CMH) as a potential sustainable solution that establishes a resilient community.

Design/methodology/approach

Primary data highlight the underlying challenges of coastal-housing developed by monitoring the day-to-day operations of the community and conducting interviews with community members. Secondary data came from existing literature on coastal-housing rules and regulations, CMH and similar ideas. The study used a hypothetical CMH cluster design, with three primary objectives in mind: future settlement re-arrangement, economic sustainability and environmental sustainability. To achieve the objectives, the research used a comparative examination of the current constructed form and CMH, as well as a computer-aided simulation approach.

Findings

Primary findings encompass issues of a given coastal area, including surrounding site studies, sustainability and resiliency demands due to broad exposure to the natural calamities. Driving toward a “CMH” based home design has the ability to create strategies for a resilient and sustainable community development while taking three primary objectives into account.

Research limitations/implications

A pilot project is needed to analyze the socio-cultural impact and overall construction feasibility.

Practical implications

This research could be implemented to transform an informal construction system into a technical, resilient, sustainable architectural and engineering solution to build resilient communities.

Originality/value

Numerous research projects have focused on the environmental sustainability of CMH. However, this study focuses on construction sustainability considering three major aspects which are yet to be addressed.
“Now I can see”: creative women fight against machismo in Chilean advertising
Authors: Mensa Marta , Grow Jean M.
Published: December 2021

Purpose

This study aims to explore sexist codes in the creative departments of Chilean advertising agencies, where women represent only 4.7% of all creatives.

Design/methodology/approach

This study provides new insights into the experiences of women in advertising through 18 in-depth interviews with Chilean creative women.

Findings

The results show that gender discrimination begins in universities, where male professors are often the same people who hire creative talent into the advertising agencies and prefer men, which continues throughout women’s careers.

Originality/value

While there are numerous studies of advertising creative women in North American and European agencies, there are few on creative women in South American and virtually none on creative women in Chilean agencies.