bluuebunny/crossref_metadata_2025 huggingface dataset:
Pan-Canadian survey on the impact of the COVID-19 pandemic on cervical cancer screening and management
Authors: El-Zein Mariam , Ali Rami , Farah Eliya , Botting-Provost Sarah , Franco Eduardo L. ,   Survey Study Group
Published: September 2022

Background

The COVID-19 pandemic has caused disruptions to cancer care by delaying diagnoses and treatment, presenting challenges and uncertainties for both patients and physicians. We conducted a nationwide online survey to investigate the effects of the pandemic and capture modifications, prompted by pandemic-related control measures, on cervical cancer screening-related activities from mid-March to mid-August 2020, across Canada.

Methods

The survey consisted of 61 questions related to the continuum of care in cervical cancer screening and treatment: appointment scheduling, tests, colposcopy, follow-up, treatment of pre-cancerous lesions/cancer, and telemedicine. We piloted the survey with 21 Canadian experts in cervical cancer prevention and care. We partnered with the Society of Canadian Colposcopists, Society of Gynecologic Oncology of Canada, Canadian Association of Pathologists, and Society of Obstetricians and Gynecologists of Canada, which distributed the survey to their members via email. We reached out to family physicians and nurse practitioners via MDBriefCase. The survey was also posted on McGill Channels (Department of Family Medicine News and Events) and social media platforms. The data were analyzed descriptively.

Results

Unique responses were collected from 510 participants (16 November 2020 - 28 February 2021), representing 418 fully- and 92 partially-completed surveys. Responses were from Ontario (41.0%), British Columbia (21.0%), and Alberta (12.8%), and mostly comprised family physicians/general practitioners (43.7%), and gynecologist/obstetrician professionals (21.6%). Cancelled screening appointments were mainly reported by family physicians/general practitioners (28.3%), followed by gynecologist/obstetrician professionals (19.8%), and primarily occurred in private clinics (30.5%). Decreases in the number of screening Pap tests and colposcopy procedures were consistently observed across Canadian provinces. About 90% reported that their practice/institution adopted telemedicine to communicate with patients.

Conclusions

The area most severely impacted by the pandemic was appointment scheduling, with an important level of cancellations reported. Survey results may inform resumptions of various fronts in cervical cancer screening and management.
A machine learning approach identifies unresolving secondary pneumonia as a contributor to mortality in patients with severe pneumonia, including COVID-19
Authors: Gao Catherine A. , Markov Nikolay S. , Stoeger Thomas , Pawlowski Anna , Kang Mengjia , Nannapaneni Prasanth , Grant Rogan A. , Pickens Chiagozie , Walter James M. , Kruser Jacqueline M. , Rasmussen Luke , Schneider Dan , Starren Justin , Donnelly Helen K. , Donayre Alvaro , Luo Yuan , Scott Budinger GR , Wunderink Richard G. , Misharin Alexander V. , Singer Benjamin D. ,   The NU SCRIPT Study Investigators
Published: September 2022

Background

Patients with severe SARS-CoV-2 pneumonia experience longer durations of critical illness yet similar mortality rates compared to patients with severe pneumonia secondary to other etiologies. As secondary bacterial infection is common in SARS-CoV-2 pneumonia, we hypothesized that unresolving ventilator-associated pneumonia (VAP) drives the apparent disconnect between length-of-stay and mortality rate among these patients.

Methods

We analyzed VAP in a prospective single-center observational study of 585 mechanically ventilated patients with suspected pneumonia, including 190 patients with severe SARS-CoV-2 pneumonia. We developed CarpeDiem, a novel machine learning approach based on the practice of daily ICU team rounds to identify clinical states for each of the 12,495 ICU patient-days in the cohort. We used the CarpeDiem approach to evaluate the effect of VAP and its resolution on clinical trajectories.

Findings

Patients underwent a median [IQR] of 4 [2,7] transitions between 14 clinical states during their ICU stays. Clinical states were associated with differential hospital mortality. The long length-of-stay among patients with severe SARS-CoV-2 pneumonia was associated with prolonged stays in clinical states defined by severe respiratory failure and with a lower frequency of transitions between clinical states. In all patients, including those with COVID-19, unresolving VAP episodes were associated with transitions to unfavorable states and hospital mortality.

Interpretation

CarpeDiem offers a machine learning approach to examine the effect of VAP on clinical outcomes. Our findings suggest an underappreciated contribution of unresolving secondary bacterial pneumonia to outcomes in mechanically ventilated patients with pneumonia, including due to SARS-CoV-2.

Abstract Figure

Graphical abstract

Disentangling the contributions of ICU complications and interventions to ICU outcomes. (A) Traditional approaches evaluate the ICU stay as a black box with severity of illness measured on presentation and dichotomized survival at an arbitrary time point (e.g., day 28) or on ICU or hospital discharge. Hence, the effect of intercurrent complications and interventions cannot be easily measured, a problem that is compounded when ICU stays are long or significantly differ between groups. (B) Defining the ICU course by clinical features during each day in the ICU permits the association of a complication or intervention with transitions toward clinical states associated with favorable or unfavorable outcomes.
Knowledge of behavioural risk factors for types 2 diabetes mellitus and its associated factors among reproductive-age women in Arba Minch town, Gamo zone, 2022
Authors: Seyoum Tinsae , Tesfaye Selamnesh , Shiferaw Yohannes , Hailu Rahel , Tefera Dagim , Gebru zeleke
Published: September 2022

Background

Type 2 diabetes accounts for over 90% of all types of diabetes. It is caused by a combination of behavioral risk factors. Currently, it is a serious health problem, especially in reproductive-age women associated with reproductive disorders. To prevent it, knowledge is vital, but there is a scarcity of data on behavioral risk factors in Ethiopia.

Objective

To assess knowledge of the behavioral risks of Type 2 diabetes mellitus and its associated factors among reproductive-age women in Gamo zone, Arba Minch town, 2022.

Materials and Methods

A community-based cross-sectional study was employed, and all women in the town were considered as the source population. A multistage sampling procedure with simple random sampling was adopted for the recruitment of kebeles. A systematic random selection procedure was also applied to the household with a 13th interval. A total of 623 samples were completed with an interview questionnaire. A bivariate logistic model was used to calculate the crude odds ratio, and multivariate analysis to control for confounding and identify the association for model fitting variables with AOR.

Result

The level of BRF knowledge among reproductive women is 47.0% [95% CI, 43.5-50.9], with the following factors having significant associations: average family income 3000–5000 Eth. Birr 1.81 [95% CI, 1.03-3.18], >= 5001 Eth. Birr 1.93 [95% CI, 1.02-3.68], DM in the friend or relatives 4.03[95% CI,1.56-10.46], Family history of DM 9.47 [95% CI, 4.74–18.90], source of information: health workers 1.87 [95% CI, 1.04-3.34] and friend or relatives 1.65 [95%CI,1.04-2.62].

Conclusion

The knowledge of behavioral risk factors for type 2 diabetes was poor among study participants. Family income, DM in the friend or relatives, family history of DM, and source of information were the associated factors with good knowledge. Health education about behavioral risk factors should be given emphasis broadly for women.
Water exchange rates measure active transport and homeostasis in neural tissue
Authors: Williamson Nathan H. , Ravin Rea , Cai Teddy X. , Falgairolle Melanie , O’Donovan Michael J. , Basser Peter J.
Published: September 2022

For its size, the brain is the most metabolically active organ in the body. Most of its energy demand is used to maintain stable homeostatic physiological conditions. Altered homeostasis and active states are hallmarks of many diseases and disorders. Yet there is currently no reliable method to assess homeostasis and absolute basal activity or activity-dependent changes non-invasively. We propose a novel, high temporal resolution low-field, high-gradient diffusion exchange NMR method capable of directly measuring cellular metabolic activity via the rate constant for water exchange across cell membranes. Using viable ex vivo neonatal mouse spinal cords, we measure a component of the water exchange rate which is active, i.e., coupled to metabolic activity. We show that this water exchange rate is sensitive primarily to tissue homeostasis and viability and provides distinct functional information in contrast to the Apparent Diffusion Coefficient (ADC), which is sensitive primarily to tissue microstructure but not activity.

SIGNIFICANCE STATEMENT

Despite what physiology text-books may report, water transport across membranes is not only a passive process. However, current understanding is limited because standard techniques can only measure net flux (the difference between water moving in and water moving out). Even so, water is constantly exchanging between the inside and outside of cells and organelles without net flux during homeostasis. We developed a Magnetic Resonance method able to “see” water molecules exchanging on shorter timescales than could be observed before. In neural tissue we find most water exchange is active, that is, linked to ATP-driven processes. This method may one day be translated to clinical MRI applications for measuring cellular function and activity in the human brain and body.
High-resolution profiling of neoantigen-specific T cell receptor activation signatures links moderate stimulation patterns to resilience and sustained tumor control
Authors: Füchsl Franziska , Untch Johannes , Kavaka Vladyslav , Jarosch Sebastian , Vogelsang Carolin , Krätzig Niklas de Andrade , Gosmann Dario , Rad Roland , Busch Dirk , Beltrán Eduardo , Bräunlein Eva , Krackhardt Angela M.
Published: September 2022

Neoantigen-specific T cell receptors (neoTCRs) promise a safe, highly personalized therapeutic approach in anti-tumor immunotherapy. Substantial progress has been made regarding their identification whereas detailed functional assessment of single TCR characteristics impacting therapeutic efficacy is lacking.

We previously identified and functionally characterized neoTCRs specific for neoepitopes derived from KIF2C and SYTL4 demonstrating differences in functional avidity in a patient with metastatic melanoma. In this work, we now combined single-cell TCR- and RNA-sequencing using stimulated peripheral blood derived CD8+T cells of this patient and thereby identified two new neoTCRs recognizing the previously identified mutated epitope KIF2CP13L. Analyzing patient-derived neoTCR expressing T cells, we detected distinct activation patterns as a measure for substantial heterogeneity within oligoclonal T cell responses towards neoantigens upon specific ex vivo-restimulation. Moreover, neoTCR-transgenic T cells from healthy donors were employed for detailed in vitro and in vivo fine-characterization focusing on TCR-intrinsic functional patterns. Most importantly, in a xenogeneic mouse model experimentally simulating rechallenge of tumor infiltrating lymphocytes (TILs) after adoptive T cell transfer, we found that T cells expressing neoTCRs with a moderate activation profile provide a stable and more sustained anti-tumor response upon repeated in vivo tumor challenge as compared to neoTCRs with a stronger, burst-like reactivity. These insights have significant implications for engineering TCR-transgenic T cells for therapeutic purposes.

One Sentence Summary

Combining TCR specificity linked single-cell transcriptomics with in vitro and in vivo characterization of transgenic T cells helps to decipher functional potential and persistence of neoantigen-specific T cell receptors (TCRs) for TCR-transgenic T cell-based adoptive cellular anti-tumor immunotherapy.
The giant diploid faba genome unlocks variation in a global protein crop
Authors: Jayakodi Murukarthick , Golicz Agnieszka A. , Kreplak Jonathan , Fechete Lavinia I. , Angra Deepti , Bednář Petr , Bornhofen Elesandro , Zhang Hailin , Boussageon Raphaël , Kaur Sukhjiwan , Cheung Kwok , Čížková Jana , Gundlach Heidrun , Hallab Asis , Imbert Baptiste , Keeble-Gagnère Gabriel , Koblížková Andrea , Kobrlová Lucie , Krejčí Petra , Mouritzen Troels W. , Neumann Pavel , Nadzieja Marcin , Nielsen Linda Kærgaard , Novák Petr , Orabi Jihad , Padmarasu Sudharsan , Robertson-Shersby-Harvie Tom , Robledillo Laura Ávila , Schiemann Andrea , Tanskanen Jaakko , Törönen Petri , Warsame Ahmed O. , Wittenberg Alexander H.J. , Himmelbach Axel , Aubert Grégoire , Courty Pierre-Emmanuel , Doležel Jaroslav , Holm Liisa U. , Janss Luc L. , Khazaei Hamid , Macas Jiří , Mascher Martin , Smýkal Petr , Snowdon Rod J. , Stein Nils , Stoddard Frederick L. , Tayeh Nadim , Torres Ana M. , Usadel Björn , Schubert Ingo , O’Sullivan Donal Martin , Schulman Alan H. , Andersen Stig Uggerhøj
Published: September 2022

Increasing the proportion of locally produced plant protein in currently meat-rich diets could substantially reduce greenhouse gas emission and loss of biodiversity. However, plant protein production is hampered by the lack of a cool-season legume equivalent to soybean in agronomic value. Faba bean (Vicia faba L.) has a high yield potential and is well-suited for cultivation in temperate regions, but genomic resources are scarce. Here, we report a high-quality chromosome-scale assembly of the faba bean genome and show that it has grown to a massive 13 Gb in size through an imbalance between the rates of amplification and elimination of retrotransposons and satellite repeats. Genes and recombination events are evenly dispersed across chromosomes and the gene space is remarkably compact considering the genome size, though with significant copy number variation driven by tandem duplication. Demonstrating practical application of the genome sequence, we develop a targeted genotyping assay and use high-resolution genome-wide association (GWA) analysis to dissect the genetic basis of hilum colour. The resources presented constitute a genomics-based breeding platform for faba bean, enabling breeders and geneticists to accelerate improvement of sustainable protein production across Mediterranean, subtropical, and northern temperate agro-ecological zones.
In host evolution of Exophiala dermatitidis in cystic fibrosis lung micro-environment
Authors: Kurbessoian Tania , Murante Daniel , Crocker Alex , Hogan Deborah A. , Stajich Jason E.
Published: September 2022

Individuals with cystic fibrosis (CF) are susceptible to chronic lung infections that lead to inflammation and irreversible lung damage. While most respiratory infections that occur in CF are caused by bacteria, some are dominated by fungi such as the slow-growing black yeast Exophiala dermatitidis. Here, we analyze isolates of E. dermatitidis cultured from two samples, collected from a single subject two years apart. One isolate genome was sequenced using long-read Nanopore technology as an in-population reference to use in comparative single nucleotide polymorphism (SNP) and insertion-deletion (INDEL) variant analyses of twenty-three isolates. We then used population genomics and phylo-genomics to compare the isolates to each other as well as the type strain E. dermatitidis NIH/UT8656. Within the CF lung population, three E. dermatitidis clades were detected, each with varying mutation rates. Overall, the isolates were highly similar suggesting that they were recently diverged. All isolates were MAT 1-1, which was consistent with their high relatedness and the absence of evidence for mating or recombination between isolates. Phylogenetic analysis grouped sets of isolates into clades that contained isolates from both early and late time points indicating there are multiple persistent lineages. Functional assessment of variants unique to each clade identified alleles in genes that encode transporters, cytochrome P450 oxidoreductases, iron acquisition and DNA repair processes. Consistent with the genomic heterogeneity, isolates showed some stable phenotype heterogeneity in melanin production, subtle differences in antifungal minimum inhibitory concentrations, growth on different substrates. The persistent population heterogeneity identified in lung-derived isolates is an important factor to consider in the study of chronic fungal infections, and the analysis of changes in fungal pathogens over time may provide important insights into the physiology of black yeasts and other slow-growing fungi in vivo.
CURLYLEAF is a key modulator of apoplast water status in Arabidopsis leaf
Authors: Wu Jingni , Zhang Jinyu , Mei Xiao , Ye Luhuan , Chen Tao , Wang Yiping , Liu Menghui , Zhang Yijing , Xin Xiu-Fang
Published: September 2022

The apoplast of plant leaf, the intercellular space between mesophyll cells, is normally largely filled with air with a minimal amount of water in it, which is essential for key physiological processes such as gas exchange to occur. Interestingly, phytopathogens exploit virulence factors to induce a water-rich environment, known as “water soaking”, in the apoplast of the infected leaf tissue to promote disease. We propose that plants evolved a “water soaking” pathway, which normally keeps a “minimized and balanced” water level in the leaf apoplast for plant growth but is disturbed by microbial pathogens to facilitate infection. Investigation of the “water soaking” pathway and leaf water control mechanisms is a fundamental, yet previously-overlooked, aspect of plant physiology. To identify key components in the “water soaking” pathway, we performed a genetic screen to isolate Arabidopsis severe water soaking (sws) mutants that show leaf water over-accumulation under high air humidity, a condition required for visible water soaking. Here we report the sws1 mutant, which displays rapid water soaking upon high humidity treatment due to a loss-of-function mutation in CURLY LEAF (CLF), encoding a histone methyl-transferase in the POLYCOMB REPRESSIVE COMPLEX 2 (PRC2). We found that the sws1 (clf) mutant exhibits an enhanced abscisic acid (ABA) level and stomatal closure, which are indispensable for its water soaking phenotype and mediated by CLF’s direct regulation of a group of ABA-associated NAC transcription factors, NAC019/055/072. Interestingly, the clf mutant showed a weakened immunity, which likely also contributes to the water soaking phenotype. In addition, the clf plant supports a significantly higher level of Pseudomonas syringae pathogen-induced water soaking and bacterial multiplication, in an ABA pathway and NAC019/055/072-dependent manner. Collectively, our study probes into a fundamental question in plant biology and demonstrates CLF as a key modulator of leaf water status via epigenetic regulation of ABA pathway and stomatal movement.
Cadmium treatment induces endoplasmic reticulum stress and unfolded protein response in Arabidopsis thaliana
Authors: De Benedictis Maria , Gallo Antonia , Migoni Danilo , Papadia Paride , Roversi Pietro , Santino Angelo
Published: September 2022

We report about the response of Arabidopsis thaliana to chronic and temporary Cd2+ stress, and the Cd2+ induced activation of ER stress and unfolded protein response (UPR). Cd2+-induced UPR proceeds mainly through the bZIP60 arm, which in turn activates relevant ER stress marker genes such as BiP3, CNX, PDI5 and ERdj3B in a concentration- (chronic stress) or time- (temporary stress) dependent manner. A more severe Cd-stress triggers programmed cell death (PCD) through the activation of the NAC089 transcription factor. Toxic effects of Cd2+ exposure are reduced in the Atbzip28/bzip60 double mutant in terms of primary root length and fresh shoot weight, likely due to reduced UPR and PCD activation. We also hypothesised that the enhanced Cd2+ resistance of the Atbzip28/bzip60 double mutant is due to an increase in brassinosteroids signaling, since the amount of the brassinosteroid insensitive1 receptor (BRI1) protein decreases under Cd2+ stress only in Wt plants. These data highlight the complexity of the UPR pathway, since the ER stress response is strictly related to the type of the treatment applied and the multifaceted connections of ER signaling. The reduced sensing of Cd2+ stress in plants with UPR defects can be used as a novel strategy for phytoremediation.
Foliar application of preparations as a method of protecting plants from the penetration of lead
Authors: Wierzbicka M. , Bodzon K. , Naziębło A. , Tarnawska Z. , Wróbel M.
Published: September 2022

Due to the contamination of soil with lead, there is still a danger of lead penetrating into our diet through crops. So far, no method has been developed to reduce the concentration of this toxic element in plants and to prevent it from entering the biological cycle. In this paper, an attempt was made for the first time to reduce lead concentrations in plants by using foliar calcium preparations.

This was based on the hypothesis that an increased amount of calcium in the plant would lead to the reduction in the amount of lead as the entry routes of calcium and lead are similar; therefore, an increase in the amount of calcium will result in the saturation of the routes through which lead enters cells (e.g. calcium channels). It should be clarified that the research was experimental. Three crop species (Linum usitatissimumL.,Solanum lycopersicumL.,Cucumis sativusL.) were tested at the organismal level, whereas the epidermis ofAllium cepaL. was used to conduct tests at the cellular level. The InCa calcium transport activator (by Plant Impact) was selected for the test, followed by calcium nitrate. The preparations were administered foliarly. Lead, on the other hand, was applied to roots before adding lead nitrate into the mineral medium. The plants were cultivated hydroponically. The growth and development of seedlings, the concentration of lead in roots and shoots and the microscopic visualisation of lead in plant organisms and cells were studied. Ultimately, the InCa activator administered foliarly was shown to reduce the concentration of lead in plant organs by approximately 44%.

Further findings revealed that the mechanism of this process mainly resulted from the supply of calcium nitrate to plant leaves. A commercial calcium foliar fertiliser also showed a similar effect.

The potential to reduce the uptake of lead by crops by approximately 44% is a very satisfactory result. In addition, spraying plants with InCA biostimulant and calcium nitrate is environmentally friendly. This is cutting-edge research that was described for the first time in the present paper.
Inhibition of Phosphodiesterase 12 results in Antiviral Activity against several RNA Viruses including SARS-CoV-2
Authors: Thursz Mark , Sadiq Fouzia , Tree Julia A. , Karayiannis Peter , Beasley David W. C. , Dejnirattisai Wanwissa , Mongkolsapaya Juthathip , Screaton Gavin , Wand Matthew , Elmore Michael J. , Carroll Miles W. , Matthews Ian , Thomas Howard
Published: September 2022

Phosphodiesterase 12 (PDE12) is a negative regulator of the type 1 interferon (IFN) response and here we show that PDE12 inhibitors (lead compounds 63 and 17) are associated with increased RNAseL activity, are well tolerated at the therapeutic range and inhibit, both in vitro and in vivo, the replication of several RNA viruses including hepatitis C virus (HCV), dengue virus (DENV), West Nile Virus (WNV) and SARS-CoV-2.
Combination Ad26.RSV.preF/RSV preF protein vaccine induces superior humoral, cellular, and protective immunity compared with individual vaccine components in preclinical models
Authors: Saeland Eirikur , van der Fits Leslie , Bolder Renske , Heemskerk-van der Meer Marjolein , Drijver Joke , van Polanen Yolinda , Vaneman Cornelis , Tettero Lisanne , Cox Freek , Serroyen Jan , Jorgenssen Matthew J. , Langedijk Johannes P.M. , Schuitemaker Hanneke , Callendret Benoit , Zahn Roland C.
Published: September 2022

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease for which no licensed vaccine is available. We have previously shown that a prefusion (preF) conformation– stabilized RSV F protein antigen and an adenoviral vector encoding RSV preF protein (Ad26.RSV.preF) are immunogenic and protective in animals when administered as single components. Here, we evaluated a combination of the 2 components. Strong induction of both humoral and cellular responses was shown in RSV-naïve and pre-exposed mice and pre-exposed African green monkeys (AGMs). Both components of the combination vaccine contributed to humoral immune responses, while the Ad26.RSV.preF component was the main contributor to cellular immune responses in both mice and AGMs. Immunization with the combination elicited superior protection against RSV A2 challenge in cotton rats. These results demonstrate the advantage of a combination vaccine and support further clinical development.
Gaze following in Archosauria – Alligators and palaeognath birds suggest dinosaur origin of visual perspective taking
Authors: Zeiträg Claudia , Reber Stephan A. , Osvath Mathias
Published: September 2022

Visual perspective taking marks an evolutionary shift in the formation of advanced social cognition. In humans, it is foundational for our communication and understanding of others. Visual perspective taking has also been found in some other primates, a few songbirds, and some canids. Despite its essential role for social cognition, visual perspective taking has only been fragmentedly studied in animals, leaving its evolution and origins uncharted. To begin to narrow this knowledge gap, we investigated extant archosaurs by comparing the neurocognitively least derived extant birds – palaeognaths – with the closest living relatives of birds, the crocodylians. In a gaze following paradigm, we showed that palaeognaths engage in visual perspective taking and grasp the referentiality of gazes, while crocodylians do not This suggests that visual perspective taking originated in early birds or non-avian dinosaurs – likely earlier than in mammals.
Inflammation-related pathology in the olfactory epithelium: its impact on the olfactory system in psychotic disorders
Authors: Yang Kun , Hasegawa Yuto , Bhattarai Janardhan P , Hua Jun , Dower Milan , Etyemez Semra , Prasad Neal , Duvall Lauren , Paez Adrian , Smith Amy , Wang Yingqi , Zhang Yun-Feng , Lane Andrew P. , Ishizuka Koko , Kamath Vidyulata , Ma Minghong , Kamiya Atsushi , Sawa Akira
Published: September 2022

Smell deficits and neurobiological changes in the olfactory bulb (OB) and olfactory epithelium (OE) have been observed in schizophrenia and related disorders. The OE is the most peripheral olfactory system located outside the cranium, and is connected with the brain via direct neuronal projections to the OB. Nevertheless, it is unknown whether and how a disturbance of the OE affects the OB in schizophrenia and related disorders. Addressing this gap would be the first step in studying the impact of OE pathology in the disease pathophysiology in the brain. In this cross-species study, we observed that chronic, local OE inflammation with a set of upregulated genes in an inducible olfactory inflammation (IOI) mouse model led to a volume reduction, layer structure changes, and alterations of neuron functionality in the OB. Furthermore, IOI model also displayed behavioral deficits relevant to negative symptoms (avolition) in parallel to smell deficits. In first episode psychosis (FEP) patients, we observed a significant alteration in immune/inflammation-related molecular signatures in olfactory neuronal cells (ONCs) enriched from biopsied OE and a significant reduction in the OB volume, compared with those of healthy controls (HC). The increased expression of immune/inflammation-related molecules in ONCs was significantly correlated to the OB volume reduction in FEP patients, but no correlation was found in HCs. Moreover, the increased expression of human orthologues of the IOI genes in ONCs was significantly correlated with the OB volume reduction in FEP, but not in HCs. Together, our study implies a potential mechanism of the OE-OB pathology in patients with psychotic disorders (schizophrenia and related disorders). We hope that this mechanism may have a cross-disease implication, including COVID-19-elicited mental conditions that include smell deficits.
Changes in capture availability due to infection can lead to correctable biases in population-level infectious disease parameters
Authors: Holmes Iris A. , Durso Andrew M. , Myers Christopher R. , Hendry Tory A.
Published: September 2022

Correctly identifying the strength of selection parasites impose on hosts is key to predicting epidemiological and evolutionary outcomes. However, behavioral changes due to infection can alter the capture probability of infected hosts and thereby make selection difficult to estimate by standard sampling techniques. Mark-recapture approaches, which allow researchers to determine if some groups in a population are less likely to be captured than others, can mitigate this concern. We use an individual-based simulation platform to test whether changes in capture rate due to infection can alter estimates of three key outcomes: 1) reduction in offspring numbers of infected parents, 2) the relative risk of infection for susceptible genotypes compared to resistant genotypes, and 3) change in allele frequencies between generations. We find that calculating capture probabilities using mark-recapture statistics can correctly identify biased relative risk calculations. For detecting fitness impact, the bounded nature of the distribution possible offspring numbers results in consistent underestimation of the impact of parasites on reproductive success. Researchers can mitigate many of the potential biases associated with behavioral changes due to infection by using mark-recapture techniques to calculate capture probabilities and by accounting for the shapes of the distributions they are attempting to measure.
Seasonal stability and species specificity of environmentally acquired chemical mating signals in orchid bees
Authors: Darragh Kathy , Linden Tess A , Ramirez Santiago R
Published: September 2022

Traits that mediate reproductive isolation between species, such as those involved in mate choice and/or recognition, are predicted to experience stabilizing selection towards the species mean. Male orchid bees collect chemical compounds from many sources, such as plants and fungi, which they use as a perfume signal (pheromone) during courtship display. Environmentally acquired signals are more prone to variation as source availability can vary through space and time. Here, we investigate the seasonality and species-specificity of male perfumes across an entire year in three sympatric species ofEuglossaorchid bees. Our analysis revealed considerable within-species variation in perfumes. However, species-specificity was maintained consistently throughout the year, suggesting that these perfumes could play an important role in reproductive isolation. Our analysis also identified strong correlations in the abundance of some compounds, possibly due to shared collection sources between species. Our study suggests that orchid bee perfumes are robust in the face of environmental changes in resource availability.
Multiplatform Modeling of Atrial Fibrillation Identifies Phospholamban as Central Regulator of Cardiac Rhythm
Authors: Kervadec Anaïs , Kezos James , Ni Haibo , Yu Michael , Spiering Sean , Kannan Suraj , Andersen Peter , Grandi Eleonora , Ocorr Karen , Colas Alexandre R.
Published: September 2022

Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans, present in > 33 million people worldwide. Although AF is often developed secondary to cardiovascular diseases, endocrine disorders, or lifestyle factors, recent GWAS studies have identified >200 genetic variants that substantially contribute to AF risk. However, it is currently not known how these genetic predispositions contribute to the initiation and/or maintenance of AF-associated phenotypes. In this context, one major barrier to progress is the lack of experimental systems enabling to rapidly explore the function of large cohort of genes on rhythm parameters in models with human atrial relevance. To address these modeling challenges, we have developed a new multi-model platform enabling 1) high-throughput characterization of the role of AF-associated genes on action potential duration and rhythm parameters at the cellular level, using human iPSC-derived atrial-like cardiomyocytes (ACMs), and at the whole organ level, using the Drosophila heart model, and 2) validation of the physiological relevance of our experimental results using computational models of heterogenous human adult atrial myocytes (HAMs) and tissue. As proof of concept, we screened a cohort of 20 AF-associated genes and identified Phospholamban (PLN) loss of function as a top conserved hit that significantly shortens action potential duration in ACMs, HAMs and fly cardiomyocytes. Remarkably, while PLN knock-down (KD) was not sufficient to induce arrhythmia phenotypes, addition of environmental stressors (i.e fibroblasts, β-adrenergic stimulation) to the model systems, led to the robust generation of irregular beat to beat intervals, delayed after depolarizations, and triggered action potentials, as compared to controls. Finally, to delineate the mechanism underlying PLN KD-dependent arrhythmia, we used a logistic regression approach in HAM populations, and predicted that PLN functionally interacts with both NCX (loss of function) and L-type calcium channels (gain of function) to mediate these arrhythmic phenotypes. Consistent with our predictions, co-KD of PLN and NCX in ACMs and flies, led to increased arrhythmic events, while treatment of ACMs with L-type calcium channel inhibitor, verapamil, reverted these phenotypes. In summary, these results collectively demonstrate that our integrated multi-model system approach was successful in identifying and characterizing conserved roles (i.e regulation of Ca2+ homeostasis) for AF-associated genes and phenotypes, and thus paves the way for the discovery and molecular delineation of new gene regulatory networks controlling atrial rhythm with application to AF.
Mouse paralaminar amygdala excitatory neurons migrate and mature during adolescence
Authors: Alderman P.J. , Saxon D. , Torrijos-Saiz L.I. , Sharief M. , Biagiotti S.W. , Page C.E. , Melamed A. , Kuo C.T. , Garcia-Verdugo J.M. , Herranz-Pérez V. , Corbin J.G. , Sorrells S.F.
Published: September 2022

The human amygdala paralaminar nucleus (PL) contains immature excitatory neurons that exhibit protracted maturation into adolescence; however, whether a similar population exists in mice is unknown. We discovered a previously undescribed region with immature doublecortin (Dcx)+ excitatory neurons adjacent to the mouse basolateral amygdala, and similar to humans, these neurons mature during adolescence and are distinct from adjacent intercalated cells. Despite their immature features, these neurons are born during embryogenesis, populate the mouse PL prior to birth, and remain in an immature stage of development until adolescence. In the postnatal brain, a subpopulation of these excitatory neurons surprisingly migrate into the neighboring endopiriform cortex, peaking between P21–P28. In humans, cells with the molecular identity of mouse PL neurons populate the PL as early as 18 gestational weeks, and also exhibit migratory morphology into adolescence (13 years). The finding of a similar region in both mice and humans suggests a potentially conserved cellular mechanism for neuron recruitment and migration during adolescence, a key time period for amygdala circuit maturation and behavioral changes.
Neural population dynamics of human working memory
Authors: Li Hsin-Hung , Curtis Clayton E.
Published: September 2022

Temporally evolving neural processes maintain working memory (WM) representations of information no longer available in the environment. Nonetheless, the dynamics of WM remain largely unexplored in the human cortex. With fMRI, we found evidence of both stable and dynamic WM representations in human cortex during a memory-guided saccade task. The stability of WM varied across brain regions with early visual cortex exhibiting the strongest dynamics. Leveraging population receptive field modeling, we visualized and made the neural dynamics interpretable. Early in the trial, neural responses in V1 were dominated by narrowly tuned activation at the location of the peripheral target. Over time, activity spread toward foveal locations and targets were represented by diffuse activation among voxels with receptive fields along a line between the fovea and the target. We suggest that the WM dynamics in early visual cortex reflects a transformation of sensory inputs into abstract task-related representations.
Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer
Authors: Marin Arnaldo , Mamun Abdullah Al , Akamatsu Hiroaki , Ye Dan , Sudhan Dhivya R. , Brown Benjamin P. , Eli Lisa , Marcelain Katherine , Meiler Jens , Arteaga Carlos L. , Hanker Ariella B.
Published: September 2022

HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.
Models of Throughput for Multi-Cell, Multi-Type Droplet Microfluidics
Authors: Krinsman William
Published: September 2022

New experimental platforms encapsulate multiple cells per microfluidic droplet, with each cell belonging to one of multiple possible types. The motivating example comes from microbial ecology, where we want to observe the interactions of microbial strains. Because droplets are formed randomly, we want to accurately predict the data throughput, the numbers of droplets containing desired combinations of cell types.

Herein I identify the default statistical model for predicting the data throughput of multi-cell, multi-type droplet microfluidics experiments, which fits to cell type count data. I explain the assumptions behind this model and issues that in practice may cause these assumptions to fail. One such issue, “compositional heterogeneity”, is unique to multi-type experiments. I show how to modify the default statistical model to describe the consequences of these issues, without needing to mechanistically model their causes.

In practice, only two of these issues may substantially change the data throughput predictions. The changes depend on both (1) which combination of these issues are present, and (2) the precise definition of data throughput. Finally, I show that for a given experimental platform one can estimate the severity of these two issues, enabling more accurate data throughput predictions that account for these two issues.
Extending Comparison Methods for Unsigned Networks to Signed Networks
Authors: Krinsman William
Published: September 2022

We can allow the edges of networks to have both negative and positive weights. For example, signed networks can describe the interactions of microbes. To evaluate the performance of estimators for signed networks, we need quantitative comparison methods for signed networks. Finding such comparison methods is done most easily by extending a comparison method for unsigned networks.

Almost all methods reported in the literature for quantitatively comparing networks implicitly assume that edge weights are non-negative. Naive attempts to modify these methods to be applicable to signed networks can lead to nonsensical conclusions. Herein I identify requirements that should be satisfied by reasonable methods for comparing signed networks, most importantly the “double penalization principle”. I extend several comparison methods for unsigned networks while satisfying these requirements. Finally, I give examples where these extensions behave reasonably but naive extensions do not.
Benchmark data and software for assessing genome-wide CRISPR-Cas9 screening pipelines
Authors: Iannuzzi Raffaele , Manipur Ichcha , Pacini Clare , Behan Fiona M. , Guarracino Mario R. , Garnett Mathew J. , Savino Aurora , Iorio Francesco
Published: September 2022

Genome-wide recessive genetic screens using lentiviral CRISPR-guide RNA libraries are widely performed in mammalian cells to functionally characterise individual genes and for the discovery of new anti-cancer therapeutic targets. As the effectiveness of such powerful and precise tools for cancer pharmacogenomic is emerging, reference datasets for their quality assessment and the validation of the underlying experimental pipelines are becoming increasingly necessary. Here, we provide a dataset, an R package, and metrics for the assessment of novel experimental pipelines upon the execution of a single calibration viability screen of the HT-29 human colon cancer cell line, employing a commercially available genome-wide library of single guide RNAs: the Human Improved Genome-wide Knockout CRISPR (Sanger) Library. This dataset contains results from screening the HT-29 in multiple batches with the Sanger library, and outcomes from several levels of quality control tests on the resulting data. Data and accompanying R package can be used as a toolkit for benchmarking newly established experimental pipelines for CRISPR-Cas9 recessive screens, via the generation of a final quality-control report.
Deletion of 12-lipoxygenase normalizes platelet function after storage and transfusion in thrombocytopenic mice
Authors: Larsen Hannah J. , Byrne Daire , Bailey S. Lawrence , Stolla Massiel C. , Holinstat Michael , Fu Xiaoyun , Stolla Moritz
Published: September 2022

Objective

Platelets for transfusion are stored for 5-7 days. During storage, platelets undergo numerous detrimental functional changes. In the current study, we sought to understand how genetic deletion of 12 –lipoxygenase (12-LOX) affects platelets during storage, before, and after transfusion.

Approach and Results

We obtained platelets from wild-type (WT) and 12-LOX-/-mice and performed storage studies for 24 and 48 hours. Using LC-MS/MS-MRM, we showed that ω-3 and ω-6 fatty acids increased significantly in stored platelets from 12-LOX-/-mice, while oxylipins were significantly lower than in WT platelets. The circulation time of fresh 12-LOX-/-platelets was significantly shorter than that of fresh WT platelets, but no differences were observed after storage. Baseline αIIbβ3 integrin activation was significantly lower before and after 24 hours of storage in 12-LOX-/-platelets than in WT platelets. Surprisingly, after transfusion, we observed more baseline αIIbβ3 integrin activation in 12-LOX-/-platelets than in WT platelets. In line with this, transfusion of stored 12-LOX-/-platelets led to more frequent and significantly faster vessel occlusions than transfusion of stored WT platelets in a FeCl3-induced carotid artery injury model in thrombocytopenic mice.

Conclusion

Deleting 12-LOX improves the post-transfusion function of stored murine platelets. Pharmacologic inhibition of 12-LOX or dietary alterations of ω-3 and ω-6 PUFAs could significantly enhance human platelet quality and function after storage. Future studies must determine the feasibility and safety of 12-LOX inhibition in stored and transfused human platelets.
Two cyclic electron flows around photosystem I differentially participate in C4photosynthesis
Authors: Ogawa Takako , Kobayashi Kana , Taniguchi Yukimi Y. , Shikanai Toshiharu , Nakamura Naoya , Yokota Akiho , Munekage Yuri N.
Published: September 2022

C4plants assimilate CO2more efficiently than C3plants because of their C4cycle that concentrates CO2. However, the C4cycle requires additional ATP molecules, which may be supplied by the cyclic electron flow around photosystem I. One cyclic electron flow route, which depends on a chloroplast NADH dehydrogenase-like (NDH) complex, is suggested to be crucial for C4plants despite the low activity in C3plants. The other route depends on proton gradient regulation 5 (PGR5) and PGR5-like photosynthetic phenotype 1 (PGRL1), which is considered a major cyclic electron flow route to generate the proton gradient across the thylakoid membrane in C3plants. However, its contribution to C4photosynthesis is still unclear. In this study, we investigated the contribution of the two cyclic electron flow routes to the NADP-malic enzyme subtype of C4photosynthesis inFlaveria bidentis. We observed that the suppression of the NDH-dependent route drastically delayed growth and decreased the CO2assimilation rate to approximately 30% of the wild-type rate. On the other hand, the suppression of the PGR5/PGRL1-dependent route did not affect plant growth and resulted in a CO2assimilation rate that was approximately 80% of the wild-type rate. Our data indicate that the NDH-dependent cyclic electron flow substantially contributes to the NADP-malic enzyme subtype of C4photosynthesis and that the PGR5/PGRL1-dependent route cannot complement the NDH-dependent route inF. bidentis. These findings support the fact that during the C4evolution, the photosynthetic electron flow may be optimized to provide the energy required for C4photosynthesis.
Morphological evolution of bird wings follows a mechanical sensitivity gradient determined by the aerodynamics of flapping flight
Authors: Rader Jonathan , Hedrick Tyson L.
Published: September 2022

The physical principles that govern the function of biological structures also mediate their evolution, but the evolutionary drivers of morphological traits within complex structures can be difficult to predict. We used morphological traits measured from 1096 3-dimensional bird wing scans from 178 species to test how two frameworks for relating morphology to evolution interact. We examined whether the modular organization of the wing into handwing and armwing regions, or the relationship between trait morphology and functional output (i.e. mechanical sensitivity, driven here by flapping flight aerodynamics) dominate evolutionary rate (σ2) and mode. Our results support discretization of the armwing and handwing as morphological modules, but morphological disparity andσ2varied continuously with the mechanical sensitivity gradient and were not modular. Thus, mechanical sensitivity should be considered an independent driver of evolutionary dynamics, distinct from morphological modularity.

Teaser

Mechanical sensitivity drives wing shape evolution in birds and may be fundamental to the evolution of biomechanical systems.