bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of Neck or Back Pain in Ambulatory Care
Authors: Roblin Douglas W. , Goodrich Glenn K. , Davis Teaniese L. , Gander Jennifer C. , McCracken Courtney E. , Weinfield Nancy S. , Ritzwoller Debra P.
Published: March 2023

Background/Objective:

In recent years, 2 circumstances have changed provider-patient interactions in ambulatory care: (1) the replacement of virtual for in-person visits and (2) the COVID-19 pandemic. We studied the potential impact of each event on provider practice and patient adherence by comparing the frequency of the association of provider orders, and patient fulfillment of those orders, by visit mode and pandemic period, for incident neck or back pain (NBP) visits in ambulatory care.

Methods:

Data were extracted from the electronic health records of 3 Kaiser Permanente regions (Colorado, Georgia, and Mid-Atlantic States) from January 2017 to June 2021. Incident NBP visits were defined from ICD-10 coded as primary or first listed diagnoses on adult, family medicine, or urgent care visits separated by at least 180 days. Visit modes were classified as virtual or in-person. Periods were classified as prepandemic (before April 2020 or the beginning of the national emergency) or recovery (after June 2020). Percentages of provider orders for, and patient fulfillment of orders, were measured for 5 service classes and compared on: virtual versus in-person visits, and prepandemic versus recovery periods. Comparisons were balanced on patient case-mix using inverse probability of treatment weighting.

Results:

Ancillary services in all 5 categories at each of the 3 Kaiser Permanente regions were substantially ordered less frequently on virtual compared with in-person visits in both the prepandemic and recovery periods (both P ≤ 0.001). Conditional on an order, patient fulfillment within 30 days was high (typically ≥70%) and not likely meaningfully different between visit modes or pandemic periods.

Conclusions:

Ancillary services for incident NBP visits were ordered less frequently during virtual than in-person visits in both prepandemic and recovery periods. Patient fulfillment of orders was high, and not significantly different by mode or period.
Ustekinumab Use in Pediatric Inflammatory Bowel Disease: A French Multicenter Study From the Pediatric GETAID
Authors: Koudsi Mounzer , Martinez-Vinson Christine , Pigneur Bénédicte , Willot Stéphanie , Djamal Djeddi , Enaud Raphael , Rebeuh Julie , Dupont Claire , Dabadie Alain , Bertrand Valérie , Hugot Jean-Pierre , Lachaux Alain , Ruemmele Franck , Viala Jérôme , Duclaux-Loras Rémi , Pédiatrique GETAID
Published: March 2023

Objectives:

Ustekinumab is known to be efficient in adult patients suffering from moderate to severe Crohn disease (CD) and ulcerative colitis (UC) resistant to anti-tumor necrosis factor-alpha (TNF-α). Here, we described the clinical course of treatment with ustekinumab in French pediatric inflammatory bowel disease (IBD) patients treated with ustekinumab.

Methods:

This study includes all pediatric patients treated by ustekinumab injection for IBD (CD and UC), between January 2016 and December 2019.

Results:

Fifty-three patients were enrolled, 15 males and 38 females. Forty-eight patients (90%) had a diagnosis of CD and 5 (9.4%) had UC. Sixty-five percent of CD patients presented an ileocolitis. Perineal disease was observed in 20 out of 48 CD patients (41.7%), among them 9 were treated surgically. All patients included were resistant to anti-TNF-α treatment. Fifty-one percent had presented side effects linked to anti-TNF-α, including psoriasis and anaphylactic reaction. The average Pediatric Crohn Disease Activity Index (PCDAI) at induction was 28.7 (5–85), 18.7 (0–75) at 3 months of treatment and 10 (0–35) at the last follow-up. The average Pediatric Ulcerative Colitis Activity Index at induction was 47 (25–65), 25 (15–40) at 3 months of treatment and 18.3 (0–35) at the last follow-up. No severe side effects were observed.

Conclusion:

In this retrospective, multicentral study, ustekinumab proved to be efficient in pediatric patients resistant to anti-TNF-α. PCDAI has been significantly improved in patients with severe disease, treated with ustekinumab.
In Silico Localization of Perilymph Proteins Enriched in Meńier̀e Disease Using Mammalian Cochlear Single-cell Transcriptomics
Authors: Arambula Alexandra M. , Gu Shoujun , Warnecke Athanasia , Schmitt Heike A. , Staecker Hinrich , Hoa Michael
Published: March 2023

Hypothesis:

Proteins enriched in the perilymph proteome of Meńier̀e disease (MD) patients may identify affected cell types. Utilizing single-cell transcriptome datasets from the mammalian cochlea, we hypothesize that these enriched perilymph proteins can be localized to specific cochlear cell types.

Background:

The limited understanding of human inner ear pathologies and their associated biomolecular variations hinder efforts to develop disease-specific diagnostics and therapeutics. Perilymph sampling and analysis is now enabling further characterization of the cochlear microenvironment. Recently, enriched inner ear protein expression has been demonstrated in patients with MD compared to patients with other inner ear diseases. Localizing expression of these proteins to cochlear cell types can further our knowledge of potential disease pathways and subsequent development of targeted therapeutics.

Methods:

We compiled previously published data regarding differential perilymph proteome profiles amongst patients with MD, otosclerosis, enlarged vestibular aqueduct, sudden hearing loss, and hearing loss of undefined etiology (controls). Enriched proteins in MD were cross-referenced against published single-cell/single-nucleus RNA-sequencing datasets to localize gene expression to specific cochlear cell types.

Results:

In silico analysis of single-cell transcriptomic datasets demonstrates enrichment of a unique group of perilymph proteins associated with MD in a variety of intracochlear cells, and some exogeneous hematologic and immune effector cells. This suggests that these cell types may play an important role in the pathology associated with late MD, suggesting potential future areas of investigation for MD pathophysiology and treatment.

Conclusions:

Perilymph proteins enriched in MD are expressed by specific cochlear cell types based on in silico localization, potentially facilitating development of disease-specific diagnostic markers and therapeutics.
Post-ictal Rhythmic Thalamic Activity of the Centromedian Nucleus
Authors: Arredondo Kristen , Ostendorf Adam P. , Ahrens Stephanie , Beatty Christopher W. , Pindrik Jonathan , Shaikhouni Ammar
Published: March 2023

Introduction:

Deep brain stimulation of the centromedian nucleus of the thalamus (CMN) to treat drug-resistant epilepsy has been of interest for decades. However, little is known about the electrophysiological activity of the CMN during seizures. We describe a novel CMN EEG finding associated with seizure: post-ictal rhythmic thalamic activity.

Methods:

Five patients with drug-resistant epilepsy of unknown etiology with focal onset seizures underwent stereoelectroencephalography monitoring as part of evaluation for potential resective surgery or neuromodulation. Two patients had previously undergone complete corpus callosotomy and vagus nerve stimulation. A standardized plan for implantation included targets in the bilateral CMN.

Results:

Each patient had frontal onset seizures, and two patients had additional insular, parietal, or mesial temporal onset seizures. Contacts of CMN were involved synchronously or rapidly after onset in most recorded seizures, particularly those with frontal onset. Focal onset hemiclonic and bilateral tonic–clonic seizures spread to involve cortical contacts with high-amplitude rhythmic spiking followed by abrupt offset with diffuse voltage attenuation. A post-ictal rhythmic 1.5 to 2.5 Hz delta frequency pattern, post-ictal rhythmic thalamic activity, emerged in CMN contacts amid the suppression of background activity in cortical contacts. In the two patients with corpus callosotomy, unilateral seizure spread and ipsilateral post-ictal rhythmic thalamic activity were observed.

Conclusions:

We observed post-ictal rhythmic thalamic activity in five patients with stereoelectroencephalography monitoring of the CMN with convulsive seizures. This rhythm appears late in ictal evolution and may signal an important role of the CMN in seizure termination. Furthermore, this rhythm may help identify CMN involvement in the epileptic network.
Clinical and microbiological characteristics of Chryseobacterium species isolates from bloodstream infections from a university hospital: a descriptive, retrospective study
Authors: Chaudhary Radhika , Kar Mitra , Jamwal Ashima , Dubey Akanksha , Singh Romya , Tejan Nidhi , Sahu Chinmoy , Patel Sangram Singh , Kumari Pooja , Ghar Malay
Published: March 2023

Abstract
Introduction: Chryseobacterium species are emerging bacteria capable of causing nosocomial infections in immunocompromised patients or patients with indwelling medical devices.
Hypothesis/ Gap statement: Information about the incidence of Chryseobacterium bacteremia from worldwide literature is limited.
Aim: We aimed to recognize the clinical characteristics, frequency of distribution of different Chryseobacterium species isolates, and their antimicrobial susceptibility profile from bloodstream infections. 
Methods: We performed a retrospective cohort study to identify all isolates of Chryseobacterium species from bloodstream infection from January 2018 to November 2022 at a university hospital in North India.
Results: We identified 42 non-duplicate isolates of Chryseobacterium species from bloodstream infection in the duration of our study. Mean age of the patients was 48.35 ± 16.63 years. Men (22/42, 52.2%) were more commonly affected in comparison to women (20/42, 47.6%) but the difference was not significant. The most common species identified was C.indologenes (40/42, 95.24%) followed by C. gleum (2/42, 4.76%). The co-morbidities commonly encountered in our study were chronic kidney disease (21/42, 50.0%) followed by diabetes mellitus (12/42, 28.6%) and chronic obstructive pulmonary disease (8/42, 19.05%). All patients had intravenous access to medications or fluid management via a central or peripheral line and mechanical ventilation was observed in 39 (39/42, 92.86%) patients. All the isolates were susceptible to minocycline (100%), followed by doxycycline (97.6%) and trimethoprim-sulfamethoxazole (95.2%).
Conclusion: Chryseobacterium species are capable of causing pneumonia, bacteremia and urinary tract infection in immunocompromised patients. Early diagnosis and prompt treatment with appropriate antibiotics can prevent progression to septicemia.
Anatomical Substrates and Connectivity for Parkinson’s Disease Bradykinesia Components after STN-DBS
Authors: Kim Min Jae , Shi Yiwen , Lee Jasmine , Salimpour Yousef , Anderson William S. , Mills Kelly A.
Published: March 2023

Background

Parkinsonian bradykinesia is rated using a composite scale incorporating slowed frequency of repetitive movements, decrement amplitude, and arrhythmicity. Differential localization of these movement components within basal ganglia would drive the development of more personalized network-targeted symptomatic therapies.

Methods

Using an optical motion sensor, amplitude and frequency of hand movements during grasping task were evaluated with subthalamic nucleus (STN)-Deep Brain Stimulation (DBS) “on” or “off” in 15 patients with Parkinson’s disease (PD). The severity of bradykinesia was assessed blindly using the MDS-UPDRS Part-III scale. Volumes of activated tissue (VAT) of each subject were estimated where changes in amplitude and frequency were mapped to identify distinct anatomical substrates of each component in the STN. VATs were used to seed a normative functional connectome to generate connectivity maps associated with amplitude and frequency changes.

Results

STN-DBS-induced change in amplitude was negatively correlated with change in MDS-UPDRS-III right (r = -0.65, p < 0.05) and left hand grasping scores (r = -0.63, p < 0.05). The change in frequency was negatively correlated with amplitude for both right (r = -0.63, p < 0.05) and left hand (r = -0.57, p < 0.05). The amplitude and frequency changes were represented as a spatial gradient with overlapping and non-overlapping regions spanning the dorsolateral-ventromedial axis of the STN. Whole-brain correlation maps between functional connectivity and motor changes were also inverted between amplitude and frequency changes.

Conclusion

DBS-associated changes in frequency and amplitude were topographically and distinctly represented both locally in STN and in whole-brain functional connectivity.
Establishing the relationships between adiposity and reproductive factors: a multivariable Mendelian randomization analysis
Authors: Prince Claire , Howe Laura D , Sharp Gemma C , Fraser Abigail , Richmond Rebecca C
Published: March 2023

Background

Few studies have investigated associations between adiposity and reproductive factors using causal methods, both of which have a number of consequences on disease. Here we assess whether adiposity at different points in the lifecourse affects reproductive factors differently and independently, and the plausibility of the impact of reproductive factors on adiposity.

Methods

We used genetic data from UK Biobank and other consortia for eight reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age first had sexual intercourse and lifetime number of sexual partners, and two adiposity traits: childhood body size and adulthood body mass index (BMI). We applied multivariable mendelian randomization to account for genetic correlation and estimate causal effects of childhood and adulthood adiposity, independently of each other, on reproductive factors. Additionally, we estimated the effects of reproductive factors, independently of other relevant reproductive factors, on adulthood adiposity.

Findings

We found a higher childhood body size leads to an earlier age at menarche, which in turn leads to higher adulthood BMI. Furthermore, we find contrasting and independent effects of childhood body size and adulthood BMI on age at first birth (Beta 0.22 SD (95% confidence interval:0.14,0.31) vs -2.49 (−2.93,-2.06) per 1 SD increase), age at last birth (0.13 (0.06,0.21) vs -1.86 (−2.23,-1.48) per 1 SD increase), age at menopause (0.17 (0.09,0.25) vs -0.99 (−1.39,-0.59) per 1 SD increase), and likelihood of having children (Odds ratio 0.97 (0.95,1.00) vs 1.20 (1.06,1.37) per 1 SD increase).

Conclusions

We highlight the importance of untangling the effects of exposures at different timepoints across the lifecourse, as demonstrated with adiposity, where accounting for measures at one point in the lifecourse can alter the direction and magnitude of effects at another time point and should therefore be considered in further studies.
Green Heart Louisville: Intra-urban, hyperlocal land-use regression modeling of ultrafine particles
Authors: Prathibha Pradeep , Yeager Raymond , Bhatnagar Aruni , Turner Jay
Published: March 2023

Exposure to ultrafine particles (UFP) is increasingly linked to adverse health outcomes. While nation-wide air monitoring networks in the United States do not measure UFP, small-scale measurements have revealed persistent patterns in urban UFP. This project maps hyperlocal UFP in a 12 km2study area of a health effects study in Louisville, KY, through mobile measurements to elucidate the relationship between the urban landscape and UFP exposures. We measured UFP number concentration along all drivable streets (∼340 km) during daytime and nighttime on both weekdays and weekends. After deconvoluting UFP levels to isolate local signals from neighborhood and urban signals, we fitted a land-use regression (LUR) model to explain differences in local UFP as a function of characteristics of the built and natural environment.

Median UFP in the study domain was 6,850 #/cm3, which is comparable to urban background measured or estimated for other U.S. cities. UFP was higher during the weekend than on weekdays, potentially due to changes in local activity (e.g. increased restaurant hours) apparent at fine spatial scales. The final LUR model explained 61% of the spatial heterogeneity in log(UFP). Leave-one-area-out cross validation revealed overprediction in regions farther from highways and underprediction in regions with dense food service locations and major roads. This suggests that additional mobile measurements to capture longer-term, robust UFP may yield improved models.
MOVER: Medical Informatics Operating Room Vitals and Events Repository
Authors: Samad Muntaha , Rinehart Joseph , Angel Mirana , Kanomata Yuzo , Baldi Pierre , Cannesson Maxime
Published: March 2023

Artificial Intelligence (AI) holds great promise for transforming the healthcare industry. However, despite its potential, AI is yet to see widespread deployment in clinical settings in significant part due to the lack of publicly available clinical data and the lack of transparency in the published AI algorithms. There are few clinical data repositories publicly accessible to researchers to train and test AI algorithms, and even fewer that contain specialized data from the perioperative setting. To address this gap, we present and release the Medical Informatics Operating Room Vitals and Events Repository, which includes data from 58,799 unique patients and 83,468 surgeries collected from the UCI Medical Center over a period of seven years. MOVER is freely available to all researchers who sign a data usage agreement, and we hope that it will accelerate the integration of AI into healthcare settings, ultimately leading to improved patient outcomes.
Pharmacological characterization of the endocannabinoid sensor GRABeCB2.0
Authors: Singh Simar , Sarroza Dennis , English Anthony , McGrory Maya , Dong Ao , Zweifel Larry , Land Benjamin B. , Li Yulong , Bruchas Michael R. , Stella Nephi
Published: March 2023

Introduction

The endocannabinoids (eCBs), 2-arachidonoylglycerol (2-AG) and arachidonoyl ethanolamine (AEA), are produced by separate enzymatic pathways, activate cannabinoid receptors with distinct pharmacology, and differentially regulate pathophysiological processes. The genetically encoded sensor, GRABeCB2.0, detects real-time changes in eCB levels in cells in culture and preclinical model systems; however, its activation by eCB analogues produced by cells and by phyto-cannabinoids remains uncharacterized, a current limitation when interpreting changes in its response. This information could provide additional utility for the tool in in vivo pharmacology studies of phyto-cannabinoid action.

Methods

GRABeCB2.0was expressed in cultured HEK293 cells. Live cell confocal microscopy and high-throughput fluorescent signal measurements.

Results

2-AG increased GRABeCB2.0fluorescent signal (EC50= 85 nM), and the cannabinoid 1 receptor (CB1R) antagonist, SR141617, decreased GRABeCB2.0signal (SR1, IC50= 3.3 nM), responses that mirror their known potencies at cannabinoid 1 receptors (CB1R). GRABeCB2.0fluorescent signal also increased in response to AEA (EC50= 815 nM), the eCB analogues 2-linoleoylglycerol and 2-oleoylglycerol (2-LGand2-OG, EC50s = 1.5 and 1.0 μM, respectively), Δ9-tetrahydrocannabinol (Δ9-THC) andΔ8-THC(EC50s = 1.6 and 2.0 μM, respectively), and the artificial CB1R agonist, CP55,940 (CP, EC50= 82 nM); however their potencies were less than what has been described at CB1R. Cannabidiol (CBD) did not affect basal GRABeCB2.0fluorescent signal and yet reduced the 2-AG stimulated GRABeCB2.0responses (IC50= 8.8 nM).

Conclusions

2-AG and SR1 modulate the GRABeCB2.0fluorescent signal with EC50s that mirror their potencies at CB1R whereas AEA, eCB analogues, THC and CP increase GRABeCB2.0fluorescent signal with EC50s significantly lower than their potencies at CB1R. CBD reduces the 2-AG response without affecting basal signal, suggesting that GRABeCB2.0retains the negative allosteric modulator (NAM) property of CBD at CB1R. This study describes the pharmacological profile of GRABeCB2.0to improve interpretation of changes in fluorescent signal in response to a series of known eCBs and CB1R ligands.
Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis
Authors: Morishima Tatsuya , Fakruddin Md. , Masuda Takeshi , Wang Yuxin , Schoonenberg Vivien A. C. , Butter Falk , Arima Yuichiro , Akaike Takaaki , Tomizawa Kazuhito , Wei Fan-Yan , Suda Toshio , Takizawa Hitoshi
Published: March 2023

A lack of the mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) was recently shown to induce proteostress in embryonic stem cells. Since erythroid precursors actively synthesize the hemoglobin protein, we hypothesized thatMto1dysfunctions may result in defective erythropoiesis. Hematopoietic-specificMto1conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complex-I was severely defective in theMto1cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis and enhanced the expression of embryonic hemoglobin proteins, which induced an unfolded protein response via the IRE1α-Xbp1 signaling pathway inMto1cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in theMto1cKO fetal liverin vitro. The new point of view provided by this novel non-energy-related molecular mechanism may lead to a breakthrough in mitochondrial research.
A Systematic Investigation of Detectors for Low Signal-to-Noise Ratio EMG Signals
Authors: Yuvaraj Monisha , Raja Priyanka , David Ann , Burdet Etienne , SKM Varadhan , Balasubramanian Sivakumar
Published: March 2023

Active participation of stroke survivors during robot-assisted movement therapy is essential for sensorimotor recovery. Robot-assisted therapy contingent on movement intention is an effective way to encourage patients’ active engagement. For severely impaired stroke patients with no residual movements, a surface electromyogram (EMG) has been shown to be a viable option for detecting movement intention. Although numerous algorithms for EMG detection exist, the detector with the highest accuracy and lowest latency for low signal-to-noise ratio (SNR) remains unknown. This study, therefore, investigates the performance of thirteen existing EMG detection algorithms on simulated low SNR (0dB and -3dB) EMG signals generated using three different EMG signal models: gaussian, laplacian, and biophysical model. The detector performance was quantified using the false positive rate (FPR), false negative rate (FNR), and detection latency. Any detector that consistently showed FPR and FNR of no more than 20%, and latency of no more than 50ms, was considered an appropriate detector for use in robot-assisted therapy. The results indicate that the Modified Hodges detector – a simplified version of the threshold-based Hodges detector introduced in the current study – was the most consistent detector across the different signal models and SNRs. It consistently performed for ∼90% and ∼40% of the tested trials for 0dB and -3dB SNR, respectively. The two statistical detectors (Gaussian and Laplacian Approximate Generalized Likelihood Ratio) and the Fuzzy Entropy detectors have a slightly lower performance than Modified Hodges. Overall, the Modified Hodges, Gaussian and Laplacian Generalized Likelihood ratio, and the Fuzzy Entropy detectors were identified as the potential candidates that warrant further investigation with real surface EMG data since they had consistent detection performance on low SNR EMG data.
Endothelial cell-derived lactate triggers mesenchymal stem cell histone lactylation to attenuate osteoporosis
Authors: Wu Jinhui , Hu Miao , Jiang Heng , Ma Jun , Xie Chong , Zhang Zheng , Zhou Xin , Zhao Jianquan , Tao Zhengbo , Meng Yichen , Cai Zhuyun , Song Tengfei , Zhang Chenglin , Gao Rui , Song Hongyuan , Gao Yang , Lin Tao , Wang Ce , Zhou Xuhui
Published: March 2023

Blood vessels play a role in osteogenesis and osteoporosis; however, the role of vascular metabolism is unclear. The present study found that ovariectomized mice exhibit reductions in bone blood vessel density and expression of endothelial glycolytic regulator pyruvate kinase M2 (PKM2). Additional data showed that endothelial cell (EC)-specific deletion of Pkm2 impair osteogenesis and worsen osteoporosis in mice. This was attributed to the impaired differentiation ability toward osteoblast of bone mesenchymal stem cells (BMSCs). Mechanistically, EC-specific deletion of Pkm2 reduce serum lactate levels secreted by ECs, which affect histone lactylation of BMSCs. We identified collagen type I alpha 2 chain, cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1, and transcription factor 7 like 2 as histone H3K18 lactylation-regulated osteogenic genes using joint CUT&Tag and RNA-sequencing analyses. The overexpression of PKM2 in ECs, addition of lactate, and exercise were observed to restore the phenotype of endothelial Pkm2-deficient mice. Furthermore, metabolomics of the serum indicated that osteoporosis patients showed a relatively low lactate level. The histone lactylation and related osteogenic genes of BMSCs in osteoporosis patients also decreased. In conclusion, the glycolysis of ECs fuels the differentiation of BMSCs into osteoblasts through histone lactylation, and exercise partially ameliorates osteoporosis through increased serum lactate.
Effect of Adult Neurogenesis on Sparsely Synchronized Rhythms of The Granule Cells in The Hippocampal Dentate Gyrus
Authors: Kim Sang-Yoon , Lim Woochang
Published: March 2023

We are concerned about the main encoding granule cells (GCs) in the hippocampal dentate gyrus (DG). Young immature GCs (imGCs) appear through adult neurogenesis. In comparison to the mature GCs (mGCs) (born during development), the imGCs show high activation due to lower firing threshold. On the other hand, they receive low excitatory drive from the entorhinal cortex via perforant paths and from the hilar mossy cells with lower connection probabilitypc(= 20x%) (x: synaptic connectivity fraction; 0 ≤x≤ 1) than the mGCs with the connection probabilitypc(= 20 %). Thus, the effect of low excitatory innervation (reducing activation degree) for the imGCs counteracts the effect of their high excitability. We consider a spiking neural network for the DG, incorporating both the mGCs and the imGCs. With decreasingxfrom 1 to 0, we investigate the effect of young adult-born imGCs on the sparsely synchronized rhythms (SSRs) of the GCs (mGCs, imGC, and whole GCs). For eachx, population and individual firing behaviors in the SSRs are characterized in terms of the amplitude measureMa(X)(X=m, im, wfor the mGCs, the imGCs, and the whole GCs, respectively) (representing the population synchronization degree) and the random phase-locking degreeLd(X)(characterizing the regularity of individual single-cell discharges), respectively. We also note that, for 0 ≤x≤ 1, the mGCs and the imGCs exhibit pattern separation (i.e., a process of transforming similar input patterns into less similar output patterns) and pattern integration (making association between patterns), respectively. Quantitative relationship between SSRs and pattern separation and integration is also discussed.
RNA Sensing and Innate Immunity Constitutes a Barrier for Interspecies Chimerism
Authors: Hu Yingying , Sun Hai-Xi , Sakurai Masahiro , Jones Amanda E. , Liu Lizhong , Cheng Tianlei , Zheng Canbin , Li Jie , Ravaux Benjamin , Luo Zhou , Ding Yi , Liu Tianbin , Wu Yan , Chen Elizabeth H. , Chen Zhijian J. , Abrams John M. , Gu Ying , Wu Jun
Published: March 2023

Interspecies chimera formation with human pluripotent stem cells (PSCs) holds great promise to generate humanized animal models and provide donor organs for transplant. However, the approach is currently limited by low levels of human cells ultimately represented in chimeric embryos. Different strategies have been developed to improve chimerism by genetically editing donor human PSCs. To date, however, it remains unexplored if human chimerism can be enhanced in animals through modifying the host embryos. Leveraging the interspecies PSC competition model, here we discovered retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling, an RNA sensor, in “winner” cells plays an important role in the competitive interactions between co-cultured mouse and human PSCs. We found that genetic inactivation ofDdx58/Ifih1-Mavs-Irf7axis compromised the “winner” status of mouse PSCs and their ability to outcompete PSCs from evolutionarily distant species during co-culture. Furthermore, by usingMavs-deficient mouse embryos we substantially improved unmodified donor human cell survival. Comparative transcriptome analyses based on species-specific sequences suggest contact-dependent human-to-mouse transfer of RNAs likely plays a part in mediating the cross-species interactions. Taken together, these findings establish a previously unrecognized role of RNA sensing and innate immunity in “winner” cells during cell competition and provides a proof-of-concept for modifying host embryos, rather than donor PSCs, to enhance interspecies chimerism.
Sustained improvements in brain health and metabolic markers 24 months following bariatric surgery
Authors: Legault Marianne , Pelletier Mélissa , Lachance Amélie , Lachance Marie-Ève , Zeighami Yashar , Gauthier Marie-Frédérique , Iceta Sylvain , Biertho Laurent , Fulton Stephanie , Richard Denis , Dagher Alain , Tchernof André , Dadar Mahsa , Michaud Andréanne
Published: March 2023

Background

Obesity and its metabolic complications are associated with lower gray matter (GM) and white matter (WM) density, whereas weight loss after bariatric surgery leads to an increase in both measures. These increases of GM and WM density are significantly associated with post-operative weight loss and improvement of the metabolic/inflammatory profiles. While our recent studies demonstrated widespread increases in WM density 4 and 12 months after bariatric surgery, it is not clear if theses changes persist over time. The underlying mechanisms also remain unknown. In this regard, numerous studies demonstrate that the enlargement or hypertrophy of mature adipocytes, particularly in the visceral fat compartment, is an important marker of adipose tissue dysfunction and obesity-related cardiometabolic abnormalities.

Objective

To assess whether the previously observed increases in WM and GM densities are maintained 24 months post-surgery, and to examine if pre-operative abdominal omental (OM) and subcutaneous (SC) adipocyte diameters are associated with WM and GM changes after bariatric surgery.

Methods

32 participants undergoing bariatric surgery were recruited. WM and GM densities were assessed from T1-weighted MRIs acquired prior to and 4-, 12-, and 24-months post-surgery using voxel-based morphometry. OM and SC adipose tissue samples were collected during the surgical procedure. OM and SC adipocyte diameters were measured by microscopy of fixed adipose tissue samples. Linear mixed-effects models were performed controlling for age, sex, surgery type, initial BMI, and diabetic status.

Results

The average weight loss at 24 months was 33.5±7.2%. A widespread increase in WM density was observed 24 months post-surgery mainly in the cerebellum, brainstem, and corpus callosum (p<0.05, FDR) as well as some regions in GM density. Greater baseline OM adipocyte diameter was associated with greater changes in total WM density at 24 months (p=0.008). A positive trend was observed between SC adipocyte diameter and changes in total WM density at 24 months (p=0.05).

Conclusion

Our results show prolonged increases of WM and GM densities up to 24 months post-bariatric surgery. Greater preoperative OM adipocyte diameter is associated with greater increases in WM density at 24 months, suggesting that individuals with excess visceral adiposity might benefit the most from surgery.
HIVtat Alters Epithelial Differentiation State and Increases HPV16 Infectivity in Oral Keratinocytes
Authors: Seaman William T , Madden Victoria , Webster-Cyriaque Jennifer
Published: March 2023

Human Papillomavirus (HPV)-associated oral disease has increased during the era of HIV antiretroviral therapy. HPV and HIV proteins may be co-present at mucosal surfaces. Recent published studies have determined that HIVtat is secreted in the saliva and has been detected in oral mucosa even in the context of antiretroviral therapy. We hypothesized that HIVtat promoted oral HPV pathogenesis. Clinical HPV16 cloned episomes were introduced into differentiated oral epithelial cells (OKF6tert1). HIVtat mediated transactivation, DNA damage, oxidative stress, and effects on cellular differentiation were assessed. Detection of keratin 10 and of loricrin confirmed terminal differentiation. Sodium butyrate-treated (NaB) cells demonstrated an eight-fold increase in cross-linked involucrin, suggesting full terminal differentiation. HIVtat modulated this differentiation both in the presence and absence of NaB. Later viral events, including E6* and E1^E4 gene expression were assessed. HIVtat mediated relief of repressed L1 expression that mapped to a known inhibitory region (nucleotides 5561-6820). Viruses from HIVtat co-expressing cells exhibited robust de novo HPV16 infection. In conclusion, a novel oral keratinocyte monolayer system supported replication of an HPV16 clinical isolate where direct HIVtat and oral HPV interactions enhanced HPV de novo infection.
Differentiated Oral Epithelial Cells Support the HPV Life Cycle
Authors: Seaman William T , Saladyanant Thatsanee , Madden Victoria , Webster-Cyriaque Jennifer
Published: March 2023

Human Papillomavirus (HPV) associated oral disease continues to increase, both in the context of immune competence and of immune suppression. There are few models of oral HPV infection and current models are laborious. We hypothesized that differentiated oral epithelial cells could support the HPV life cycle. Clinical HPV16 cloned episomes were introduced into differentiated oral epithelial cells (OKF6tert1). Viral and cellular gene expression was assessed in the presence or absence of sodium butyrate, a differentiating agent that moved the cells to full terminal differentiation. Detection of keratin 10, cross-linked involucrin, and loricrin in the presence and absence of sodium butyrate confirmed terminal differentiation. Increasing sodium butyrate concentrations in the absence of HPV, were associated with decreased suprabasal markers and increased terminal differentiation markers. However, in the presence of HPV and of increasing sodium butyrate concentrations, both mitotic and suprabasal markers were increased and the terminal differentiation marker, loricrin, decreased. In this unique differentiated state, early and late viral gene products were detected including spliced mRNAs for E6*, E1^E4, and L1. E7 and L1 proteins were detected. The ratio of late (E1^E4) to early (E6/E7) transcripts in HPV16+ OKF6tert1 cells was distinct compared to HPV16+ C33a cells. Consistent with permissive HPV replication, DNA damage responses (phospho-chk2, gamma-H2AX), HPV E2-dependent LCR transactivation, and DNase-resistant particles were detected and visualized by transmission electron microscopy. In sum, monolayers of differentiated immortalized oral epithelial cells supported the full HPV life cycle. HPV may optimize the differentiation state of oral epithelial cells to facilitate its replication.
Standing wave mesoscopy
Authors: Foylan Shannan , Schniete Jana Katharina , Kölln Lisa Sophie , Dempster John , Hansen Carsten Gram , Shaw Michael , Bushell Trevor John , McConnell Gail
Published: March 2023

Standing wave (SW) microscopy is a method that uses an interference pattern to excite fluorescence from labelled cellular structures and produces high-resolution images of three-dimensional objects in a two-dimensional dataset. SW microscopy is performed with high magnification, high numerical aperture objective lenses, and while this results in high resolution images, the field of view is very small. Here we report upscaling of this interference imaging method from the microscale to the mesoscale using the Mesolens, which has the unusual combination of a low magnification and high numerical aperture. With this method, we produce SW images within a field of view of 4.4 mm x 3.0 mm that can readily accommodate over 16,000 cells in a single dataset. We demonstrate the method using both single-wavelength excitation and the multi-wavelength SW method TartanSW. We show application of the method for imaging of fixed and living cells specimens, with the first application of SW imaging to study cells under flow conditions.
Host plant affects the larval gut microbial communities of the generalist herbivoresHelicoverpa armigeraandSpodoptera frugiperda
Authors: Rodrigues Pedro A. P. , Cavichiolli de Oliveira Nathalia , Omoto Celso , Girke Thomas , Cônsoli Fernando L.
Published: March 2023

Investigations on symbiotic associations between Lepidoptera and bacteria have been inconclusive as to whether these microorganisms represent transient or persistent associations. One reason for this is that most studies have sampled the microbiota from only a few species and frequently from laboratory-reared animals. We sequenced the 16S rRNA gene to profile the gut microbiome of the field collected, agricultural pestsHelicoverpa armigeraandSpodoptera frugiperda. We found that variation in the structure of bacterial communities is in great part associated with their host diet. Moreover,Enterococcus, among a few other taxa, is consistently present in all samples regardless of the plant hosts were collected. The larval gut bacteria composition matches previously published data in the same or related species, indicating that associations with bacteria taxa such asEnterococcusare persistent despite geographical variation and sampling techniques. Based on our phylogenetic analysis it is not clear, however, ifEnterococciassociated with Lepidoptera are necessarily different from environmental bacteria. We conclude that to fully understand the nature of Lepidoptera - gut bacteria associations it will be necessary to conduct larger sampling efforts and combine them with identification methods of bacterial strains that go beyond screening of the 16S rRNA gene.
Ambient temperature crystal structure ofEscherichia coliCyaY protein displays alternate conformation
Authors: Shafiei Alaleh , Baldir Nilufer , Na Jongbum , Kim Jin Hae , DeMirci Hasan
Published: March 2023

Frataxin is a 23 KDa mitochondrial iron-binding protein that is involved in biogenesis of iron sulfur clusters. A deficiency in frataxin leads to Friedreich’s ataxia, a progressive neurodegenerative disorder. The bacterial ortholog of eukaryotic mitochondrial frataxin, CyaY, is thought to play a role in iron sulfur cluster assembly as an iron supplier, making it an important target for study. Here, we present the first ambient temperature crystal structure of CyaY protein fromEscherichia coli, obtained using the Turkish Light Source “Turkish DeLight”. This study reveals the dynamic structural characteristics of CyaY at near-physiological temperature and displays an alternate conformation, highlighting the importance of temperature considerations in protein structure characterization and providing new insights into the protein’s flexibility.
Genome mining unveils a class of ribosomal peptides with two amino termini
Authors: Ren Hengqian , Dommaraju Shravan R. , Huang Chunshuai , Cui Haiyang , Pan Yuwei , Nesic Marko , Zhu Lingyang , Sarlah David , Mitchell Douglas A. , Zhao Huimin
Published: March 2023

The era of inexpensive genome sequencing and improved bioinformatics tools has reenergized the study of natural products, including the ribosomally synthesized and post-translationally modified peptides (RiPPs). In recent years, RiPP discovery has challenged preconceptions about the scope of post-translational modification chemistry, but genome mining of new RiPP classes remains an unsolved challenge. Here, we report a RiPP class defined by an unusual (S)-N2,N2-dimethyl-1,2-propanediamine (Dmp)-modifiedC-terminus, which we term the daptides. Nearly 500 daptide biosynthetic gene clusters (BGCs) were identified by analyzing the RiPP Recognition Element (RRE), a common substrate-binding domain found in half of prokaryotic RiPP classes. A representative daptide BGC fromMicrobacterium paraoxydansDSM 15019 was selected for experimental characterization. Derived from aC-terminal threonine residue, the class-defining Dmp is installed over three steps by an oxidative decarboxylase, aminotransferase, and methyltransferase. Daptides uniquely harbor two positively charged termini, and thus we suspect this modification could aid in membrane targeting, as corroborated by hemolysis assays. Our studies further show that the oxidative decarboxylation step requires a functionally unannotated accessory protein. Fused to theC-terminus of the accessory protein is an RRE domain, which delivers the unmodified substrate peptide to the oxidative decarboxylase. This discovery of a class-defining post-translational modification in RiPPs may serve as a prototype for unveiling additional RiPP classes through genome mining.
Global loss of cellular m6A RNA methylation following infection with different SARS-CoV-2 variants
Authors: Vaid Roshan , Mendez Akram , Thombare Ketan , Burgos-Panadero Rebeca , Robinot Rémy , Fonseca Barbara F. , Gandasi Nikhil R. , Ringlander Johan , Hassan Baig Mohammad , Dong Jae-June , Cho Jae Yong , Reinius Björn , Chakrabarti Lisa A. , Nystrom Kristina , Mondal Tanmoy
Published: March 2023

Insights into host–virus interactions during SARS-CoV-2 infection are needed to understand COVID-19 pathogenesis and may help to guide the design of novel antiviral therapeutics.N6-Methyladenosine modification (m6A), one of the most abundant cellular RNA modifications, regulates key processes in RNA metabolism during stress response. Gene expression profiles observed postinfection with different SARS-CoV-2 variants show changes in the expression of genes related to RNA catabolism, including m6A readers and erasers. We found that infection with SARS-CoV-2 variants causes a loss of m6A in cellular RNAs, whereas m6A is detected abundantly in viral RNA. METTL3, the m6A methyltransferase, shows an unusual cytoplasmic localization postinfection. The B.1.351 variant has a less-pronounced effect on METTL3 localization and loss of m6A than did the B.1 and B.1.1.7 variants. We also observed a loss of m6A upon SARS-CoV-2 infection in air/liquid interface cultures of human airway epithelia, confirming that m6A loss is characteristic of SARS-CoV-2-infected cells. Further, transcripts with m6A modification are preferentially down-regulated postinfection. Inhibition of the export protein XPO1 results in the restoration of METTL3 localization, recovery of m6A on cellular RNA, and increased mRNA expression. Stress granule formation, which is compromised by SARS-CoV-2 infection, is restored by XPO1 inhibition and accompanied by a reduced viral infection in vitro. Together, our study elucidates how SARS-CoV-2 inhibits the stress response and perturbs cellular gene expression in an m6A-dependent manner.
Consumers’ behavioural responses to price promotions of organic products: an introspective pre-study and an online field experiment
Authors: Isojärvi Jyrki , Aspara Jaakko
Published: March 2023

Purpose

While most marketing research on organic products refers to the premium price levels of organic products, little research exists on consumers’ behavioural responses to price promotions or discounts of organic products. The present study aims to fill this research gap.

Design/methodology/approach

To develop alternative hypotheses about consumers’ behavioural responses to price promotions of organic fast-moving consumer good (FMCG) products, the authors used the researcher-introspection method in a pre-study. To test the hypotheses developed based on the pre-study, the authors conducted a field experiment on online advertising of an FMCG sold in drugstores. In the field experiment, the authors exposed consumers to an online ad featuring either a price promotion (−20%) or the regular price of the product. The ads also varied in terms of whether they contained explicit organic claims or not, and whether they included implicit organic cues or not.

Findings

The price promotion increased the clickthrough rate of the ad both when combined with an explicit organic claim and when combined with the implicit cue of green product pack. The results suggest that consumers do not have significant suspicions about price promotions of organic products, but rather presume that the price promotion of an organic FMCG product is a periodical promotional action, similar to the price promotions for conventional, non-organic products. Also, consumers seem to assume that the regular prices of organic FMCG products are so high that the retailer/manufacturer can well afford periodic price discounts.

Research limitations/implications

The present research shifts the focus of organic marketing research from the premium price levels to the effectiveness of price promotions and discounts. Further, the present results contrast with certain earlier studies that have questioned the effectiveness of price promotions for organic products.

Practical implications

The results have different implications for marketing managers of brands not yet providing organic product versions in the market, of brands producing non-organic products, which cannot easily be rendered organic, and of brands offering organic products in the market.

Originality/value

This is, to the best of the authors’ knowledge, the first empirical study and field experiment on price promotions of organic products, including explicit organic claims.
Social media managers’ customer orientation, service climate and social media followers’ willingness to pay: moderated mediation model with triadic data
Authors: Varela-Neira Concepción , Coelho Filipe , Camoiras-Rodríguez Zaira
Published: March 2023

Purpose

This paper aims to examine the relationship between the interaction of the social media manager’s customer orientation and the service climate perceived by supervisors, on the customer’s perception of brand authenticity and, through it, on the willingness to pay a price premium.

Design/methodology/approach

This study uses triadic data from 200 social media followers, 20 social media managers and 20 supervisors from a range of industries.

Findings

The findings show that the customer orientation of the brand social media managers interacts with their work context to influence social media followers’ perceptions of brand authenticity, and ultimately, their willingness to pay a premium price. Finally, product involvement moderates the relationship between brand authenticity and willingness to pay a premium price.

Research limitations/implications

This study shows how and when the disposition of brand social media managers affects the attitudes and intentions of the social media followers. Further research should continue this novel line of research and explore in greater depth the impact of social media managers and their environments.

Practical implications

Social media managers’ values should fit those of their organization. This organization-person fit reflects on social media and improves social media followers’ perceptions of brand authenticity and, consequently, their willingness to pay a premium price.

Originality/value

Leveraging participation in social media is currently a key issue for firms. However, the internal determinants of successful social media usage have received limited attention from researchers. Therefore, this research contributes to the social media literature by suggesting the need to consider the characteristics of social media managers and their context to promote the outcomes of social media usage, specifically brand authenticity and willingness to pay a premium price.