bluuebunny/crossref_metadata_2025 huggingface dataset:
Pdif-mediated antibiotic resistance genes transfer in bacteria identified by pdifFinder
Authors: Shao Mengjie , Ying Nanjiao , Liang Qian , Ma Nan , Leptihn Sebastian , Yu Yunsong , Chen Huan , Liu Chengzhi , Hua Xiaoting
Published: December 2022

Modules consisting of antibiotic resistance genes (ARGs) flanked by inverted repeat Xer-specific recombination sites were thought to be mobile genetic elements that promote horizontal transmission. Less frequently, the presence of mobile modules in plasmids, which facilitate a pdif-mediated ARGs transfer, has been reported. Here, numerous ARGs and toxin-antitoxin genes have been found in pdif site pairs. However, the mechanisms underlying this apparent genetic mobility is currently not understood, and the studies relating to pdif-mediated ARGs transfer onto most bacterial genera are lacking. We developed the web server pdifFinder based on an algorithm called PdifSM that allows the prediction of diverse pdif-ARGs modules in bacterial genomes. Using test set consisting of almost 32 thousand plasmids from 717 species, PdifSM identified 481 plasmids from various bacteria containing pdif sites with ARGs. We found 28-bp-long elements from different genera with clear base preferences. The data we obtained indicate that XerCD-dif site-specific recombination mechanism may have evolutionary adapted to facilitate the pdif-mediated ARGs transfer. Through multiple sequence alignment and evolutionary analyses of duplicated pdif-ARGs modules, we discovered that pdif sites allow an interspecies transfer of ARGs but also across different genera. Mutations in pdif sites generate diverse arrays of modules which mediate multidrug-resistance, as these contain variable numbers of diverse ARGs, insertion sequences and other functional genes. The identification of pdif-ARGs modules and studies focused on the mechanism of ARGs co-transfer will help us to understand and possibly allow controlling the spread of MDR bacteria in clinical settings. The pdifFinder code, standalone software package and description with tutorials are available at https://github.com/mjshao06/pdifFinder.
A recombinant Der p 1-specific allergen-toxin demonstrates superior killing of allergen-reactive IgG+ hybridomas in comparison to its recombinant allergen-drug conjugate
Authors: Daramola A K , Akinrinmade O A , Fajemisin E A , Naran K , Mthembu N , Hadebe S , Brombacher F , Huysamen A M , Fadeyi O E , Hunter R , Barth S
Published: December 2022

Introduction

Current treatments for asthma help to alleviate clinical symptoms but do not cure the disease. In this study, we explored a novel therapeutic approach for the treatment of house dust mite allergen Der p 1induced asthma by aiming to eliminate specific population of B-cells involved in memory IgE response to Der p 1.

Materials and Methods

To achieve this aim, we developed and evaluated two different proDer p 1-based fusion proteins; an allergen-toxin (proDer p 1-ETA) and an allergen-drug conjugate (ADC) (proDer p 1-SNAP-AURIF) against Der p 1 reactive hybridomas as an in vitro model for Der p 1 reactive human B-cells. The strategy involved the use of proDer p 1 allergen as a cell-specific ligand to selectively deliver the bacterial protein toxin Pseudomonas exotoxin A (ETA) or the synthetic small molecule toxin Auristatin F (AURIF) into the cytosol of Der p 1 reactive cells for highly efficient cell killing.

Results

As such, we demonstrated recombinant proDer p 1 fusion proteins were selectively bound by Der p 1 reactive hybridomas as well as primary IgG1+ B-cells from HDM-sensitized mice. The therapeutic potential of proDer p 1-ETAʹ and proDer p 1-SNAP-AURIF was confirmed by their selective cytotoxic activities on Der p 1 reactive hybridoma cells. The allergen-toxin demonstrated superior cytotoxic activity, with IC50 values in the single digit nanomolar value, compared to the ADC.

Discussions

Altogether, the proof-of-concept experiments in this study provide a promising approach for the treatment of patients with house dust mite-driven allergic asthma.
Influence of Preservatives on Insulin in Postmortem Blood: Application to a Case of Insulin Aspart Suicide
Authors: Arbouche Nadia , Macoin Elisa , Raul Jean-Sébastien , Kintz Pascal
Published: December 2022

Insulin aspart (NovoRapid®, NovoMix®, Novolog® and Fiasp®) is a fast-acting analog of human insulin, indicated in the treatment of type I and II diabetes. It is administered before meals to mimic the physiological insulin secretion that follows a rise in blood glucose. Its misuse for the purposes of suicide and murder and in the context of factitious order has often been described. In forensic medicine, the identification of insulin in biological samples has always been complex. In this paper, we present a case of suicide of a 64-year-old man who died after the injection of insulin aspart. He was suffering from terminal lung cancer and left a letter explaining the reasons for his suicide. Four empty NovoRapid® pens were found near the body. Body examination was unremarkable, and the femoral blood was collected in two dry Vacutainer™ tubes (red cap) and two sodium fluoride (NaF) tubes (gray cap). A liquid chromatography coupled to high-resolution mass spectrometry method was used to identify and discriminate insulin aspart from human insulin after immunopurification in the blood samples and in the pens. Blood specimens tested positive for insulin aspart with the concentrations of 36 and 37 ng/mL in dry tubes and 58 and 71 ng/mL in tubes containing NaF when tested ∼3 weeks after the collection of the specimens. The contents of the pens also matched with insulin aspart. The stability of insulin in blood is a critical point in the interpretation of the concentrations due to their rapid decrease caused by the activity of proteases in blood. During a degradation study implemented to compare three preservatives and dry tubes, suitable insulin aspart stability was observed with disodium salt of ethylenediaminetetracetic acid and NaF. Given that NaF is standard in forensic toxicology for measuring blood alcohol concentrations, the authors suggest its use for blood collection when insulin intoxication is suspected.
Firearm Suicide Prevention in the U.S. Military: Recommendations From a National Summit
Authors: Betz Marian E , Stanley Ian H , Anestis Michael D , Bryan Craig J , Buck-Atkinson Jessica , Carey Neil , Ghahramanlou-Holloway Marjan , Morrissey Brooke Heintz , Holloway Kathryn , Houtsma Claire , Kennedy Rachel , Paine Christopher M , Ramchand Rajeev , Simonetti Joseph , Walsh Adam , Wright-Kelly Erin
Published: December 2022

The U.S. DoD has identified firearm suicide prevention as a key operational priority. One vital approach to addressing firearm suicides is through promoting lethal means safety, which involves the voluntary use of secure storage for personally owned firearms and/or temporarily moving firearms out of the home during risk periods. Despite promising approaches to lethal means safety, critical gaps remain in research, programming, and communication among and across scientists, DoD programmatic leaders, front-line commanders, and service members. To address these gaps, the first-ever national “Firearm Suicide Prevention in the Military: Messaging and Interventions Summit” was convened in June 2022, bringing together DoD personnel and researchers with expertise in firearm suicide prevention and lethal means safety. The Summit identified 10 recommendations to enhance firearm suicide prevention messaging and interventions in the U.S. military, including (1) repeal or amend prohibitions on questioning service members about personal firearms; (2) develop, examine, and use common language for firearm injury prevention; (3) implement a universal approach to training on comprehensive firearm injury prevention; (4) encourage leadership across disciplines and levels; (5) aim for broad culture change; (6) support innovative research; (7) consider various outcome measures; (8) promote “cultural competence” for better communication; (9) reduce territorialism; and (10) develop creative partnerships. Ultimately, these recommendations can facilitate productive partnerships with a shared goal: to develop, test, and implement strategies that standardize lethal means safety and reduce firearm suicides and other firearm injuries or harm among service members.
A comprehensive review on graphene-based materials as biosensors for cancer detection
Authors: Alsharabi Rim M , Rai Suyash , Mohammed Hamed Y , Farea Maamon A , Srinivasan Sesha , Saxena Preeti S , Srivastava Anchal
Published: December 2022

Nowadays, cancer is increasingly becoming one of the foremost threats to human being life worldwide, and diagnosing this deadly disease is one of the major priorities of researchers. Described as a monolayer-thin-sheet of hexagonally patterned carbon atoms, ‘graphene’ is considered an innovative evergreen carbon material ideal for a wide array of sensing applications and nanotechnologies. Graphene-based materials (GBMs) have acquired a huge share of interest in the scope of biosensor fabrication for early and accurate cancer diagnosis. Herein, we have insights reviewed the various routes and technologies for synthesized graphene, and GBMs including 3D graphene (i.e. hydrogels, foams, sponges and porous) and 0D graphene (i.e. quantum dots). Moreover, we have introduced the different types of graphene/GBMs biosensors (i.e. electrochemical biosensors, optical biosensors, field-effect transistors biosensors, electrochemiluminescence biosensors and microfluidics biosensors) and their merits and applications for cancer pre-stage detection.
Tomato MED25 regulates fruit ripening by interacting with EIN3-like transcription factors
Authors: Deng Lei , Yang Tianxia , Li Qian , Chang Zeqian , Sun Chuanlong , Jiang Hongling , Meng Xianwen , Huang Tingting , Li Chang-Bao , Zhong Silin , Li Chuanyou
Published: December 2022

Fruit ripening relies on the precise spatiotemporal control of RNA polymerase II (Pol II)-dependent gene transcription, and the evolutionarily conserved Mediator (MED) coactivator complex plays an essential role in this process. In tomato (Solanum lycopersicum), a model climacteric fruit, ripening is tightly coordinated by ethylene and several key transcription factors. However, the mechanism underlying the transmission of context-specific regulatory signals from these ripening-related transcription factors to the Pol II transcription machinery remains unknown. Here, we report the mechanistic function of MED25, a subunit of the plant Mediator transcriptional coactivator complex, in controlling the ethylene-mediated transcriptional program during fruit ripening. Multiple lines of evidence indicate that MED25 physically interacts with the master transcription factors of the ETHYLENE-INSENSITIVE 3 (EIN3)/EIN3-LIKE (EIL) family, thereby playing an essential role in pre-initiation complex formation during ethylene-induced gene transcription. We also show that MED25 forms a transcriptional module with EIL1 to regulate the expression of ripening-related regulatory as well as structural genes through promoter binding. Furthermore, the EIL1–MED25 module orchestrates both positive and negative feedback transcriptional circuits, along with its downstream regulators, to fine-tune ethylene homeostasis during fruit ripening.
Cataract surgery in myopic eyes
Authors: Elhusseiny Abdelrahman M. , Salim Sarwat
Published: December 2022

Purpose of review

We discuss the preoperative, intraoperative, and postoperative considerations for cataract surgery in eyes with high myopia. We also reviewed the recent literature on refractive outcomes and complications of cataract surgery in myopic eyes.

Recent findings

Several novel intraocular lens (IOL) power calculation formulas have recently been developed to optimize refractive outcomes. Haigis formula is the most accurate among the third-generation IOL formulas. Novel formulas such as Barrett Universal II, Kane, and modified Wang-Koch adjustment for Holladay I formula provide a better refractive prediction compared with old formulas. Intraoperatively, the chopping technique is preferred to minimize pressure on weak zonules and reduce the incidence of posterior capsule rupture. Anterior capsular polishing is recommended to reduce the risk of postoperative capsular contraction syndrome (CCS). Postoperatively, complications such as refractive surprises, intraocular pressure spikes, and CCS remain higher in myopic eyes. Only 63% of myopic patients with axial length more than 26 mm achieve a visual acuity at least 20/40 after cataract surgery, mainly because of coexisting ocular comorbidities.

There are multiple preoperative, intraoperative, and postoperative considerations when performing cataract surgery in myopic eyes. Further research is needed to optimize the refractive outcomes in these eyes and determine the best IOL formula. Surgeons should be adept and knowledgeable with different techniques to manage intraoperative complications.
Hemoglobin Levels Among Male Agricultural Workers
Authors: Lin Yuzhou , Heng Siyu , Anand Shuchi , Deshpande Sameer K. , Small Dylan S.
Published: December 2022

Objective

Estimate agricultural work's effect on hemoglobin (Hgb) level in men. A negative effect may indicate presence of chronic kidney disease of uncertain etiology.

Methods

We use Demographic and Health Surveys data from seven African and Asian countries and use matching to control for seven confounders.

Results

On average, Hgb levels were 0.09 g/dL lower among agricultural workers compared with matched controls. Significant effects were observed in Ethiopia, India, Lesotho, and Senegal, with effects from 0.07 to 0.30 g/dL lower Hgb level among agricultural workers. The findings were robust to multiple control groups and a modest amount of unmeasured confounding.

Conclusions

Men engaged in agricultural work in four of the seven countries studied have modestly lower Hgb levels. Our data support integrating kidney function assessments within Demographic and Health Surveys and other population-based surveys.
Acellular nipple scaffold development, characterization, and preliminary biocompatibility assessment in a swine model
Authors: Oganesyan Ruben V. , Lellouch Alexandre G. , Acun Aylin , Lupon Elise , Taveau Corentin B. , Burlage Laura C. , Lantieri Laurent A. , Randolph Mark A. , Cetrulo Curtis L. , Uygun Basak E.
Published: December 2022

Background:

The gold standard in nipple reconstruction remains the autologous skin flap. Unfortunately the results are not satisfying with up to 75% loss of nipple projection over time.1–8 Existing studies investigated the use of primates as a source of implants.9,10 We hypothesized that porcine nipple can serve as a perfect shape-supporting implant due to functional similarities to human nipple.11,12 Our group developed a decellularization protocol to obtain an acellular nipple scaffold (ANS) for nipple reconstruction.

Methods:

Tissue samples were collected from 8 disease-free female Yorkshire pigs (60–70 kg) and then decellularized. The decellularization efficiency and extracellular matrix (ECM) characterization was performed histologically and quantitatively (DNA, total collagen, elastin, and glycosaminoglycan content). In vitro and in vivo biocompatibility was determined by human dermal fibroblast culture and subcutaneous implantation of six ANS in a single Yorkshire pig (60–70 kg) respectively. Inflammation and adverse events were monitored daily based on local clinical signs.

Results:

We showed that all cellular structures and 96% of DNA (321.7±57.6 vs. 11.7±10.9 ng DNA/mg wet tissue, in native and ANS, respectively, p<0.001) can be successfully removed. However, this was associated with a decrease in collagen (89.0±11.4 and 58.8±9.6 μg collagen/mg (p<0.001)) and elastin (14.2±1.6 and 7.9±2.4 μg elastin/mg (p<0.05)) and increase in GAG content (5.0±0.7 and 6.0 ± 0.8 ng/mg (p<0.05)). ANS can support continuous cell growth in vitro and during preliminary biocompatibility tests in vivo.

Conclusions:

This is a preliminary report a novel promising ANS for nipple reconstruction, but more research is needed to validate results.
Racial and ethnic disparities in interhospital transfer for complex emergency general surgical disease across the United States
Authors: Iantorno Stephanie E. , Bucher Brian T. , Horns Joshua J. , McCrum Marta L.
Published: December 2022

BACKGROUND

Differential access to specialty surgical care can drive health care disparities, and interhospital transfer (IHT) is one mechanism through which access barriers can be realized for vulnerable populations. The association between race/ethnicity and IHT for patients presenting with complex emergency general surgery (EGS) disease is understudied.

METHODS

Using the 2019 Nationwide Emergency Department Sample, we identified patients 18 years and older with 1 of 13 complex EGS diseases based on International Classification of Diseases, Tenth Revision, diagnosis codes. The primary outcome was IHT. A series of weighted logistic regression models was created to determine the association of race/ethnicity with the primary outcome while controlling for patient and hospital characteristics.

RESULTS

Of 387,610 weighted patient encounters from 989 hospitals, 59,395 patients (15.3%) underwent IHT. Compared with non-Hispanic White patients, rates of IHT were significantly lower for non-Hispanic Black (15% vs. 17%; unadjusted odds ratio (uOR) [95% confidence interval (CI)], 0.58 [0.49–0.68]; p < 0.001), Hispanic/Latinx (HL) (9.0% vs. 17%; uOR [95% CI], 0.48 [0.43–0.54]; p < 0.001), Asian/Pacific Islander (Asian/PI) (11% vs. 17%; uOR [95% CI], 0.84 [0.78–0.91]; p < 0.001), and other race/ethnicity (12% vs. 17%; uOR [95% CI], 0.68 [0.57–0.81]; p < 0.001) patients. In multivariable models, the adjusted odds of IHT remained significantly lower for HL (adjusted odds ratio [95% CI], 0.76 [0.72–0.83]; p < 0.001) and Asian/PI patients (adjusted odds ratio [95% CI], 0.73 [0.62–0.86]; p < 0.001) but not for non-Hispanic Black and other race/ethnicity patients (p > 0.05).

CONCLUSION

In a nationally representative sample of emergency departments across the United States, patients of minority race/ethnicity presenting with complex EGS disease were less likely to undergo IHT when compared with non-Hispanic White patients. Disparities persisted for HL and Asian/PI patients when controlling for comorbid conditions, hospital and residential geography, neighborhood socioeconomic status, and insurance; these patients may face unique barriers in accessing surgical care.

LEVEL OF EVIDENCE

Prognostic and Epidemiologic; Level III.
Safety and efficacy of daridorexant in the treatment of insomnia: a systematic review and meta-analysis of randomized controlled trials
Authors: Albadrani Muayad saud , albadrani Muhannad saud , Fadlalmola Hammad Ali , Elhusein Amal Mohamed , Abobaker Randa Mohamed , Merghani Magda Mubarak , Gomaa Salma Mohammed , Abdalla Abdalla Mohamed , Alhujaily Muhanad , Omair Altufayl Abdulrahman , Ali Abdalla Adel Mohamed , Masada Huda Khalafallah , Veerabhadra Swamy DS , AL-Sayaghi Khaled M.
Published: December 2022

Daridorexant is a novel dual orexin receptor antagonist used in treating insomnia disorder. Daridorexant improves sleep quality without impairing daytime functioning. We assess the safety and efficacy of this novel drug in the treatment of insomnia. We performed a systematic search for electronic databases in SCOPUS, PubMed, Web of Science and the Cochrane library. Seven randomized controlled trials were included in this review, with 2425 participants enrolled. Daridorexant was superior to placebo in reducing wake time after sleep onset (MD = −13.26; 95% CI, −15.48 to −11.03; P < 0.00001), latency to persistent sleep (MD = −7.23; 95% CI, −9.60 to −4.85; P < 0.00001), with increasing the total sleep time (MD = 14.80; 95% CI, 11.18–18.42; P < 0.00001) and subjective total sleep time (MD = 14.80; 95% CI, 11.18–18.42], P < 0.00001). The 25 mg and 50 mg were the most officious doses. Treatment with daridorexant has resulted in a slightly higher incidence of adverse events [risk ratio (RR) = 1.19; 95% CI, 1.05–1.35;, P = 0.005], specifically somnolence (RR = 1.19; 95% CI, 1.13–3.23; P = 0.005) and fatigue (RR = 2.01; 95% CI, 1.21–3.36; P = 0.007). Daridorexant is superior to placebo in improving sleep quality. However, the drug resulted in a slightly higher incidence of adverse events, including somnolence and fatigue.
Bacterial survivors: evaluating the mechanisms of antibiotic persistence
Authors: Shi Xiaoyi , Zarkan Ashraf
Published: December 2022

Bacteria withstand antibiotic onslaughts by employing a variety of strategies, one of which is persistence. Persistence occurs in a bacterial population where a subpopulation of cells (persisters) survives antibiotic treatment and can regrow in a drug-free environment. Persisters may cause the recalcitrance of infectious diseases and can be a stepping stone to antibiotic resistance, so understanding persistence mechanisms is critical for therapeutic applications. However, current understanding of persistence is pervaded by paradoxes that stymie research progress, and many aspects of this cellular state remain elusive. In this review, we summarize the putative persister mechanisms, including toxin–antitoxin modules, quorum sensing, indole signalling and epigenetics, as well as the reasons behind the inconsistent body of evidence. We highlight present limitations in the field and underscore a clinical context that is frequently neglected, in the hope of supporting future researchers in examining clinically important persister mechanisms.
Substance use in youth at genetic and clinical high risk for psychosis
Authors: Amir Carolyn M. , Kapler Simon , Hoftman Gil , Kushan Leila , Zinberg Jamie , Cadenhead Kristin S. , Kennedy Leda , Cornblatt Barbara A. , Keshavan Matcheri , Mathalon Daniel H. , Perkins Diana O. , Stone William , Tsuang Ming T. , Walker Elaine F. , Woods Scott W. , Cannon Tyrone D. , Addington Jean , Bearden Carrie E
Published: December 2022

Background

Elevated rates of alcohol, tobacco, and cannabis use are observed in both patients with psychotic disorders and individuals at clinical high risk for psychosis (CHR-P), and strong genetic associations exist between substance use disorders and schizophrenia. While individuals with 22q11.2 deletion syndrome (22qDel) are at increased genetic risk for psychosis, initial evidence suggests that they have strikingly low rates of substance use. In the current study, we aimed to directly compare substance use patterns and their neurobehavioral correlates in genetic and clinical high-risk cohorts.

Methods

Data on substance use frequency and severity, clinical symptoms and neurobehavioral measures were collected at baseline and at 12-month follow-up visits in two prospective longitudinal cohorts: participants included 89 22qDel carriers and 65 age and sex-matched typically developing (TD) controls (40.67% male, Mage=19.26 ± 7.84 years) and 1288 CHR-P youth and 371 matched TD controls from the North American Prodrome Longitudinal Study-2 and 3 (55.74% male; Mage=18.71 ± 4.27 years). Data were analyzed both cross-sectionally and longitudinally using linear mixed models.

Results

Controlling for age, sex, and site, CHR-P individuals had significantly elevated rates of tobacco, alcohol, and cannabis use relative to TD controls, whereas 22qDel had significantly lower rates. Increased substance use frequency and severity in CHR-P individuals was associated with increased positive psychosis symptom severity, dysphoric mood, social functioning, and IQ, while higher social anhedonia was associated with lower substance use frequency and severity, across all domains at baseline. These patterns persisted when we investigated these relationships longitudinally over one-year. CHR-P youth exhibited significantly increased positive psychosis symptoms, dysphoric mood, social anhedonia, and IQ compared to 22qDel carriers, and significantly higher social functioning and lower rates of autism spectrum disorder (ASD) compared to 22qDel carriers, both at baseline and at one year follow-up.

Conclusions

Individuals at genetic and clinical high risk for psychosis have strikingly different patterns of substance use. Factors such as increased neurodevelopmental symptoms (lower IQ, higher rates of ASD) and poorer social functioning in 22qDel may help explain this distinction from substance use patterns observed in CHR-P individuals.
Quantifying individual-level heterogeneity in infectiousness and susceptibility through household studies
Authors: Anderson Thayer L , Nande Anjalika , Merenstein Carter , Raynor Brinkley , Oommen Anisha , Kelly Brendan J , Levy Michael Z , Hill Alison L
Published: December 2022

The spread of SARS-CoV-2, like that of many other pathogens, is governed by heterogeneity. “Superspreading,” or “over-dispersion,” is an important factor in transmission, yet it is hard to quantify. Estimates from contact tracing data are prone to potential biases due to the increased likelihood of detecting large clusters of cases, and may reflect variation in contact behavior more than biological heterogeneity. In contrast, the average number of secondary infections per contact is routinely estimated from household surveys, and these studies can minimize biases by testing all members of a household. However, the models used to analyze household transmission data typically assume that infectiousness and susceptibility are the same for all individuals or vary only with predetermined traits such as age. Here we develop and apply a combined forward simulation and inference method to quantify the degree of inter-individual variation in both infectiousness and susceptibility from observations of the distribution of infections in household surveys. First, analyzing simulated data, we show our method can reliably ascertain the presence, type, and amount of these heterogeneities with data from a sufficiently large sample of households. We then analyze a collection of household studies of COVID-19 from diverse settings around the world, and find strong evidence for large heterogeneity in both the infectiousness and susceptibility of individuals. Our results also provide a framework to improve the design of studies to evaluate household interventions in the presence of realistic heterogeneity between individuals.
CyclOps: Cyclical development towards operationalizing ML models for health
Authors: Krishnan Amrit , Subasri Vallijah , McKeen Kaden , Kore Ali , Ogidi Franklin , Alinoori Mahshid , Lalani Nadim , Dhalla Azra , Verma Amol , Razak Fahad , Pandya Deval , Dolatabadi Elham
Published: December 2022

Abstract

Open source software that enable research and development of machine learning (ML) models for clinical use cases are fragmented, poorly maintained and fall short in functionality. CyclOps is a software framework designed to address this gap and help accelerate the development of ML models for health. In this paper, we describe the architecture, APIs and implementation details of CyclOps, while providing benchmarks on example clinical use cases. We emphasize that CyclOps is developed to be researcher friendly, while providing APIs for building end-to-end pipelines for model development as well as deployment. We adopt software engineering and ML operations (MLOps) best practices, while providing support for handling large volumes of health data. The design of the framework is centered around the notion of iterative and cyclical development of the overall ML system, which consists of data, model development and monitoring pipelines. The coreCyclOpspackage can be installed through the Python Package Index (PyPI) and the source code is available athttps://github.com/VectorInstitute/cyclops.
BENEFIT-RISK ASSESSMENT OF COVID-19 VACCINE, MRNA (MRNA-1273) FOR MALES AGE 18-64 YEARS
Authors: Yogurtcu Osman N. , Funk Patrick R. , Forshee Richard A. , Anderson Steven A. , Marks Peter W. , Yang Hong
Published: December 2022

Since authorization of the Moderna mRNA COVID-19 Vaccine, real-world evidence has indicated its effectiveness in preventing COVID-19 cases. However, increased cases of mRNA vaccine-associated myocarditis/pericarditis have been reported, predominantly in young adults and adolescents. The Food and Drug Administration conducted benefit-risk assessment to inform review of the Biologics License Application for use of the Moderna vaccine among individuals ages 18 years and older. We modeled benefit-risk per million individuals who receive two complete doses of the vaccine. Benefit endpoints were vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, and deaths. The risk endpoints were vaccine-related myocarditis/pericarditis cases, hospitalizations, ICU admissions and deaths. The analysis was conducted on the age-stratified male population, due to data signals and previous work showing males to be the main risk group. We constructed six scenarios to evaluate the impact of uncertainty associated with pandemic dynamics, vaccine effectiveness (VE) against novel variants, and rates of vaccine-associated myocarditis/pericarditis cases on the model results. For our most likely scenario, we assumed the US COVID-19 incidence was for the week of December 25, 2021, and a VE of 30% against cases and 72% against hospitalization with the Omicron-dominant strain. Our source for estimating vaccine-attributable myocarditis/pericarditis rates was FDA’s CBER Biologics Effectiveness and Safety (BEST) System databases. Overall, our results supported the conclusion that the benefits of the vaccine outweigh its risks. Remarkably, we predicted vaccinating one million 18-25 year-old males would prevent 82,484 cases, 4,766 hospitalizations, 1,144 ICU admissions, and 51 deaths due to COVID-19, comparing to 128 vaccine-attributable myocarditis/pericarditis cases, 110 hospitalizations, zero ICU admissions, and zero deaths. Uncertainties in the pandemic trajectory, effectiveness of vaccine against novel variants, and vaccine-attributable myocarditis/pericarditis rate are important limitations of our analysis. Also, the model does not evaluate potential long-term adverse effects due to either COVID-19 or vaccine-attributable myocarditis/pericarditis.
An automated respiratory data pipeline for waveform characteristic analysis
Authors: Lusk Savannah , Ward Christopher S. , Chang Andersen , Twitchell-Heyne Avery , Fattig Shaun , Allen Genevera , Jankowsky Joanna , Ray Russell
Published: December 2022

Comprehensive and accurate analysis of respiratory and metabolic data is crucial to modelling congenital, pathogenic, and degenerative diseases converging on autonomic control failure. A lack of tools for high-throughput analysis of respiratory datasets remains a major challenge. We present Breathe Easy, a novel open-source pipeline for processing raw recordings and associated metadata into operative outcomes, publication-worthy graphs, and robust statistical analyses including QQ and residual plots for assumption queries and data transformations. This pipeline uses a facile graphical user interface for uploading data files, setting waveform feature thresholds, and defining experimental variables. Breathe Easy was validated against manual selection by experts, which represents the current standard in the field. We demonstrate Breathe Easy’s utility by examining a 2-year longitudinal study of an Alzheimer’s Disease mouse model to assess contributions of forebrain pathology in disordered breathing. Whole body plethysmography has become an important experimental outcome measure for a variety of diseases with primary and secondary respiratory indications. Respiratory dysfunction, while not an initial symptom in many of these disorders, often drives disability or death in patient outcomes. Breathe Easy provides an open-source respiratory analysis tool for all respiratory datasets and represents a necessary improvement upon current analytical methods in the field.
Like mother, like daughter? Phenotypic plasticity, environmental covariation, and heritability of size in a parthenogenetic wasp
Authors: Tovar Alicia , Monahan Scott , Mugoya Trevor , Kristan Adrian , Welch Walker , Dettmers Ryan , Arce Camila , Buck Theresa , Ruben Michele , Rothenberg Alexander , Saisho Roxane , Cartmill Ryan , Skaggs Timothy , Reyes Robert , Lee MJ , Obrycki John J , Kristan William , Sethuraman Arun
Published: December 2022

Dinocampus coccinellae (Hymenoptera:Braconidae, Euphorinae) is a solitary, generalist Braconid parasitoid wasp that reproduces through thelytokous parthenogenesis, an asexual process in which diploid daughters emerge from unfertilized eggs, and uses over fifty diverse species of coccinellid ladybeetles worldwide as hosts. Here we utilized a common garden and reciprocal transplant experiment using parthenogenetic lines of D. coccinellae presented with three different host ladybeetle species of varying sizes, across multiple generations to investigate heritability, plasticity, and environmental covariation of body size. We expected positively correlated parent-offspring parasitoid regressions, indicative of heritable size variation, from unilineal (parent and offspring reared on same host species) lines, since these restrict environmental variation in phenotypes. In contrast, because multilineal (parent and offspring reared on different host species) lines would induce phenotypic plasticity of clones reared in varying environments, we expected negatively correlated parent-offspring parasitoid regressions. Contrary to expectations, our results indicate (1) little heritable variation in body size, (2) strong independence of offspring size on the host environment, (3) a consistent signal of size-host tradeoff wherein small mothers produced larger offspring, and vice versa, independent of host environment. Our study offers support for a constrained fecundity advantage model of Cope's Law, wherein D. coccinellae maintains phenotypic plasticity in body size despite parthenogenetic reproduction.
Deep mutational scanning to predict antibody escape in SARS-CoV-2 Omicron subvariants
Authors: Alcantara Mellissa C , Higuchi Yusuke , Kirita Yuhei , Matoba Satoaki , Hoshino Atsushi
Published: December 2022

The major concern of COVID-19 therapeutic monoclonal antibodies is the loss of efficacy to continuously emerging SARS-CoV-2 variants. To predict the antibodies efficacy to the future Omicron subvariants, we conducted deep mutational scanning (DMS) encompassing all single mutations in the receptor binding domain of BA.2 strain. In case of bebtelovimab that preserves neutralization activity against BA.2 and BA.5, broad range of amino acid substitutions at K444, V445 and G446 and some substitutions at P499 and T500 were indicated to achieve the antibody escape. Among currently increasing subvariants, BA2.75 carrying G446S partly and XBB with V445P and BQ.1 with K444T completely evade the neutralization of bebtelovimab, consistent with the DMS results. DMS can comprehensively characterize the antibody escape for efficient and effective management of future variants.
Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy
Authors: Ferrian Selena , Cao Aiqin , Mccaffrey Erin F. , Saito Toshie , Greenwald Noah F. , Nicolls Mark R. , Bruce Trevor , Zamanian Roham T. , Rosario Patricia Del , Rabinovitch Marlene , Angelo Michael
Published: December 2022

Rationale

Elucidating the immune landscape within and surrounding pulmonary arteries (PAs) is critical in understanding immune-driven vascular pathology in pulmonary arterial hypertension (PAH). Although more severe vascular pathology is often observed in hereditary (H)PAH patients withBMPR2mutations, the involvement of specific immune cell subsets remains unclear.

Methods

We used cutting-edge multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to compare PAs and adjacent tissue in PAH lungs (idiopathic (I)PAH and HPAH) with unused donor lungs.

Measurements

We quantified immune cells’ proximity and abundance, focusing on those linked to vascular pathology, and evaluated their impact on pulmonary arterial smooth muscle cells (SMCs) and endothelial cells (ECs).

Results

Distinct immune infiltration patterns emerged between PAH subtypes, with intramural involvement independently linked to PA occlusive changes. Notably, we identified monocyte-derived dendritic cells (mo-DCs) within PA subendothelial and adventitial regions, influencing vascular remodeling by promoting SMC proliferation and suppressing endothelial gene expression across PAH subtypes. In HPAH patients, pronounced immune dysregulation encircled PA walls, characterized by heightened perivascular inflammation involving TIM-3+ T cells. This correlated with an expanded DC subset expressing IDO-1, TIM-3, and SAMHD1, alongside increased neutrophils, SMCs, and α-SMA+ECs, reinforcing the severity of pulmonary vascular lesions.

Conclusions

This study presents the first architectural map of PAH lungs, connecting immune subsets not only with specific PA lesions but also with heightened severity in HPAH compared to IPAH. Our findings emphasize the therapeutic potential of targeting mo-DCs, neutrophils, cellular interactions, and immune responses to alleviate severe vascular pathology in IPAH and HPAH.
Inducible non-human primate models of retinal degeneration for testing end stage therapies and understanding disease mechanisms
Authors: Ail Divya , Nava Diane , Hwang In Pyo , Brazhnikova Elena , Nouvel-Jaillard Céline , Dentel Alexandre , Joffrois Corentin , Rousseau Lionel , Dégardin Julie , Bertin Stephane , Sahel José-Alain , Goureau Olivier , Picaud Serge , Dalkara Deniz
Published: December 2022

The anatomical differences between the retinas of humans and most animal models pose a challenge for testing novel therapies. Non-human primate (NHP) retina is anatomically closest to the human retina with the presence of a high acuity region called the fovea. However, there is a lack of relevant NHP models for retinal degeneration that can be used for preclinical studies of vision restoration. To address this unmet need we aimed to generate inducible NHP models of photoreceptor degeneration. We generated three cynomolgus macaque models using distinct strategies. We used two genetically targeted strategies using optogenetics and Crispr-Cas9 to ablate specifically rods to mimic rod-cone dystrophy. Additionally, we created an acute model by physical separation of the photoreceptors and retinal pigment epithelium using a polymer patch. Retinal degeneration was evaluated in all three models by in-life exams such as fundus imaging, optical coherence tomography, adaptive optics and electroretinography. In the genetic models we observed punctuate areas of degeneration in the injected area marked by disorganization of outer segments, loss of rod photoreceptors and thinning of the outer nuclear layer. In the acute model, the degeneration was faster and involved both rods and cones. Among the three distinct NHP models, the Crispr-Cas9 based approach was the most advantageous model in view of recapitulating disease specific features and its ease of implementation. The acute model however resulted in the fastest degeneration making it the most relevant model for testing end-stage vision restoration therapies such as stem cell transplantation.
Enhanced Protection from SARS-CoV-2 Variants by MVA-Based Vaccines Expressing Matched or Mismatched S Proteins Administered Intranasally to hACE2 Mice
Authors: Cotter Catherine A. , Americo Jeffrey L. , Earl Patricia L. , Moss Bernard
Published: December 2022

The continuous evolution of SARS-CoV-2 strains is contributing to the prolongation of the global pandemic. We previously reported the prevention or more rapid clearance of SARS-CoV-2 from the nasal turbinates and lungs of susceptible K18-hACE2 mice that had been vaccinated intranasally (IN) rather than intramuscularly (IM) with a recombinant MVA (rMVA) expressing a modified S protein of the ancestor SARS-CoV-2 strain. Here, we constructed additional rMVAs and pseudoviruses expressing modified S protein of SARS-CoV-2 variants and compared the ability of vaccines with S proteins that were matched or mismatched to neutralize variants, bind to S proteins and protect K18-hACE2 mice against SARS-CoV-2 challenge. Although vaccines with matched S proteins induced higher neutralizing antibodies, vaccines with mismatched S proteins still protected against severe disease and reduced virus and mRNAs in the lungs and nasal turbinates, though not as well as vaccines with matched S proteins. In mice earlier primed and boosted with rMVA expressing ancestral S, antibodies to the latter increased after one immunization with rMVA expressing Omicron S, but neutralizing antibody to Omicron required a second immunization. Passive transfer of Wuhan immune serum with Omicron S binding but undetectable neutralizing activities reduced infection of the lungs by the variant. Notably, the reduction in infection of the nasal turbinates and lungs was significantly greater when the rMVAs were administered IN rather than IM and this held true for vaccines that were matched or mismatched to the challenge SARS-CoV-2.
Single-cell transcriptomic analysis of human pleura reveals stromal heterogeneity and informs in vitro models of mesothelioma
Authors: Obacz Joanna , Nibhani Reshma , Adams Taylor S. , Schupp Jonas C. , Valer Jose Antonio , Veale Niki , Aresu Giuseppe , Coonar Aman S. , Peryt Adam , Biffi Giulia , Kaminski Naftali , Francies Hayley , Rassl Doris M. , Garnett Matthew J , Rintoul Robert C. , Marciniak Stefan J.
Published: December 2022

The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here we present the first comprehensive single cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiplein vitromodels of benign and malignant mesothelial cells, and characterise these through comparison within vivotranscriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at single cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. For example, it has already enabled us to shed light on the transdifferentiation of mesothelial cells allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro.
EEG is better left alone
Authors: Delorme Arnaud
Published: December 2022

Automated preprocessing methods are critically needed to process the large publicly-available EEG databases, but the optimal approach remains unknown because we lack data quality metrics to compare them. Here, we designed a simple yet robust EEG data quality metric assessing the percentage of significant channels between two experimental conditions within a 100 ms post-stimulus time range. Because of volume conduction in EEG, given no noise, most brain-evoked related potentials (ERP) should be visible on every single channel. Using three publicly available collections of EEG data, we showed that, with the exceptions of high-pass filtering and bad channel interpolation, automated data corrections had no effect on or significantly decreased the percentage of significant channels. Referencing and advanced baseline removal methods were significantly detrimental to performance. Rejecting bad data segments or trials could not compensate for the loss in statistical power. Automated Independent Component Analysis rejection of eyes and muscles failed to increase performance reliably. We compared optimized pipelines for preprocessing EEG data maximizing ERP significance using the leading open-source EEG software: EEGLAB, FieldTrip, MNE, and Brainstorm. Only one pipeline performed significantly better than high-pass filtering the data.
A Unitary Mechanism Underlies Adaptation to Both Local and Global Environmental Statistics in Time Perception
Authors: Wang Tianhe , Luo Yingrui , Ivry Richard B. , Tsay Jonathan S. , Pöppel Ernst , Bao Yan
Published: December 2022

Our sense of the passage of time flexibly adapts to the statistical properties of the temporal context. Humans and non-human species exhibit a perceptual bias towards the mean of durations previously observed as well as serial dependence, a perceptual bias towards the duration of recently processed events. Here we asked whether those two phenomena arise from a unitary mechanism or reflect the operation of two distinct systems that adapt separately to the global and local statistics of the environment. We employed a set of duration reproduction tasks in which the target duration was sampled from distributions with different variances and means. The central tendency and serial dependence biases were jointly modulated by the range and the variance of the prior. These effects were well-captured by a unitary mechanism model in which temporal expectancies are updated after each trial based on perceptual observations. Alternative models that assume separate mechanisms for global and local contextual effects failed to capture the empirical results.

Teaser

Time perception of humans is shaped by a common mechanism that is sensitive to short-term and long-term environmental changes.
COVID-19 vaccine coverage targets to inform reopening plans in a low incidence setting
Authors: Conway Eamon , Walker Camelia , Baker Chris , Lydeamore Michael , Ryan Gerard E. , Campbell Trish , Miller Joel C. , Yeung Max , Kabashima Greg , Wood James , Rebuli Nic , McCaw James M. , McVernon Jodie , Golding Nick , Price David J. , Shearer Freya M.
Published: December 2022

Since the emergence of SARS-CoV-2 in 2019 through to mid-2021, much of the Australian population lived in a COVID-19 free environment. This followed the broadly successful implementation of a strong suppression strategy, including international border closures. With the availability of COVID-19 vaccines in early 2021, the national government sought to transition from a state of minimal incidence and strong suppression activities to one of high vaccine coverage and reduced restrictions but with still-manageable transmission. This transition is articulated in the national “re-opening” plan released in July 2021. Here we report on the dynamic modelling study that directly informed policies within the national re-opening plan including the identification of priority age groups for vaccination, target vaccine coverage thresholds and the anticipated requirements for continued public health measures — assuming circulation of the Delta SARS-CoV-2 variant. Our findings demonstrated that adult vaccine coverage needed to be at least 70% to minimise public health and clinical impacts following the establishment of community transmission. They also supported the need for continued application of test-trace-isolate-quarantine and social measures during the vaccine roll-out phase and beyond.