bluuebunny/crossref_metadata_2025 huggingface dataset:
Nighttime Sedations in the Pediatric Emergency Department
Authors: Lubin Yael , Weiser Giora
Published: November 2022

Introduction

Procedural sedation and analgesia (PSA) is the standard of care for many procedures in the pediatric emergency department (PED). Although generally performed by skilled PED physicians, in Israeli PEDs, during nighttime hours, it is mainly performed by pediatric residents. The safety of PSA by residents is considered comparable yet has not been evaluated regarding nighttime performance.

Methods

A retrospective study review of PSA performed in the PED at night (1:00 a.m.–7:00 a.m.). To evaluate these events, we compared each case of nighttime PSA to 2 daytime PSA cases from 2017 to 2019. Adverse events were evaluated using the Quebec criteria.

Results

The study included 451 sedations performed on 438 children from January 2017 to January 2019. Adverse events (AEs) occurred in 29 (6.4%) of the sedations. Serious AEs were uncommon. This included mostly bag-valve-mask ventilation used in 13 (2.9%) of the cases. Of these, 12 were daytime sedations. There was a clear association between abscess drainage during daytime hours and AEs.

Conclusions

Sedations performed during nighttime hours by pediatric residents seem safe and effective. This should strengthen the empowerment of residents to perform sedations when necessary even at late hours of the night. Recognizing cases at higher risk may avoid possible AEs.
Post-COVID-19 respiratory problems: burden and management
Authors: Kessler Anna , Heightman Melissa , Brennan Ewen
Published: November 2022

Purpose of review

To describe the burden of post-COVID respiratory sequelae in posthospital and nonhospitalized COVID-19 survivors and to describe the priorities of clinical management.

Recent findings

Due to varying definitions of ‘Long COVID’ or ‘Post-COVID’, the prevalence of post-COVID sequelae or persisting symptoms is challenging to estimate but ranges from 2.3 to 51%. Risk factors for persistent post-COVID symptoms include age, female sex, deprivation, presence of comorbidities; and in posthospital COVID-19 survivors, the severity of acute infection. Common post-COVID respiratory symptoms include breathlessness, cough and chest pain and many individuals also experience exercise intolerance. The most common pulmonary function test abnormality is impaired diffusing capacity for carbon monoxide. In posthospital COVID-19 survivors, the prevalence of interstitial lung damage is 5–11%. Disordered breathing is common in all post-COVID patients and respiratory physiotherapy is helpful.

The vast numbers of COVID-19 infections globally implies that a large number of people will be affected by post-COVID sequelae even with conservative estimates. A significant number of people are affected for several months and up to years following acute infection. Post-COVID sequelae have a detrimental impact on quality of life and ability to work.
Rhizopus homothallicus, an uncommon causative agent of Rhino-orbital mucormycosis: Case report
Authors: SAHA UMA SHANKAR , Gupta Minakshi , Kumar Alok , Mishra Minakshi
Published: November 2022

Introduction: Rhizopus oryzae is the most common mucorales to cause angio-invasive infections though other species may also be found. This case is about a rare species of Mucorales.
Case presentation: A patient in late 60s, known diabetic for about last 10 years presented with headache and nasal congestion with history of fever few days back. patient had history of close contact with spouse who was diagnosed as COVID-19 positive. As condition did not improved with symptomatic treatment given earlier further workup was done and biopsy was taken from affected sinus. Microscopic examination (KOH Mount) showed few broad aseptate hyaline hyphae with right angle branching suggestive of mucormycosis.  Fungal culture in SDA media incubated at 37 o C and 25 o C showed white cottony growth within 3 days, which turned slight brown to black colour in upper side of growth in next 1-2 days. LCB mount showed broad, aseptate hyphae with not-well-developed sporangiophores bearing few globose sporangia and many large number of golden brown zygospores with stellate walls and with suspensor cells, which was identified as Rhizopus homothallicus.
Conclusion: Our purpose of reporting this case was to highlight the fact that though uncommon this species may emerge sporadically. More cases like this may be reported in future from other parts of the world as well.
mon this species may emerge sporadically. More cases like this may be reported in future from other parts of the world as well.
Accurate prediction of children’s target height from their mid-parental height
Authors: Zeevi Danny , Yehuda Adi Ben , Zangen David , Kruglyak Leonid
Published: November 2022

Background

For the past 50 years, standard guidelines have recommended the use of sex-adjusted mid-parental height to predict a child’s final height. Here, we studied the accuracy of this procedure.

Methods

We used height data in a cohort of 23 very large nuclear families (Mean = 11 adult children per family). We compared the actual final height of the children to their height predicted by the standard procedure, as well as to alternative height predictions that incorporate corrections of mid-parental height for age, sex, and regression to the mean.

Results

Standard mid-parental height explained 36% of the variance in children’s heights, with a heritability of 74%, and children were on average 2.7 cm taller than predicted by their target heights. When we introduced a non-linear correction for the age of the parents, employed a multiplicative (rather than additive) correction for sex, and accounted for regression to the mean, the variance explained increased to 40%, heritability increased to 80%, and prediction bias was reduced from 2.7 cm to 0.14 cm (representing an improvement in prediction by half a standard deviation of the height distribution). We further measured the empirical distribution of heights of adult children around their predicted height. We describe how this distribution can be used to estimate the probability that a child’s height is within the normal expected range.

Conclusions and Relevance

Based on these observations, we propose an improved method for predicting children’s target heights. Our procedure for determining whether the deviation of a child’s projected height from the target height is in the normal range can be used to assess whether the child should be tested further for potential medical abnormalities.
Singletrome: A method to analyze and enhance the transcriptome with long noncoding RNAs for single cell analysis
Authors: Rahman Raza Ur , Ahmad Iftikhar , Sparks Robert , Saad Amel Ben , Mullen Alan
Published: November 2022

Single cell RNA sequencing (scRNA-seq) has revolutionized the study of gene expression in individual cell types from heterogeneous tissue. To date, scRNA-seq studies have focused primarily on expression of protein-coding genes, as the functions of these genes are more broadly understood and more readily linked to phenotype. However, long noncoding RNAs (lncRNAs) are even more diverse than protein-coding genes, yet remain an underexplored component of scRNA-seq data. While less is known about lncRNAs, they are widely expressed and regulate cell development and the progression of diseases including cancer and liver disease. Dedicated lncRNA annotation databases continue to expand, but most lncRNA genes are not yet included in reference annotations applied to scRNA-seq analysis. Simply creating a new annotation containing known protein-coding and lncRNA genes is not sufficient, because the addition of lncRNA genes that overlap in sense and antisense with protein-coding genes will affect how reads are counted for both protein-coding and lncRNA genes. Here we introduce Singletrome, an enhanced human lncRNA genome annotation for scRNA-seq analysis, by merging protein-coding and lncRNA databases with additional filters for quality control. Using Singletrome to characterize expression of lncRNAs in human peripheral blood mononuclear cell (PBMC) and liver scRNA-seq samples, we observed an increase in the number of reads mapped to exons, detected more lncRNA genes, and observed a decrease in uniquely mapped transcriptome reads, indicating improved mapping specificity. Moreover, we were able to cluster cell types based solely on lncRNAs expression, providing evidence of the depth and diversity of lncRNA reads contained in scRNA-seq data. Our analysis identified lncRNAs differentially expressed in specific cell types with development of liver fibrosis. Importantly, lncRNAs alone were able to predict cell types and human disease pathology through the application of machine learning. This comprehensive annotation will allow mapping of lncRNA expression across cell types of the human body facilitating the development of an atlas of human lncRNAs in health and disease.
Improving the preclinical and clinical success rates of LMW drugs depends on radical revisions to the status quo scientific foundations of medicinal chemistry: a case study on COVID Mproinhibition
Authors: Pearlstein Robert A. , Wan Hongbin , Williams Sarah
Published: November 2022

The poor preclinical and clinical success rates of low molecular weight (LMW) compounds can be partially attributed to the inherent trial-and-error nature of pharmaceutical research, which is limited largely toretrospectivedata-driven, rather thanprospectiveprediction-driven human relevant workflows stemming from: 1) inadequate scientific understanding of structure-activity, structure-property, and structure-free energy relationships; 2) disconnects between empirical models derived from in vitro equilibrium data (e.g., Hill and Michaelis-Menten models) vis-à-vis the native non-equilibrium cellular setting (where the pertinent metrics consist of rates, rather than equilibrium state distributions); and 3) inadequate understanding of the non-linear dynamic (NLD) basis of cellular function and disease. We argue that the limit of understanding of cellular function/dysfunction and pharmacology based onempiricalprinciples (observation/inference) has been reached, and that further progress depends on understanding these phenomena at thefirst principlestheoretical level. Toward that end, we have been developing and applying a theory (called “Biodynamics”) on the general mechanisms by which: 1) cellular functions are conveyed by dynamic multi-molecular/-ionic (multi-flux) systems operating in the NLD regime; 2) cellular dysfunction results from molecular dysfunction; 3) molecular structure and function are powered by covalent/non-covalent forms of free energy; and 4) cellular dysfunction is corrected pharmacologically. Biodynamics represents a radical departure from the status quo empirical science and reduction to practice thereof, replacing: 1) the interatomic contact model of structure-free energy and structure-property relationships with a solvation free energy model; 2) equilibrium drug-target occupancy models with dynamic models accounting for time-dependent drug and target/off-target binding site buildup and decay; and 3) linear models of molecular structure-function and multi-molecular/-ionic systems conveying cellular function and dysfunction with NLD models that more realistically capture the emergent non-linear behaviors of such systems. Here, we apply our theory to COVID Mproinhibition and overview its implications for a holistic, in vivo relevant approach to drug design.
Genomic Characterization of Rare Earth Binding byShewanella oneidensis
Authors: Medin Sean , Schmitz Alexa M. , Pian Brooke , Mini Kuunemuebari , Reid Matthew C. , Holycross Megan , Gazel Esteban , Wu Mingming , Barstow Buz
Published: November 2022

Rare earth elements (REE) are essential ingredients of sustainable energy technologies, but separation of individual REE is one of the hardest problems in chemistry today1. Biosorption, where molecules adsorb to the surface of biological materials, offers a sustainable alternative to environmentally harmful solvent extractions currently used for separation of rare earth elements (REE). The REE-biosorption capability of some microorganisms allows for REE separations that, under specialized conditions, are already competitive with solvent extractions2, suggesting that genetic engineering could allow it to leapfrog existing technologies. To identify targets for genomic improvement we screened 3,373 mutants from the whole genome knockout collection of the known REE-biosorbing microorganismShewanella oneidensisMR-13,4. We found 130 genes that increased biosorption of the middle REE europium, and 112 that reduced it. We verified biosorption changes from the screen for a mixed solution of three REE (La, Eu, Yb) using Inductively Coupled Plasma Mass Spectrometry (ICP-MS) in solution conditions with a range of ionic strengths and REE concentrations. We found, among other things, that disruptions of a key regulatory component of the arc system (hptA), which regulates cellular response to anoxic environments and polysaccharide biosynthesis related genes (wbpQ, wbnJ, SO_3183) consistently increase biosorption across all our solution conditions. Our largest total biosorption change comes from ourSO_4685—a capsular polysaccharide (CPS) synthesis gene—disruption which results in an up to 79% increase in biosorption andnusA—a regulatory protein—disruption which results in an up to 35% decrease in biosorption. Knockouts ofglnA, pyrD, andSO_3183increase relative biosorption affinity for ytterbium over lanthanum in multiple solution conditions tested, while many other genes we explored have more complex binding affinity changes. Taken together, these results begin to elucidate how various genes affect the membrane chemistry ofS. oneidensisand offer potential targets for improving biosorption and separation of REE.
Language gene polymorphism pattern survey provided important information for education context in human evolution
Authors: Xia Wei , Zhang Zhizhou
Published: November 2022

Study on language gene polymorphism patterns (LGPP) across different populations could provide important information on human evolution. In this study, as a preliminary observation, we adopted 148 single nucleic polymorphism (SNP) sites from 13 language genes, each with 4-13 SNPs. These SNPs were screened across 112 whole genome sequences (including 59 ancient genomes ranging from 2000 BP to 120000 BP) from five continents (Africa, Asia, Europe, North America, and South America). We found that four distinct LGPPs featured across human evolution history, though it is still to decipher whether they correspond to the three batches of out-of-Africa ancient humans and modern human; Surprisingly, ten ancient samples from the small country, Nepal, contain all 4 basic LGPPs, suggesting that the southern foothills and nearby of the Qinghai-Tibet Plateau were likely an agglomeration place for ancient humans; Chinese samples also have 3-4 basic LGPPs. Of note, some types of Neanderthals and Denisovans possessed a LGPP almost the same as modern humans.
Longitudinal proteomic investigation of COVID-19 vaccination
Authors: Wang Yingrui , Zhu Qianru , Sun Rui , Yi Xiao , Huang Lingling , Hu Yifan , Ge Weigang , Gao Huanhuan , Ye Xinfu , Song Yu , Shao Li , Li Yantao , Li Jie , Guo Tiannan , Shi Junping
Published: November 2022

Although the development of COVID-19 vaccines has been a remarkable success, the heterogeneous individual antibody generation and decline over time are unknown and still hard to predict. In this study, blood samples were collected from 163 participants who next received two doses of an inactivated COVID-19 vaccine (CoronaVac®) at a 28-day interval. Using TMT-based proteomics, we identified 1715 serum and 7342 peripheral blood mononuclear cells (PBMCs) proteins. We proposed two sets of potential biomarkers (seven from serum, five from PBMCs) using machine learning, and predicted the individual seropositivity 57 days after vaccination (AUC = 0.87). Based on the four PBMC’s potential biomarkers, we predicted the antibody persistence until 180 days after vaccination (AUC = 0.79). Our data highlighted characteristic hematological host responses, including altered lymphocyte migration regulation, neutrophil degranulation, and humoral immune response. This study proposed potential blood-derived protein biomarkers for predicting heterogeneous antibody generation and decline after COVID-19 vaccination, shedding light on immunization mechanisms and individual booster shot planning.

Highlights

Longitudinal proteomics of PBMC and serum from individuals vaccinated with CoronaVac®.

Machine learning models predict neutralizing antibody generation and decline after COVID-19 vaccination.

The adaptive and the innate immune responses are stronger in the seropositive groups (especially in the early seropositive group).

Vaccine-induced immunity involves in lymphocyte migration regulation, neutrophil degranulation, and humoral immune response.
T-SEM of 11 Major Psychiatric Disorders: Identification of Gene Expression Patterns for Cross-Disorder Risk and Drug Repurposing
Authors: Grotzinger Andrew D. , Singh Kritika , Miller-Fleming Tyne W. , Lam Max , Mallard Travis T. , Chen Yu , Liu Zhaowen , Ge Tian , Smoller Jordan W.
Published: November 2022

Structured Abstract

Importance

Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy.

Objective

To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes.

Design

This genomic study applied a multivariate transcriptomic method, Transcriptome-wide Structural Equation Modeling (T-SEM), to investigate gene expression patterns associated with four genomic factors indexing shared risk across 11 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. Public databases describing drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk.

Main Outcomes and Measures

Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes.

Results

In total, T-SEM identified 451 genes whose expression was associated with the genomic factors and 41 genes with disorder-specific effects. We find the most hits for a Thought Disorders factor defined by bipolar disorder and schizophrenia. We identify 39 existing pharmacological interventions that could be repurposed to target gene expression hits for this same factor.

Conclusions and Relevance

The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.
Integrative analyses of neuroimaging, clinical, and multi-omics data identified meaningful Alzheimer’s disease progression subtypes
Authors: An Qiyuan , Zhang Mengliang , Hu Xinyue , Su Chang , Wang Fei , Zhu Yingying
Published: November 2022

Alzheimer’s Disease (AD) is a common neurodegenerative disorder with diverse clinical manifestations. To better understand differences between diverse manifestations, we investigate from the difference in MRI ROI volumes among subtypes to their related different gene pathways. In this study, we identify three subtypes of AD development with fast, moderate, and slow progression rates from the MRI ROI volume biomarkers in the ADNI cohort. We further find differentially expressed proteins in CSF fluids among these AD patients and related significantly different genetic pathways. A total of 159 patients’ data are included for analysis. We identify three distinct subtypes from the hierarchical clustering on MRI ROI volume biomarkers. Subtype 1, characterized as fast progression, consists of 34 patients (21.9%). Subtype 2, as moderate progression, comprises 77 patients (49.6%). Subtype 3, as slow progression, consists of 44 patients (28.3%). These subtypes show significantly differences in cognitive test scores and corresponding genetic pathways.
KA-Search: Rapid and exhaustive sequence identity search of known antibodies
Authors: Olsen Tobias H. , Abanades Brennan , Moal Iain H. , Deane Charlotte M.
Published: November 2022

Antibodies with similar amino acid sequences, especially across their complementary-determining regions, often share properties. Finding that an antibody of interest has a similar sequence to naturally expressed antibodies in healthy or diseased repertoires is a powerful approach for the prediction of antibody properties, such as immunogenicity or antigen specificity. However, as the number of available antibody sequences is now in the billions and continuing to grow, repertoire mining for similar sequences has become increasingly computationally expensive. Existing approaches are limited by either being low-throughput, non-exhaustive, not antibody specific, or only searching against entire chain sequences. Therefore, there is a need for a specialized tool, optimized for a rapid and exhaustive search of any antibody region against all known antibodies, to better utilize the full breadth of available repertoire sequences.

We introduce Known Antibody Search (KA-Search), a tool that allows for the rapid search of billions of antibody sequences by sequence identity across either the whole chain, the complementarity-determining regions, or a user defined antibody region. We show KA-Search in operation on the ∼2.4 billion antibody sequences available in the OAS database. KA-Search can be used to find the most similar sequences from OAS within 30 minutes using 5 CPUs. We give examples of how KA-Search can be used to obtain new insights about an antibody of interest. KA-Search is freely available athttps://github.com/oxpig/kasearch.
The evolution of the age of onset of resistance to infectious disease
Authors: Buckingham Lydia J. , Ashby Ben
Published: November 2022

Abstract

Many organisms experience an increase in disease resistance as they age but the time of life at which this change occurs varies. Increases in resistance are partially due to prior exposure and physiological constraints but these cannot fully explain the observed patterns of age-related resistance. An alternative explanation is that developing resistance at an earlier age incurs costs to other life-history traits. Here, we explore how trade-offs with host reproduction or mortality affect the evolution of the onset of resistance, depending on when during the host’s life-cycle the costs are paid (only when resistance is developing, only when resistant or throughout the lifetime). We find that the timing of the costs is crucial to determining evolutionary outcomes, often making the difference between resistance developing at an early or late age. Accurate modelling of biological systems therefore relies on knowing not only the shape of trade-offs but also when they take effect. We also find that the evolution of the rate of onset of resistance can result in evolutionary branching. This provides an alternative, possible evolutionary history of populations which are dimorphic in disease resistance, where the rate of onset of resistance has diversified rather than the level of resistance.
Model-driven optimal experimental design for calibrating cardiac electrophysiology models
Authors: Lei Chon Lok , Clerx Michael , Gavaghan David J. , Mirams Gary R.
Published: November 2022

Models of the cardiomyocyte action potential (AP) have contributed immensely to the understanding of heart function, pathophysiology, and the origin of heart rhythm disturbances. However, AP models are nonlinear, complex, and can contain more than a hundred differential equations, making them difficult to parameterise. Therefore, cellular cardiac models have been limited to describing ‘average cell’ dynamics, when cell-specific models would be ideal to uncover inter-cell variability but are too experimentally challenging to be achieved. Here, we focus on automatically designing experimental protocols that allow us to better identify cell-specific maximum conductance values for each major current type—optimal experimental designs—for both voltage-clamp and current-clamp experiments. We show that optimal designs are able to perform better than many of the existing experiment designs in the literature in terms of identifying model parameters and hence model predictive power. For cardiac cellular electrophysiology, this approach will allow researchers to define their hypothesis of the dynamics of the system and automatically design experimental protocols that will result in theoretically optimal designs.
FkpA Enhances Membrane Protein Folding using an Extensive Interaction Surface
Authors: Devlin Taylor A. , Marx Dagan C. , Roskopf Michaela A. , Bubb Quenton R. , Plummer Ashlee M. , Fleming Karen G.
Published: November 2022

Outer membrane protein (OMP) biogenesis in gram-negative bacteria is managed by a network of periplasmic chaperones that includes SurA, Skp, and FkpA. These chaperones bind unfolded OMPs (uOMPs) in dynamic conformational ensembles to suppress uOMP aggregation, facilitate diffusion across the periplasm, and enhance OMP folding. FkpA primarily responds to heat-shock stress, but its mechanism is comparatively understudied. To determine FkpA chaperone function, we monitored the folding of a cognate client uOmpA171and found that FkpA increases the folded uOmpA171population but also slows the folding rate, dual functions distinct from the other periplasmic chaperones. The results indicate that FkpA behaves as a chaperone and not as a folding catalyst to directly influence the uOmpA171folding trajectory. We determine the binding affinity between FkpA and uOmpA171by globally fitting sedimentation velocity titrations and found it to be intermediate between the known affinities of Skp and SurA for uOMP clients. Notably, complex formation steeply depends on the urea concentration, suggestive of an extensive binding interface. Initial characterizations of the complex using photo-crosslinking indicates that the binding interface spans the inner surfaces of the entire FkpA molecule. In contrast to prior findings, folding and binding experiments performed using subdomain constructs of FkpA demonstrate that the full-length chaperone is required for full activity. Together these results support that FkpA has a distinct and direct effect on uOMP folding and that it achieves this by utilizing an extensive chaperone-client interface.

Significance

The periplasmic chaperone network is required for the survival and virulence of gram-negative bacteria. Here we find that the chaperone FkpA enhances outer membrane protein folding and tightly binds its clients with an extensive interaction interface. This modified holdase function of FkpA distinguishes it from other periplasmic chaperones and complements their functions to ensure robust outer membrane biogenesis.
A microwell platform for high-throughput longitudinal phenotyping and selective retrieval of organoids
Authors: Sockell Alexandra , Wong Wing , Longwell Scott , Vu Thy , Karlsson Kasper , Mokhtari Daniel , Schaepe Julia , Lo Yuan-Hung , Cornelius Vincent , Kuo Calvin , Van Valen David , Curtis Christina , Fordyce Polly M.
Published: November 2022

Organoids are powerful experimental models for studying the ontogeny and progression of diseases including cancer. Organoids are conventionally cultured in bulk using an extracellular matrix mimic. However, organoids in bulk culture physically overlap, making it impossible to track the growth of individual organoids over time in high throughput. Moreover, local spatial variations in bulk matrix properties make it difficult to assess whether observed phenotypic heterogeneity between organoids results from intrinsic cell differences or microenvironment variability. Here, we developed a microwell-based method that enables high-throughput quantification of image-based parameters for organoids grown from single cells, which can be retrieved from their microwells for sequencing and molecular profiling. Coupled with a deep-learning image processing pipeline, we characterized phenotypic traits including growth rates, cellular movement, and apical-basal polarity in two CRISPR-engineered human gastric organoid models, identifying genomic changes associated with increased growth rate and changes in accessibility and expression correlated with apical-basal polarity.
Integrated Multi-Omics Analysis of Brain Aging in Female Nonhuman Primates Reveals Altered Signaling Pathways Relevant to Age-Related Disorders
Authors: Cox Laura A. , Puppala Sobha , Chan Jeannie , Zimmerman Kip D. , Hamid Zeeshan , Ampong Isaac , Huber Hillary F. , Li Ge , Jadhav Avinash Y. L. , Wang Benlian , Li Cun , Baxter Mark G. , Shively Carol , Clarke Geoffrey D. , Register Thomas C. , Nathanielsz Peter W. , Olivier Michael
Published: November 2022

The prefrontal cortex (PFC) has been implicated as a key brain region responsible for age-related cognitive decline. Little is known about aging-related molecular changes in PFC that may mediate these effects. To date, no studies have used untargeted discovery methods with integrated analyses to determine PFC molecular changes in healthy female primates. We quantified PFC changes associated with healthy aging in female baboons by integrating multiple omics data types (transcriptomics, proteomics, metabolomics) from samples across the adult age span. Our integrated omics approach using unbiased weighted gene co-expression network analysis (WGCNA) to integrate data and treat age as a continuous variable, revealed highly interconnected known and novel pathways associated with PFC aging. We found GABA tissue content associated with these signaling pathways, providing one potential biomarker to assess PFC changes with age. These highly coordinated pathway changes during aging may represent early steps for aging-related decline in PFC functions, such as learning and memory, and provide potential biomarkers to assess cognitive status in humans.
A comprehensive survey of long-range tertiary interactions and motifs in non-coding RNA structures
Authors: Bohdan Davyd R. , Voronina Valeria V. , Bujnicki Janusz M. , Baulin Eugene F.
Published: November 2022

Understanding the 3D structure of RNA is key to understanding RNA function. RNA 3D structure is modular and can be seen as a composition of building blocks of various sizes called tertiary motifs. Currently, long-range motifs formed between distant loops and helical regions are largely less studied than the local motifs determined by the RNA secondary structure. We surveyed long-range tertiary interactions and motifs in a non-redundant set of non-coding RNA 3D structures. A new dataset of annotated LOng-RAnge RNA 3D modules (LORA) was built using an approach that does not rely on the automatic annotations of non-canonical interactions. An original algorithm, ARTEM, was developed for annotation-, sequence- and topology-independent superposition of two arbitrary RNA 3D modules. The proposed methods allowed us to identify and describe the most common long-range RNA tertiary motifs. Three basic interaction types were identified to be recurrent in the long-range RNA 3D modules: ribose-ribose interactions, canonical Type I and Type II A-minor interactions, and previously undescribed staple interactions. These three interaction types were found to be different building blocks of the same complex staple motifs common to non-coding RNA 3D structures.
Feasibility of intranasal delivery of thin-film freeze-dried, mucoadhesive AS01B-adjuvanted vaccine powders
Authors: Yu Yu-Sheng , AboulFotouh Khaled , Williams Gerallt , Suman Julie , Cano Chris , Warnken Zachary N. , Williams Robert O. , Cui Zhengrong
Published: November 2022

Intranasal vaccination by directly applying a vaccine dry powder is appealing. However, a method that can be used to transform a vaccine from a liquid to a dry powder and a device that can be used to administer the powder to the desired region(s) of the nasal cavity are critical for a successful intranasal vaccination. In the present study, using a model vaccine that contains the liposomal AS01Bas an adjuvant and ovalbumin (OVA) as a model antigen, it was shown that thin-film freeze-drying can be applied to convert the liquid vaccine containing sucrose at a sucrose to lipid ratio of 15:1 (w/w), in the presence or absence of carboxymethyl cellulose sodium salt (CMC) as a mucoadhesive agent, into dry powders. Ultimately, the thin-film freeze-dried AS01B/OVA vaccine powder containing 1.9% w/w of CMC (i.e., TFF AS01B/OVA/CMC1.9%powder) was selected for additional evaluation because the TFF AS01B/OVA/CMC1.9%powder was mucoadhesive and maintained the integrity of the antigen and the physical properties of the vaccine. Compared to the TFF AS01B/OVA powder that did not contain CMC, the TFF AS01B/OVA/CMC1.9%powder had a lower moisture content and a higher glass transition temperature and was more porous. In addition, the TFF AS01B/OVA/CMC1.9%thin films were relatively thicker than the TFF AS01B/OVA thin films without CMC. When sprayed with the Unit Dose System Powder (UDSP) nasal device, the TFF AS01B/OVA powder and the TFF AS01B/OVA/CMC1.9%powder generated similar particle size distribution curves, spray patterns, and plume geometries. Importantly, after the TFF AS01B/OVA/CMC1.9%powder was sprayed with the UDSP nasal device, the integrity of the OVA antigen and the AS01Bliposomal adjuvant did not change. Finally, a Taguchi L8 orthogonal array was applied to identify the optimal parameters for using the UDSP device to deliver the TFF AS01B/OVA/CMC1.9%vaccine powder to the middle and lower turbinate and the nasopharynx regions in both adult and child nasal casts. Results from this study showed that it is feasible to apply the TFF technology to transform a nasal vaccine candidate from liquid to a dry powder and then use the UDSP nasal device to deliver the TFF vaccine powder to the desired regions in the nasal cavity for intranasal vaccination.
PdeMIXTA04triggers epidermal cells of placenta to differentiate into poplar catkins through forming MBW complexes withPdeMYCandPdeWD40
Authors: Zhou Fangwei , Wu Huaitong , Chen Yingnan , Tuskan Gerald A. , Yin Tongming
Published: November 2022

Differentiation of plant epidermal cells is a keen research topic in plant biology. Our study onPopulus deltoidesrevealed that epidermal cells of the female flower placenta protruded to form catkin fibers immediately after pollination. We discovered thatPdeMIXTA04was explicitly expressed in placenta of female poplar flowers. Heterologous expression ofPdeMIXTA04inArabidopsisdemonstrated that it significantly promoted the leaf epidermal cells to differentiate into trichomes. Compared with the wild type, significant increases in trichome density and trichome branches were observed on leaves of all35S:PdeMIXTA04transgenic lines. Furthermore, transformation ofPdeMIXTA04in the trichomelessArabidopsismutant(gl1)restored trichome development to that of the wild type. GUS expression in poplar, driven by the promoter ofPdeMIXTA04, also confirmed trichome-specific expression. We then screened a yeast library withPdeMIXTA04and captured two interacting genes,PdeMYCandPdeWD40. Interactions between these two proteins were verified by yeast two-hybrid (Y2H), biomolecular fluorescence complementation (BiFC), dual-luciferase (dual-LUC), and pull-down assays, indicating that PdeMIXTA04 functions through the MYB-BHLH-WD40 (MBW) ternary complex. Our work presents evidence ofPdeMIXTA04as a candidate gene for editing to resolve catkins associated pollution and provides distinctive understanding of the molecular mechanism triggering differentiation of plant epidermal cells.
Combination of Volasertib and Rapamycin Inhibits the Regrowth of TSC2-Deficient Tumors
Authors: Valianou Matthildi , Zhang Erik Y. , Johnson Daniel L. , Meyers Rhett , Markiewski Maciej M. , Karbowniczek Magdalena , Pfeffer Lawrence M. , Yu Jane J. , Bissler John J. , Astrinidis Aristotelis
Published: November 2022

Mutations inTSC1andTSC2lead to hyperactivation of mTORC1 and cause Tuberous Sclerosis Complex (TSC) and pulmonary Lymphangioleiomyomatosis (LAM). Rapamycin and rapalogs are potent inhibitors of mTORC1 activity and are approved for the treatment of TSC and LAM. Nevertheless, rapalogs do not cause tumor cell death, and cessation of therapy leads to tumor regrowth. Polo-like kinase 1 (PLK1) interacts with and phosphorylates TSC1, and PLK1 inhibition induces apoptosis and attenuates autophagy in TSC1/TSC2-deficient cells. Here we report that the PLK1 inhibitor volasertib decreases the viability and survival and induces apoptosis in 621-101 cells, a TSC-deficient renal angiomyolipoma cell line from a LAM patient. Combined with rapamycin, volasertib further decreased the survival of 621-101 cells.In vivo, volasertib reduced short-term mouse lung colonization by TSC2-deficient cells and decreased the growth of TSC2-deficient subcutaneous tumors. Mice treated with a combination of volasertib and rapamycin had slower tumor relapse after discontinuation of treatment, compared to rapamycin only. Approximately 35 days after discontinuation of treatment, we observed persistent apoptotic markers and gene expression changes for type I interferon signaling in the regrowth tumors from combination-treated mice, compared to rapamycin only. Notably, combination treatment potently inhibited the growth of subcutaneous tumors derived from the rapamycin-refractory cell line ELT3-245. Taken together, our current work demonstrates that for the management of TSC and LAM disease combination of mTORC1 and PLK1 inhibitors in some cases may be advantageous over currently used rapalog monotherapies.
Plant protoplast-based assay to screen for salicylic acid response-modulating bacteria
Authors: Miebach Moritz , Jiang Renji , Jameson Paula E. , Remus-Emsermann Mitja N.P.
Published: November 2022

Leaves host remarkably diverse microbes, collectively referred to as the leaf microbiota. While many beneficial functions have been attributed to the plant microbiota, the individual contributions of leaf-colonising bacteria range from pathogenic to mutualistic interactions. Omics approaches demonstrated that some leaf-colonising bacteria evoke substantial changes in gene expression and metabolic profiles in the plant host, including plant immunity. While omic approaches provide a system level view on cellular functions, they are costly and laborious, thereby severely limiting the throughput of the number of bacterial strains that can be testedin planta. To enable cost-effective high-throughput screens, we have developed a plant protoplast-based assay to measure real-time target gene expression changes following bacterial inoculation. Here, protoplasts were isolated from leaves of stable transgenic plants containing a pPR1:eYFP-nls construct. Changes in yellow fluorescence were captured for up to 96 treatments using a plate reader. This allowed the monitoring of changes in the salicylic acid-dependent plant immune response over time. Protoplast isolation per se evoked mild fluorescence responses, likely linked to endogenous salicylic acid production. This is advantageous in a bacterial assay, as bidirectional changes in PR1 expression can be measured. Plate reader-generated data were validated via fluorescence microscopy and RT-qPCR. Fluorescence microscopy further demonstrated heterogeneity in the response of individual protoplasts, which is potentially linked to differences in cell-type. In summary, the protoplast assay is an affordable and easily up-scalable way of measuring changes in target gene expression to bacterial colonisation.
Early maturation and hyperexcitability is a shared phenotype of cortical neurons derived from different ASD-associated mutations
Authors: Hussein Yara , Tripathi Utkarsh , Choudhary Ashwani , Nayak Ritu , Peles David , Rosh Idan , Rabinski Tatiana , Djamus Jose , Vatine Gad , Spiegel Ronen , Garin-Shkolnik Tali , Stern Shani
Published: November 2022

Autism Spectrum Disorder (ASD) is characterized mainly by social and sensory-motor abnormal and repetitive behavior patterns. Over hundreds of genes and thousands of genetic variants were reported to be highly penetrant and causative of ASD. Many of these mutations cause comorbidities such as epilepsy and intellectual disabilities (ID). In this study, we measured cortical neurons derived from induced pluripotent stem cells (iPSCs) of patients with four mutations in the genesGRIN2B, SHANK3, UBTF, as well as chromosomal duplication in the 7q11.23 region and compared them to neurons derived from a first-degree relative without the mutation. Using a whole-cell patch-clamp, we observed that the mutant cortical neurons demonstrated hyperexcitability and early maturation compared to control lines. These changes were characterized by increased sodium currents, increased amplitude and rate of excitatory postsynaptic currents (EPSCs), and more evoked action potentials in response to current stimulation in early-stage cell development (3-5 weeks post differentiation). These changes that appeared in all the different mutant lines, together with previously reported data, indicate that an early maturation and hyperexcitability may be a convergent phenotype of ASD cortical neurons.
Variation in histone configurations correlates with gene expression across nine inbred strains of mice
Authors: Tyler Anna L. , Spruce Catrina , Kursawe Romy , Haber Annat , Ball Robyn L. , Pitman Wendy A. , Fine Alexander D. , Raghupathy Narayanan , Walker Michael , Philip Vivek M. , Baker Christopher L. , Mahoney J. Matthew , Churchill Gary A. , Trowbridge Jennifer J. , Stitzel Michael L. , Paigen Kenneth , Petkov Petko M. , Carter Gregory W.
Published: November 2022

It is well established that epigenetic features, such as histone modifications and DNA methylation, are associated with variation in gene expression across cell types. Less well known is the extent to which epigenetic states vary across genetically diverse individuals, and whether such variation corresponds to inter-individual variation in gene expression. To investigate genetically driven variation in epigenetics, we conducted a survey of epigenetic modifications and gene expression in hepatocytes of nine inbred mouse strains. We surveyed four histone modifications (H3K4me1, H3K4me3, H3K27me3, and H3K27ac), and DNA methylation. We used ChromHMM to identify 14 chromatin states, each of which represented a distinct combination of the four histone modifications. We found that chromatin states varied widely across the nine strains and that epigenetic state was strongly correlated with local gene expression. We replicated this correspondence between chromatin state and gene expression in an independent population of Diversity Outbred mice in which we imputed local chromatin state. In contrast, we found that DNA methylation did not vary across the inbred strains and was not correlated with variation in gene expression in DO mice. This work suggests that chromatin state is highly influenced by local genotype and may be a primary mode through which expression quantitative trait loci (eQTLs) are mediated. Through examples, we demonstrate that naturally occurring chromatin state variation, in conjunction with gene expression, can aid in functional annotation of the mouse genome. Finally, we provide a data resource that documents variation in chromatin state in hepatocytes across genetically distinct mice.
Small-angle X-ray microdiffraction from fibrils embedded in tissue thin sections
Authors: Nepal Prakash , Al Bashit Abdullah , Yang Lin , Makowski Lee
Published: November 2022

Small-angle X-ray scattering (SAXS) from fibrils embedded in a fixed, thin section of tissue includes contributions from the fibrils, the polymeric matrix surrounding the fibrils, other constituents of the tissue, and cross-terms due to the spatial correlation between fibrils and neighboring molecules. This complex mixture severely limits the amount of information that can be extracted from scattering studies. However, availability of micro- and nano-beams has made the measurement of scattering from very small volumes possible, which, in some cases, may be dominated by a single fibrillar constituent. In such cases, information about the predominant species may be accessible. Nevertheless, even in these cases, the correlations between the positions of fibrils and other constituents have a significant impact on the observed scattering. Here, strategies are proposed to extract partial information about fibril structure and tissue organization on the basis of SAXS from samples of this type. It is shown that the spatial correlation function of the fibril in the direction perpendicular to the fibril axis can be computed and contains information about the predominant fibril structure and the organization of the surrounding tissue matrix. This has significant advantages over approaches based on techniques developed for X-ray solution scattering. Examples of correlation calculations in different types of samples are given to demonstrate the information that can be obtained from these measurements.
Promoting gender – Equitable agricultural value chains: the role of corporate social responsibility in Nigeria's Niger Delta
Authors: Uduji Joseph Ikechukwu , Okolo-Obasi Elda Nduka
Published: November 2022

Purpose

The purpose of this paper is to critically examine the multinational oil companies' (MOC) corporate social responsibility (CSR) initiatives in Nigeria. Its special focus is to investigate the impact of the global memorandum of understanding (GMoU) on promoting gender-equitable agricultural value chains in the Niger Delta region.

Design/methodology/approach

This paper adopts a quasi-experimental design that used survey research technique, aimed at gathering information from a representative sample of the population, as it is essentially cross-sectional, describing and interpreting the current situation. A total of 760 rural women (380 from the treatment group and another 380 from the control group) were sampled across the Niger Delta region.

Findings

The results from the use of a combination of a logit model and propensity score matching indicate a significant relationship between GMoU model and gender-equitable agricultural value chains in the Niger Delta, Nigeria.

Research limitations/implications

This study implies that CSR of MOCs is a critical factor in the need to integrating gender into agricultural value chains, achieving the goal of increasing agricultural growth and expanding the stable food supply.

Originality/value

This research contributes to gender debate in agricultural value chains from a CSR perspective in developing countries and rationale for demands for social projects by host communities. It concludes that business has an obligation to help in solving problems of public concern.