bluuebunny/crossref_metadata_2025 huggingface dataset:
Ecology of Eastern Equine Encephalitis Virus in the Southeastern United States: Incriminating Vector and Host Species Responsible for Virus Amplification, Persistence, and Dispersal
Authors: Burkett-Cadena Nathan D , Day Jonathan F , Unnasch Thomas R
Published: November 2021

Eastern equine encephalitis virus (EEEV; family Togaviridae, genus Alphavirus) is a mosquito-borne pathogen found in eastern North America that causes severe disease in humans and horses. The mosquito Culiseta melanura (Coquillett) (Diptera: Culicidae) is the primary enzootic vector of EEEV throughout eastern North America while several mosquito species belonging to diverse genera serve as bridge vectors. The ecology of EEEV differs between northern and southern foci, with respect to phenology of outbreaks, important vertebrate hosts, and bridge vector species. Active transmission is limited to roughly half of the year in northern foci (New York, New Hampshire, Massachusetts, Connecticut), while year-round transmission occurs in the southeastern region (particularly Florida). Multiple phylogenetic analyses indicate that EEEV strains circulating in northern foci are likely transported from southern foci by migrating birds. Bird species that overwinter or migrate through Florida, are bitten by Cs. melanura in late spring, and arrive at northern breeding grounds in May are the most likely candidates to disperse EEEV northward. Available data indicate that common yellowthroat and green heron satisfy these criteria and could serve as virus dispersers. Understanding the factors that drive the phenology of Cs. melanura reproduction in the south and the timing of avian migration from southern foci could provide insight into how confluence of these biological phenomena shapes outbreaks of EEE throughout its range. This information could be used to develop models predicting the likelihood of outbreaks in a given year, allowing vector control districts to more efficiently marshal resources necessary to protect their stakeholders.
High-Quality Genome Sequence Resource of a Rice False Smut Fungus Ustilaginoidea virens Isolate, UV-FJ-1
Authors: Bao Jiandong , Wang Rong , Gao Shilei , Wang Zhe , Fang Yu , Wu Lv , Wang Mo
Published: November 2021

Ustilaginoidea virens is the fungal pathogen causing rice false smut, resulting in not only yield lost but also grain pollution with toxic mycotoxins. Here we deployed PacBio Sequel II HIFI-read sequencing technology to generate a near-complete genome assembly for the U. virens isolate UV-FJ-1 (38.48 Mb), which was isolated from Fujian province, China. The genome assembly contains 116 contigs with N50 of 0.65 Mb and a maximum length of 2.10 Mb, and the genome completeness is ≥98% assessed by benchmarking universal single-copy orthologs (BUSCOs) and the mapping rate of Illumina short reads. Excluding 35.78% repeat sequences, we identified a total of 7,164 protein-coding genes, of which 5,818 were functionally annotated and 223 encode putative effector proteins. Moreover, 21 secondary metabolite biosynthesis gene clusters were found in UV-FJ-1 genome. Taken together, this high-quality genome assembly and gene annotation resource will provide a better insight for characterizing the biological and pathogenic mechanisms of U. virens.
Modeling the Spatial Distribution ofXylella fastidiosa: A Nonstationary Approach with Dispersal Barriers
Authors: Cendoya Martina , Hubel Ana , Conesa David , Vicent Antonio
Published: November 2021

Spatial species distribution models often assume isotropy and stationarity, implying that spatial dependence is direction-invariant and uniform throughout the study area. However, these assumptions are violated when dispersal barriers are present. Despite this, the issue of nonstationarity has been little explored in the context of plant health. The objective of this study was to evaluate the influence of barriers in the distribution of Xylella fastidiosa in the demarcated area in Alicante, Spain. Occurrence data from 2018 were analyzed through spatial Bayesian hierarchical models. The stationary model, illustrating a scenario without control interventions or geographical features, was compared with three nonstationary models: a model with mountains as physical barriers, and two models with a continuous and discontinuous perimeter barrier representing hypothetical control interventions. In the stationary model, the posterior mean of the spatial range, as the distance where two observations are uncorrelated, was 4,030 m 95% credible interval (2,907 to 5,564). This distance can be used to define the buffer zone in the demarcated area. The predicted probability of X. fastidiosa presence in the area outside the barrier was 0.46 with the stationary model, whereas it was reduced to 0.29 and 0.36 with the continuous and discontinuous barrier models, respectively. Differences between the discontinuous and continuous barrier models showed that breaks, where no control interventions were implemented, resulted in a higher predicted probability of X. fastidiosa presence in the areas with low sampling intensity. These results may help authorities prioritize the areas for surveillance and disease control.

[Formula: see text] Copyright © 2022 The Author(s). This is an open access article distributed under the CC BY 4.0 International license .
23rd Pauline Cerasoli Lecture Educating for Professionalism: The Science of Caring. The Art of Healing
Authors: Swisher Laura Lee
Published: November 2021

Although the physical therapy profession has worked tirelessly toward recognition as a true profession, we know little about best practices in educating for and evaluating professionalism. These complex and uncertain times challenge traditional notions, calling for nuanced multidimensional understandings of both collective and individual professionalism. A review of the current state of professionalism education in physical therapy, limitations of traditional reductionist notions of professionalism, and research in professionalism provides a framework for considering a multidimensional model of professionalism. By proposing a model that reconciles undermining dichotomies (such as evidence/value, individual/social, science/art, and clinical/professional), we can advance the development of alternative models of teaching professionalism. The professionalism curriculum of the future must be grounded in sound theory, a broad range of foundational and behavioral sciences, ongoing research, social values of justice and equity, a strong professional identity, and faculty committed to advancing the science and art of professionalism. It is an honor to have been selected to give the Pauline Cerasoli lecture because Polly Cerasoli was an extraordinary educator and person. I had the opportunity to meet Polly on several occasions, and others have described her professionalism as a teacher, administrator, and accreditation Team Leader. Polly lived out the meaning of professionalism and moral courage. I am grateful to the Cerasoli family for establishing this lectureship and to the Academy of Physical Therapy Educators for selecting me to present during this event named in her honor. Of course, I wish that we could be together for this event to share the rich interaction that comes with being together. However, we are fortunate be able to connect virtually. I am grateful to Texas Woman's University in Dallas and especially Dr. Ann Medley (Program Director) who was kind enough to provide the setting and technology support for this lecture. When I learned in 2019 that I had been selected for the honor of being the Polly Cerasoli lecturer, few people knew what 2020 would bring. What a year it was! Having come through the uncertain days of 2020, I have no doubt that ethics and professionalism are more important than ever.
High‐Resolution Anorectal Manometry—A Prospective Cohort Study in Healthy Infants
Authors: Gatzinsky Cathrine , Redfors Staffan , Borg Helena , Linnér Christina , Sillén Ulla , Sjöström Sofia
Published: November 2021

Objectives:

Functional gastrointestinal disorders (FGD) are common during early childhood. In severe defecation disorders, anorectal manometry (AM) is done to exclude aganglionosis. High‐resolution anorectal manometry (HRAM) can probably improve diagnostics but normative data in infants are scarce. This study aims to provide HRAM data in healthy infants overall and in subgroups of infants with FGD, defined as functional constipation (FC), infant colic (IC), and infant dyschezia (ID) (ROME 3 criteria).

Methods:

This prospective observational cohort study enrolled healthy term infants, having HRAM at 2 and 6 months, using a water‐perfused pediatric anorectal silicone catheter. Data were provided for presence of anorectal waves and recto anal inhibitory reflex (RAIR), volume needed to elicit RAIR and anal resting pressure (ARP). Questionnaires at 2 and 6 months identified subjects with FC, IC, and ID.

Results:

A total of 187 HRAM investigations were done in 107 infants, without any complications. Normal RAIR was found in all, at least on one occasion. Mean ARP increased between 2‐ and 6‐month investigations in infants without FGD. No other differences in HRAM data could be seen between infants with or without an FGD. At 2 months FC, IC, and ID were seen (2%, 4%, and 17%), whereas at 6 months only FC and ID were seen (7% and 1%).

Conclusion:

We can provide data on HRAM in infants at 2 and 6 months of age. When performing repeated HRAM in healthy infants, RAIR was found in all subjects. HRAM is safe, easy tolerable, and can be recommended in infants with or without FGD.
Parental Stress as the Mediator Between Symptom Burden and the Quality of Life of Chinese Children With Cancer
Authors: Lam Winsome , Leung Doris Y.P. , Li Su-Fang , Yi Yan-Zhi , Wang Hai-Xia , Zhou Li , Yin Yan , Chan Stephen C.W. , Chan Kitty Y.Y. , Ho Jacqueline M.C. , Wong Frances K.Y.
Published: November 2021

Background

Because of their cancer and treatment adverse effects, most pediatric oncology patients will experience 1 or more symptoms at one time that can seriously affect their quality of life. Because these children are attached to parents, their symptom burden directly influences the parental stress level and parental interpretations of their children’s quality of life.

Objective

The aim of this study was to examine the association between child-reported symptom burden and the pediatric quality of life reported by children with cancer and their parents, and whether parental perceived stress mediates these relationships.

Methods

In a cross-sectional design, convenience sampling was used to recruit 80 parent-child dyads. Advanced statistical methods were adopted to analyze the mediating effects of parental stress between children’s symptom burden and their quality of life.

Results

The results revealed that parental stress was the mediator in the relationship between child-reported symptom burden and children’s quality of life reported by parents. The results also showed that parental stress was not a mediator in the relationship between child-reported symptom burden and their quality of life. This underscored the differences in interpretations of quality of life reported by children and their parents.

Conclusion

Children’s symptom burden is an important factor in predicting parental stress level and the quality of life reported by the children. Children’s voice should be incorporated whenever possible.

Implications for Practice

The knowledge gained from this study will facilitate intervention development to enhance parents’ abilities in stress management and symptom management for their children with the support of the nursing profession.
Wernicke Encephalopathy From Olfactory Dysfunction After COVID-19 Infection
Authors: Landzberg David Ross , Bery Ekta , Chico Suhasini , Koh Sookyong , Weissman Barbara
Published: November 2021

Introduction:

Coronavirus disease 2019 (COVID-19) has affected millions of people worldwide and is caused by infection from the severe acute respiratory syndrome coronavirus-2 pathogen. While COVID-19 most commonly affects the respiratory system, multiple neurological complications have been associated with this pathogen. We report a case of Wernicke encephalopathy in a young girl with poor oral intake secondary to anosmia and dysgeusia after a COVID-19 infection.

Case Report:

After a recent infection of COVID-19, a 15-year-old girl developed an overwhelming noxious metallic tase resulting in a 30 lb weight loss from being unable to tolerate oral foods. She presented to the hospital 3 months later with bilateral horizontal conjugate gaze palsies, up beating vertical nystagmus, difficulty with limb coordination and gait ataxia. She was found to have a thiamine level of 51 nmol/L (reference range: 70 to 180 nmol/L) and her brain magnetic resonance imaging showed fluid-attenuated inversion recovery and diffusion-weighted imaging changes in the periaqueductal gray and dorsomedial thalami suggestive of Wernicke encephalopathy. She was started on parenteral thiamine replacement and had significant neurological improvement.

Conclusions:

As this pandemic continues to progress, more long-term neurological sequelae from COVID-19 such as Wernicke encephalopathy can be expected. Strong clinical suspicion for these complications is needed to allow for earlier diagnosis and faster treatment initiation.
Comparison of Oxidative and Hypoxic Stress Responsive Genes from Meta-Analysis of Public Transcriptomes
Authors: Suzuki Takayuki , Ono Yoko , Bono Hidemasa
Published: November 2021

Analysis of RNA-sequencing (RNA-seq) data is an effective means to analyze the gene expression levels under specific conditions and discover new biological knowledge. More than 74000 experimental series with RNA-seq have been stored in public databases as of October 20, 2021. Since this huge amount of expression data accumulated from past studies is a promising source of new biological insights, we focused on a meta-analysis of 1783 runs of RNA-seq data under the conditions of two types of stresses: oxidative stress (OS) and hypoxia. The collected RNA-seq data of OS were organized as the OS dataset to retrieve and analyze differentially expressed genes (DEGs). The OS-induced DEGs were compared with the hypoxia-induced DEGs retrieved from a previous study. The results from the meta-analysis of OS transcriptomes revealed two genes, CRIP1 and CRIP3, which were particularly downregulated, suggesting a relationship between OS and zinc homeostasis. The comparison between meta-analysis of OS and hypoxia showed that several genes were differentially expressed under both stress conditions, and it was inferred that the downregulation of cell cycle-related genes is a mutual biological process in both OS and hypoxia.
Autonomic dysfunction characterized by Heart Rate Variability among patients with Sepsis-related Acute Respiratory Failure
Authors: Krishnan Preethi , Marshall Curtis , Yang Philip , Bhavani Sivasubramanium V. , Holder Andre , Esper Annette , Kamaleswaran Rishikesan
Published: November 2021

Rationale

To explore the association and implications of using Heart rate variability (HRV) derived from continuous bedside monitoring as a surrogate for detection of Acute Respiratory Failure (ARF) in critically ill sepsis patients.

Objective

To analyze HRV measures derived from continuous physiological data captured before ARF-onset to determine whether statistically significant markers can be characterized when compared to sepsis controls.

Methods

Retrospective HRV analysis of sepsis patients admitted to Emory Healthcare ICUs was performed between ARF and age and gender-matched controls. HRV measures such as time domain, frequency domain, nonlinear, and complexity measures were analyzed up to 1 hour before the onset of ARF, and a random event time in the sepsis-controls. Statistical significance was computed by the Wilcoxon Rank Sum test.

Results

A total of 89 intensive care unit (ICU) patients with sepsis were included in this retrospective cohort study. Time-domain HRV measures including pNN50 (the fraction of consecutive NN intervals that differ by more than 50 ms), RMSSD (root-mean-square differences of successive NN intervals), standard deviation, interquartile range, variance, and approximate entropy for Beat-to-Beat intervals strongly distinguished ARF patients from the controls group. HRV measures for nonlinear and frequency domains were significantly altered (p<0.05) among sepsis patients with ARF compared to controls. Frequency measures such as low frequency (LF), very low frequency (VLF), high frequency (HF), and SD1/SD2 ratio nonlinear measure (SD1:SD2) also showed a significant (p<0.05) increase in the ARF group patients. Multiscale entropy complexity was lower for ARF patients compared to the control counterparts. Detrended fluctuation analysis (DFA) showed a decreasing trend in ARF patients.

Conclusions

HRV was significantly impaired across sepsis patients who developed ARF when compared to sepsis controls, indicating a potential prognostic utility for earlier identification of the need for mechanical ventilation and management of patients suspected with sepsis.
Are all Thermometers Equal? A Study of Three Infrared Thermometers to Detect Fever in an African Outpatient Clinic
Authors: Ravi Nirmal , Vithyananthan Mathura , Saidu Aisha Amira
Published: November 2021

Infrared thermometry has certain advantages over traditional oral thermometry including quick, non-invasive administration and an absence of required consumables. This study compared the performance of tympanic, temporal artery and forehead contactless thermometers with traditional oral electronic thermometer in measuring temperature in outpatients in a Nigerian secondary care hospital. A convenience sample of 100 male and 100 female adult patients (Mean age= 38.46 years, SD= 16.33 years) were recruited from a secondary care hospital in Kano, Nigeria. Temperature measurements were taken from each patient using the tympanic, temporal artery and contactless thermometers and oral electronic thermometer. Data was analyzed to assess bias and limits using scatterplots and Bland-Altman charts while sensitivity analysis was done using ROC curves. The tympanic and temporal artery thermometers systematically gave higher temperature readings compared to the oral electronic thermometer. Contactless thermometer gave lower readings compared to the oral electronic thermometer. Temporal artery thermometer had the highest sensitivity (88%) and specificity (88%) among the three infrared thermometers. Contactless thermometer showed a low sensitivity of 13% to detect fever greater than 38°C. Our study shows that replacing oral thermometers with infrared thermometers must be done with caution despite the associated convenience and cost savings.
Impact of Norway spruce pre-degradation stages induced by G. trabeum on fungal and bacterial communities
Authors: Valette Nicolas , Legout Arnaud , Goodell Barry , Alfredsen Gry , Auer Lucas , Gelhaye Eric , Derrien Delphine
Published: November 2021

In forests ecosystems, fungi and bacteria are key actors in wood degradation. However, few studies have focused on the impact of fungal pre-degradationon bacterial and fungal communities. Coniferous forests are dominated by Brown rot fungi that are involved in earliest phase of lignocellulose breakdown, and therefore, influencing the second phase of microbial colonization. This study aimed to investigate the first microbial species colonizing after intermediate and advanced pre-degradation by the brown rot fungus Gloeophyllum trabeum. Using Illumina metabarcoding, bacterial and fungal communities were monitored after 70 days from Picea abies wood blocks placed between forest floor and topsoil. Chemical composition of the wood samples was determined for each of the pre-degradation stages. We observed significant changes in the bacterial and fungal communities associated with the pre-degradation of P. abies, and that wood substrate condition acted as a gatekeeper for both microbial communities. Our data also suggested that fungal and bacterial communities could interact and act in a synergistic way during the wood decomposition process.
ConvNets Develop Organizational Principles of the Visual Cortex when using Ganglion Cell-Based Sampling
Authors: da Costa Danny , Goebel Rainer , Senden Mario
Published: November 2021

Abstract

The distribution of retinal ganglion cells in primate visual systems portrays a densely distributed central region, with an incrementally decreasing cell density as the angle of visual eccentricity increases. This results in a non-uniform sampling of the retinal image that resembles a wheelbarrow distortion. We propose that this sampling gives rise to several organizational properties of the primate visual system, including cortical magnification, linear relationship between eccentricity and receptive field sizes, eccentricity-dependent drop-off in spatial-frequency preference, and radial bias. We test this hypothesis by training a convolutional neural network to classify the orientation of sine gratings and Gabor stimuli, resampled according to retinal ganglion cell distributions. Our simulations show that introducing this sampling step gives rise to the aforementioned organizational principles in convolutional layers while only minimally affecting their classification performance. This lends credence to the notion that the retinal ganglion cell distribution is an important factor for the emergence of these organizational principles in visual systems.
Neutralizing antibodies induced in immunized macaques recognize the CD4-binding site on an occluded-open HIV-1 envelope trimer
Authors: Yang Zhi , Dam Kim-Marie A. , Bridges Michael D. , Hoffmann Magnus A.G. , DeLaitsch Andrew T. , Gristick Harry B. , Escolano Amelia , Gautam Rajeev , Martin Malcolm A. , Nussenzweig Michel C. , Hubbell Wayne L. , Bjorkman Pamela J.
Published: November 2021

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an ‘occluded-open’ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts.
Inhibition of BKCa channels protects neonatal hearts against myocardial ischemia and reperfusion injury
Authors: Sanghvi Shridhar , Szteyn Kalina , Ponnalagu Devasena , Sridharan Divya , Lam Alexender , Hansra Inderjot , Chaudhury Ankur , Majumdar Uddalak , Kohut Andrew R. , Rao Shubha Gururaja , Khan Mahmood , Garg Vidu , Singh Harpreet
Published: November 2021

BKCa channels are large-conductance calcium and voltage-activated potassium channels that are heterogeneously expressed in a wide array of cells. Activation of BKCa channels present in mitochondria of adult ventricular cardiomyocytes is implicated in cardioprotection against ischemia-reperfusion (IR) injury. However, the BKCa channel’s activity has never been detected in the plasma membrane of adult ventricular cardiomyocytes. In this study, we report the presence of the BKCa channel in the plasma membrane and mitochondria of neonatal murine and rodent cardiomyocytes which protects the heart on inhibition but not activation. Furthermore, K+ currents measured in neonatal cardiomyocyte (NCM) was sensitive to iberiotoxin (IbTx), suggesting the presence of BKCa channels in the plasma membrane. Neonatal hearts subjected to IR when post-conditioned with NS1619 during reoxygenation increased the myocardial infarction whereas IbTx reduced the infarct size. In agreement, isolated NCM also presented increased apoptosis on treatment with NS1619 during hypoxia and reoxygenation, whereas IbTx reduced TUNEL positive cells. In NCMs, activation of BKCa channels increased the intracellular reactive oxygen species post HR injury. Electrophysiological characterization of NCMs indicated that NS1619 increased the beat period, field, and action potential duration, and decreased the conduction velocity and spike amplitude. In contrast, IbTx had no impact on the electrophysiological properties of NCMs. Taken together, our data established that inhibition of plasma membrane BKCa channels in the NCM protects neonatal heart/cardiomyocytes from IR injury. Furthermore, the functional disparity observed towards the cardioprotective activity of BKCa channels in adults compared to neonatal heart could be attributed to their differential localization.
Initial approach to the Conservation Genetics of the Guatemalan Beaded Lizard (Heloderma charlesbogerti): A route to genetic rescue
Authors: González Sergio , Schrei Thomas , Lock Brad
Published: November 2021

In this study, samples from 33 Guatemalan Beaded Lizard (Heloderma charlesbogerti) were analyzed for genetic diversity. Twenty-three samples were obtained from wild individuals from two separate population areas, and 10 samples were obtained from captive individuals. Because the seasonally dry tropical forest habitat sampled for this study, is degraded and fragmented, it was hypothesized that beaded lizard populations were small and isolated and would be subject to genetic erosion and an elevated extinction risk. To test this hypothesis, eight microsatellite markers were employed to analyze 22 individual samples from the population of Cabañas, Zacapa, a single individual from the eastern-most population and 10 captive individuals of unknown origin. An average of three alleles per maker was reported for the Cabañas population, evidencing a low genetic diversity. In addition, a recent bottleneck event was detected and an effective population size of 19.6 was estimated. Demographic reconstruction using a Bayesian approach was inconclusive possibly due to a small dataset and shallow coalescence trees obtained with the generated data. No clear structuring pattern was detected for the Cabañas population and most samples from individuals in captivity were found to have similar alleles to the ones from Cabañas. Population designation is challenging without the genotyping of every wild population, but unique alleles were found in captive individuals of unknown origin that could suggest that different genotypes might exist within other, less studied, wild populations. Low genetic diversity, and a small effective population size represent a risk for the Cabañas population facing the threats of isolation, habitat loss and climate change. These findings suggest that genetic management of the Cabañas population might be utilized to avoid high rates of inbreeding and subsequent inbreeding depression.
Evaluating the heterogeneous effect of extended incubation to blastocyst transfer on the implantation outcome via causal inference
Authors: Kan-Tor Yoav , Srebnik Naama , Gavish Matan , Shalit Uri , Buxboim Amnon
Published: November 2021

In IVF treatments, extended culture to single blastocyst-transfer is the recommended protocol over cleavage-stage transfer. However, evidence-based criteria for assessing the heterogeneous implications on implantation outcome are lacking. To estimate the causal effect of blastocyst-transfer on implantation outcome, we assembled a multicenter dataset of embryo time-lapse imaging. The data includes a natural source of randomness and has a strong claim for satisfying the assumptions needed for valid causal inference. By fitting a causal forest model, we assessed the ‘Transfer Lift’, which quantifies the probability difference in embryo implantation if transferred as a blastocyst versus cleavage-stage. Blastocyst transfer increased the average implantation rate, however we revealed a subpopulation of negative Transfer Lift embryos whose implantation potential is predicted to increase via cleavage-stage transfer. We provide day-of-transfer decision-support tools that are retrospectively estimated to improve implantation rate by 32%, thus demonstrating the efficacy of embryo-level causal inference in reproductive medicine.

One Sentence Summary

A causal inference model predicts the heterogeneous effect of prolonged incubation to blastocyst transfer on embryo implantation, thus providing means for optimizing pregnancy rates in IVF treatments.
Influence of Response Criterion on Nociceptive Detection Thresholds and Evoked Potentials
Authors: van den Berg Boudewijn , Vanwinsen L. , Pezzali G. , Buitenweg Jan R.
Published: November 2021

Pain scientists and clinicians search for objective measures of altered nociceptive processing to study and stratify chronic pain patients. Nociceptive processing can be studied by observing a combination of nociceptive detection thresholds and evoked potentials. However, it is unknown whether the nociceptive detection threshold measured using a Go-/No-Go (GN) procedure can be biased by a response criterion. In this study, we compared nociceptive detection thresholds, psychometric slopes and central evoked potentials obtained during a GN procedure with those obtained during a 2-interval forced choice (2IFC) procedure to determine 1) if the nociceptive detection threshold during a GN procedure is biased by a criterion and 2) to determine if nociceptive evoked potentials observed in response to stimuli around the detection threshold are biased by a criterion. We found that the detection threshold can be higher when assessed using a GN procedure in comparison with the 2IFC procedure. The average P2 component in the central evoked potential showed on-off behavior with respect to stimulus detection and increased proportionally with the detection probability during a GN procedure. These data suggest that nociceptive detection thresholds estimated using a GN procedure are subject to a response criterion.
Unbiased Proteomics, Histochemistry, and Mitochondrial DNA Copy Number Reveal Better Mitochondrial Health in Muscle of High Functioning Octogenarians
Authors: Ubaida-Mohien Ceereena , Spendiff Sally , Lyashkov Alexey , Moaddel Ruin , MacMillan Norah J. , Filion Marie-Eve , Morais Jose A. , Taivassalo Tanja , Ferrucci Luigi , Hepple Russell T.
Published: November 2021

Background

Master athletes prove that preserving a high level of physical function up to very late in life is possible, but the mechanisms responsible for their high function remain unclear.

Methods

We performed muscle biopsies in 15 octogenarian world class track and field masters athletes (MA) and 14 non-athlete age/sex-matched controls (NA) to provide insights into mechanisms for preserving function in advanced age. Muscle samples were assessed for respiratory compromised fibers, mtDNA copy number, and proteomics by liquid-chromatography mass spectrometry.

Results

Most of the ∼800 differentially represented proteins in MA versus NA pertained to mitochondria structure/function such as electron transport capacity (ETC), cristae formation, mitochondrial biogenesis, and mtDNA-encoded proteins. In contrast, proteins from the spliceosome complex and nuclear pore were downregulated in MA. Consistent with proteomics data, MA had fewer respiratory compromised fibers, higher mtDNA copy number, and an increased protein ratio of the cristae-bound ETC subunits relative to the outer mitochondrial membrane protein voltage dependent anion channel. There was a substantial overlap of proteins overrepresented in MA versus NA with proteins that decline with aging and which are higher in physically active than sedentary individuals. However, we also found 176 proteins related to mitochondria that are uniquely differentially expressed in MA.

Discussion

We conclude that high function in advanced age is associated with preserving mitochondrial structure/function proteins, with under-representation of proteins involved in the spliceosome and nuclear pore complex. Whereas many of these differences in MA appear related to their physical activity habits, others may reflect unique biological (e.g., gene, environment) mechanisms that preserve muscle integrity and function with aging.
Structure Determination of Inactive-State GPCRs with a Universal Nanobody
Authors: Robertson Michael J. , Papasergi-Scott Makaía , He Feng , Seven Alpay B. , Meyerowitz Justin G. , Panova Ouliana , Peroto Maria Claudia , Che Tao , Skiniotis Georgios
Published: November 2021

Cryogenic electron microscopy (cryo-EM) has widened the field of structure-based drug discovery by allowing for routine determination of membrane protein structures previously intractable. However, despite representing one of the largest classes of therapeutic targets, most inactive-state G protein-coupled receptors (GPCRs) have remained inaccessible for cryo-EM because their small size and membrane-embedded nature impedes projection alignment for high-resolution map reconstructions. Here we demonstrate that the same single-chain camelid antibody (nanobody) recognizing a grafted intracellular loop can be used to obtain cryo-EM structures of different inactive-state GPCRs at resolutions comparable or better than those obtained by X-ray crystallography. Using this approach, we obtained the structure of human neurotensin 1 receptor (NTSR1) bound to antagonist SR48692, of µ-opioid receptor (MOR) bound to the clinical antagonist alvimopan, as well as the structures of the previously uncharacterized somatostatin receptor 2 (SSTR2) in the apo state and histamine receptor 2 (H2R) bound to the H2 blocker famotidine. Each of these structures yields novel insights into ligand binding and specificity. We expect this rapid, straightforward approach to facilitate the broad structural exploration of GPCR inactive states without the need for extensive engineering and crystallization.
Wound-like tumor periphery in human breast cancer predicts a convergent drug nonresponse
Authors: Li Lianhuang , Liao Xiaoxia , Fu Fangmeng , Xi Gangqin , Kang Deyong , He Jiajia , Guo Wenhui , Qiu Lida , Han Zhonghua , Wang Xingfu , Zhan Qingyuan , You Sixian , Chen Jianxin , Wang Chuan , Boppart Stephen A. , Tu Haohua
Published: November 2021

A significant portion of breast cancer patients are nonresponsive to well-established drugs and destined for a poor outcome regardless of molecular subtype. Although several (multiparameter) molecular markers have predicted their resistance to some of these drugs, profound uniparameter markers predictive of a convergent nonresponse to all these drugs remain elusive. We employ co-registered standard-multiphoton histology to representatively sample a few peripheral niches of the primary tumor, so that hundreds of patients can be stratified with either a wound-like or non-wound tumor periphery. With no fitting variable, this simple uniparameter morphological marker is: (a) highly sensitive and specific to predict a multidrug-nonresponsive phenotype that accounts for the majority of recurrence or death, independent of the molecular subtype or related adjuvant drug selection, clinical endpoint (disease-free versus overall survival), and hosting medical center; (b) robust against intratumor heterogeneity and valid at the earliest clinicopathological stage; and (c) dominant in predicting prognosis in the context of routine clinicopathological markers. Considering the mechanistic link between a wound-like extracellular matrix and a microenvironment supporting migratory or mesenchymal tumor cells, we attribute these unusual capabilities to an epithelial-mesenchymal transition nature of the morphological marker long sought after by pathologists.
A multivariate to multivariate approach for voxel-wise genome-wide association analysis
Authors: Wu Qiong , Zhang Yuan , Huang Xiaoqi , Ma Tianzhou , Hong L. Elliot , Kochunov Peter , Chen Shuo
Published: November 2021

The joint analysis of imaging-genetics data facilitates the systematic investigation of genetic effects on brain structures and functions with spatial specificity. We focus on voxel-wise genome-wide association analysis, which may involve trillions of single nucleotide polymorphism (SNP)-voxel pairs. We attempt to identify underlying organized association patterns of SNP-voxel pairs and understand the polygenic and pleiotropic networks on brain imaging traits. We propose a bi-clique graph structure (i.e., a set of SNPs highly correlated with a cluster of voxels) for the systematic association pattern. Next, we develop computational strategies to detect latent SNP-voxel bi-cliques and inference model for statistical testing. We further provide theoretical results to guarantee the accuracy of our computational algorithms and statistical inference. We validate our method by extensive simulation studies, and then apply it to the whole genome genetic and voxel-level white matter integrity data collected from 1052 participants of the human connectome project (HCP). The results demonstrate multiple genetic loci influencing white matter integrity measures on splenium and genu of the corpus callosum.
SPCS: A Spatial and Pattern Combined Smoothing Method for Spatial Transcriptomic Expression
Authors: Liu Yusong , Wang Tongxin , Duggan Ben , Sharpnack Michael , Huang Kun , Zhang Jie , Ye Xiufen , Johnson Travis S.
Published: November 2021

High dimensional, localized RNA sequencing is now possible owing to recent developments in spatial transcriptomics (ST). ST is based on highly multiplexed sequence analysis and uses barcodes to match the sequenced reads to their respective tissue locations. ST expression data suffers from high noise and drop-out events; however, smoothing techniques have the promise to improve the data interpretability prior to performing downstream analyses. Single cell RNA sequencing (scRNA-seq) data similarly suffer from these limitations, and smoothing methods developed for scRNA-seq can only utilize associations in transcriptome space (also known as one-factor smoothing methods). Since they do not account for spatial relationships, these one-factor smoothing methods cannot take full advantage ST data. In this study, we present a novel two-factor smoothing technique, Spatial and Pattern Combined Smoothing (SPCS), that employs k-nearest neighbor technique to utilize information from transcriptome and spatial relationships. By performing SPCS on multiple ST slides from pancreatic ductal adenocarcinoma (PDAC), dorsolateral prefrontal cortex (DLPFC), and simulated high-grade serous ovarian cancer (HGSOC) datasets, smoothed ST slides have better separability, partition accuracy, and biological interpretability than the ones smoothed by pre-existing one-factor methods. Source code of SPCS is provided in Github (https://github.com/Usos/SPCS).
Whole-Blood DNA Methylation Analysis Reveals Respiratory Environmental Traits Involved in COVID-19 Severity Following SARS-CoV-2 Infection
Authors: Barturen Guillermo , Carnero-Montoro Elena , Martínez-Bueno Manuel , Rojo-Rello Silvia , Sobrino Beatriz , Alcántara-Domínguez Clara , Bernardo David , Alarcón-Riquelme Marta E.
Published: November 2021

SARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ∼5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth, yet. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping.

The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We found an environmental trait-related signature that discriminates mild from severe cases, and regulates IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.
Exploring new EEG-parameters in electroconvulsive therapy
Authors: Schreiner J , Kessler U , Oedegaard KJ , Mardal KA , Oltedal L
Published: November 2021

Background

Electroconvulsive therapy (ECT) is an effective treatment against severe depressive episodes, which has been shown to induce volume changes in the hippocampus. The power spectrum of the electroencephalogram (EEG) follows a characteristic power-law relation but its utility as a metric of ECT-induced seizures has not been explored.

Objective

This study aims to evaluate a novel metric based on the power spectrum of the EEG recordings from ECT-induced seizures; its association to volume changes in the hippocampus following ECT and improvement in depression rating scores.

Methods

Depressed patients treated with ECT underwent brain MRI before- and after treatment and the EEG from each seizure was recorded (N=29). Hippocampal volume changes and EEG parameters were recorded in addition to clinician-rated and self-reported measures of depressive symptoms. The slope of the power-law in the power spectral density of the EEG was calculated. Multivariate linear models relating seizure parameters to volume change or clinical outcome was systematically and successively simplified. The best models were selected according to Akaike’s information criterion.

Results

The slope of the power-law was steeper in the right than the left hemisphere (p < 0.001). EEG measures were included in the best models of volume change for both hippocampi as well as in the models explaining clinical outcome (p = 0.014, p = 0.004).

Conclusions

A novel EEG measures was explored and contributed in models explaining the variation in volume change in the hippocampus and in clinical outcome following ECT.
A brain structural connectivity biomarker for diagnosis of autism spectrum disorder in early childhood
Authors: Jiang Xi , Shou Xiao-Jing , Zhao Zhongbo , Meng Fanchao , Le Jiao , Song Tianjia , Xu Xinjie , Ke Xiaoyan , Chen Yuzhong , Cai Xiaoe , Zhao Weihua , Kou Juan , Huo Ran , Liu Ying , Yuan Huishu , Xing Yan , Han Jisheng , Han Songping , Li Yun , Lai Hua , Zhang Lan , Jia Meixiang , Liu Jing , Kendrick Keith M. , Zhang Rong
Published: November 2021

Objective

Autism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers. This study aimed to identify and model brain-wide differences in structural connectivity using MRI diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children (3·5-6 years old).

Methods

Ninety-three ASD and 26 TD children were included in a discovery dataset and 12 ASD and 9 TD children from different sites included as independent validation datasets. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) under sedation together with symptom severity and behavioral and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed and the resulting model tested on two independent datasets.

Results

Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both symptom severity and general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification accuracy is very high in the discovery dataset 96.77%, and 91·67% and 88·89% in the two independent validation datasets.

Conclusions

Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish individual ASD from TD children and may therefore represent a robust early brain biomarker.
Obesity and accelerated epigenetic aging in a high-risk cohort of children
Authors: Etzel Laura , Hastings Waylon J. , Hall Molly A. , Heim Christine , Meaney Michael J. , Noll Jennie G. , O’Donnell Kieran J. , Pokhvisneva Irina , Rose Emma Jane , Schreier Hannah M. C. , Shenk Chad , Shalev Idan
Published: November 2021

Background

New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mass index (BMI) and accelerated epigenetic aging in a cohort of high-risk children. Participants were children (N=273, aged 8 to 14 years, 82% investigated for maltreatment) recruited to the Child Health Study, an ongoing prospective study of youth investigated for maltreatment and a comparison youth. BMI was measured as a continuous variable. Accelerated epigenetic aging of blood leukocytes was defined as the age-adjusted residuals of several established epigenetic aging clocks (Horvath, Hannum, GrimAge, PhenoAge) along with a newer algorithm, the DunedinPoAm, developed to quantify the pace-of-aging. Hypotheses were tested with generalized linear models.

Results

Higher BMI was significantly correlated with older chronological age, maltreatment status, household income, blood cell counts, and three of the accelerated epigenetic aging measures: GrimAge (r=0.29,P<.0001), PhenoAge (r=0.25,P<.0001), and DunedinPoAm (r=0.37,P<.0001). In fully adjusted models, GrimAge (b=.06;P=.007) and DunedinPoAm (b=.0017;P<.0001) remained significantly associated with higher BMI. Maltreatment-status was not independently associated with accelerated epigenetic aging after accounting for other factors.

Conclusion

In a high-risk cohort of children, higher BMI predicted epigenetic aging as assessed by two epigenetic aging clocks. These results suggest the association between obesity and accelerated epigenetic aging begins in early life, with implications for future morbidity and mortality risk.