bluuebunny/crossref_metadata_2025 huggingface dataset:
Overexpression of Interleukin-8 and Interleukin-13 as potent immune markers associated with survival and dietary habits in esophageal squamous cell carcinoma
Authors: Talukdar Jayasree , Malik Abdul , Kataki Kangkana , Choudhury Bikash Narayan , Baruah Munindra Narayan , Bhattacharyya Mallika , Alkholief Musaed , Alshamsan Aws , Sarma Manash Pratim , Bhattacharjee Minakshi , Basak Mrinmoy , Kashyap Manash Pratim , Bhattacharjee Sahana , Ali Eyashin , Keppen Chenole , Idris Mohammad Ghaznavi , Medhi Subhash
Published: October 2022

Background

Interleukin-8 (IL8), Interleukin-12 (IL12) and Interleukin-13 (IL13) are cytokines that play regulatory role in cancer pathogenesis. We analysed their expression profile to evaluate as molecular biomarkers of esophageal squamous cell carcinoma (ESCC) and their association with different parameters.

Methods

Expression analysis of IL8, IL12 and IL13 were performed by Real time qPCR in blood and tumor tissue of 120 ESCC patients. The expression profiles were associated with different clinicopathological and dietary factors. Survival and hazard analysis were also performed.

Results

When compared to normal controls, IL8 expression showed upregulation in 83% tissue samples (p=0.000) and 62% blood samples (p=0.388), IL12 expression showed upregulation in 62% tissue samples (p=0.435) and 57% blood samples (p=0.222) and IL13 expression showed upregulation in 83% tissue samples (p=0.001) and 68% blood samples (p=0.312). Significant positive correlation (p<0.05) was observed between tissue and blood level expression of IL8, IL12 and IL13. Different clinicopathological factors and dietary habits showed significant association (p<0.05) with IL8, IL12 and IL13 expression.. Statistically significant positive correlation were observed for IL8 and IL13 expression in tissue as well as IL13 and IL12 expression in both tissue and blood. Also significant negative correlation of IL8 and IL12 expression in blood and tissue were also observed. Tumor stage, node stage, metastasis, consumption of betel nut, tobacco, alcohol, hot food, smoked food, spices, IL8 expression in blood, IL13 expression in tissue and IL12 expression in blood and tissue showed significant association (p<0.05) with survival of ESCC patients.

Conclusions

Altered expression of IL8, IL12 and IL13 may be associated with ESCC progression. Overexpression of IL8 and IL13 in tissue samples may be potential biomarkers for ECSS screening. Additionally, results from both survival and hazard analysis data indicate the effects of various parameters on the survival and mortality rate of ESCC patients.
A radiofrequency coil for infants and toddlers
Authors: Gilbert Kyle M. , Nichols Emily S. , Gati Joseph S. , Duerden Emma G.
Published: October 2022

Background

Infants and toddlers are a challenging population on which to perform MRI of the brain, both in research and clinical settings. Due to the large range in head size during the early years of development, paediatric neuro-MRI requires a radiofrequency (RF) coil, or set of coils, that is tailored to head size to provide the highest image quality. Mitigating techniques must also be employed to reduce and correct for subject motion.

Objective

To develop an RF coil with a tailored mechanical-electrical design that can adapt to the head size of three-month-old infants to three-year-old toddlers.

Materials and methods

An RF coil was designed with tight-fitting coil elements to improve SNR in comparison to commercially available adult head coils, while simultaneously aiding in immobilization. The coil was designed without visual obstruction to facilitate an unimpeded view of the child’s face and the potential application of camera or motion-tracking systems.

Results

Despite the lack of elements over the face, the paediatric coil produced higher SNR over most of the brain compared to adult coils, including more than 2-fold in the periphery. Acceleration rates of 4-fold in each Cartesian direction could be achieved. Higher SNR allowed for shorter acquisition times through accelerated imaging protocols, reducing the probability of motion during a scan.

Conclusion

Modification to the acquisition protocol, with immobilization of the head through the adjustable coil geometry, and subsequently combined with a motion tracking system provides a compelling platform for scanning paediatric populations without sedation and with improved image quality.
Local prediction-learning in high-dimensional spaces enables neural networks to plan
Authors: Stöckl Christoph , Yang Yukun , Maass Wolfgang
Published: October 2022

Planning and problem solving are cornerstones of higher brain function. But we do not know how the brain does that. We show that learning of a suitable cognitive map of the problem space suffices. Furthermore, this can be reduced to learning to predict the next observation through local synaptic plasticity. Importantly, the resulting cognitive map encodes relations between actions and observations, and its emergent high-dimensional geometry provides a sense of direction for reaching distant goals. This quasi-Euclidean sense of direction provides a simple heuristic for online planning that works almost as well as the best offline planning algorithms from AI. If the problem space is a physical space, this method automatically extracts structural regularities from the sequence of observations that it receives so that it can generalize to unseen parts. This speeds up learning of navigation in 2D mazes and the locomotion with complex actuator systems, such as legged bodies. The cognitive map learner that we propose does not require a teacher, similar to self-attention networks (Transformers). But in contrast to Transformers, it does not require backpropagation of errors or very large datasets for learning. Hence it provides a blue-print for future energy-efficient neuromorphic hardware that acquires advanced cognitive capabilities through autonomous on-chip learning.

One Sentence Summary

Local synaptic plasticity is all you need for learning to solve problems
Identification of Aryl Hydrocarbon Receptor as a Barrier to HIV-1 Infection and Outgrowth in CD4+T-Cells
Authors: Chatterjee Debashree , Zhang Yuwei , Salinas Tomas Raul Wiche , Ngassaki-Yoka Christ-Dominique , Chen Huicheng , Smail Yasmine , Goulet Jean-Philippe , Bell Brendan , Routy Jean-Pierre , Ancuta Petronela
Published: October 2022

The Aryl hydrocarbon receptor (AhR) identifies “non-pathogenic” Th17-polarized CD4+T-cells in autoimmune models. Thus, we explored whether AhR restricts HIV-1 in Th17-cells, consistent with its antiviral role in macrophages. AhR-specific CRISPR/Cas9-mediated knockout and pharmacological blockade decreased AhR target gene expression (CYP1A1/IL-22/IL-17A/IL-10/ ITGB7), while increasing HIV-1 replication in CD4+T-cells. Pharmacological AhR activation caused opposite effects. AhR agonism/antagonism modulated HIV-1 replication mainly in Th17/Th22-polarized CCR6+CD4+T-cells. Single-round VSV-G-pseudotyped HIV-1 infection demonstrated that AhR acts at post-entry levels, with AhR blockade increasing the efficacy of early/late reverse transcription steps and subsequently integration/translation. In viral outgrowth assay, the AhR blockade boosted the detection of replication-competent viral reservoirs in CD4+T-cells of people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Finally, RNA-Sequencing revealed genes/pathways modulated by AhR blockade in CD4+T-cells of ART-treated PLWH, with known HIV-1 interactor activities (NCBI HIV Interactor Database) and AhR responsive elements in their promoters (ENCODE). Among them, HIC1, a repressor of Tat-mediated HIV-1 transcription and a tissue-residency inducer, represents a putative AhR mechanism of action. These results demonstrate that AhR governs an antiviral transcriptional program in CD4+T-cells and point to the use of AhR inhibitors to boost viral outgrowth in “shock and kill” HIV-1 remission/cure strategies.

Model of AhR-mediated transcriptional reprogramming with implications for “silent” HIV-1 reservoir persistence and gut homing/residency.

RNA-Sequencing revealed genes sets modulated by AhR blockade in CD4+T-cells of ART-treated PLWH, with known HIV-1 interactor activities (NCBI HIV Interactor Database) and AhR responsive elements in their promoters (ENCODE). Among them, HIC1, a repressor of Tat-mediated HIV-1 transcription and a tissue-residency regulator, represents a putative AhR mechanism of action. These results support a model in which AhR activation favors the gut homing and residencyviathe induction of ITGB7 and CXCR6 expression, respectively, and fuels the persistence of ‘silent” HIV-1 reservoirs in CD4+T-cells of ART-treated PLWH. At the opposite, pharmacological AhR blockade facilitates viral outgrowth, and by interfering with tissue residency, likely promotes the mobilization of « reactivated » reservoir cells from deep tissues into the circulations.

BRIEF SUMMARY

We identified the aryl hydrocarbon receptor as a barrier to HIV-1 infection/outgrowth in Th17-polarized CD4+T-cells and a novel therapeutic target in HIV-1 cure/remission interventions.
Mu-Transcranial Alternating Current Stimulation Induces Phasic Entrainment and Plastic Facilitation of Corticospinal Excitability
Authors: Geffen Asher , Bland Nicholas , Sale Martin V
Published: October 2022

Transcranial alternating current stimulation (tACS) has been proposed to modulate neural activity through two primary mechanisms: entrainment and neuroplasticity. The current study aimed to probe both of these mechanisms in the context of the sensorimotor µ-rhythm using transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to assess entrainment of corticospinal excitability (CSE) during stimulation (i.e., online) and immediately following stimulation, as well as neuroplastic aftereffects on CSE and µ EEG power. Thirteen participants received 3 sessions of stimulation. Each session consisted of 90 trials of µ-tACS tailored to each participant’s individual µ frequency (IMF), with each trial consisting of 16 seconds of tACS followed by 8 seconds of rest (for a total of 24 minutes of tACS and 12 minutes of rest per session). Motor evoked potentials (MEPs) were acquired at the start and end of the session (n = 41) and additional MEPs were acquired across the different phases of tACS at 3 epochs within each tACS trial (n = 90 for each epoch): early online, late online, and offline echo. Resting EEG activity was recorded at the start, end, and throughout the tACS session. The data were then pooled across the three sessions for each participant to maximise the MEP sample size per participant. We present preliminary evidence of CSE entrainment persisting immediately beyond tACS and have also replicated the plastic CSE facilitation observed in previous µ-tACS studies, thus supporting both entrainment and neuroplasticity as mechanisms by which tACS can modulate neural activity.

Graphical Abstract

Thirteen participants underwent 3 sessions of stimulation where they received 90 trials of mu-tACS (270 trials across the 3 sessions), with each trial consisting of 16 seconds of tACS (2mA at the participants individual mu frequency) followed by 8 seconds of rest. Motor evoked potentials (MEPs) were acquired at the start and end of the session (n = 41) and additional MEPs were acquired across the different phases of tACS at 3 epochs within each tACS trial (n = 90 for each epoch): early online, late online, and offline echo. We present preliminary evidence supporting entrainment of MEP amplitudes to tACS phase online to and immediately following stimulation and have also replicated the neuroplastic CSE facilitation observed in previous µ-tACS studies.
Ripple-locked coactivity of stimulus-specific neurons supports human associative memory
Authors: Kunz Lukas , Staresina Bernhard P. , Reinacher Peter C. , Brandt Armin , Guth Tim A. , Schulze-Bonhage Andreas , Jacobs Joshua
Published: October 2022

Associative memory is the ability to encode and retrieve relations between different stimuli. To better understand its neural basis, we investigated whether associative memory involves precisely timed spiking of neurons in the medial temporal lobes that exhibit stimulus-specific tuning. Using single-neuron recordings from epilepsy patients performing an associative object–location memory task, we identified the object- and place-specific neurons that encoded the separate elements of each memory. When patients encoded and retrieved particular memories, the relevant object- and place-specific neurons activated synchronously during hippocampal ripples. This ripple-locked coactivity of stimulus-specific neurons emerged over time as the patients’ associative learning progressed. Our results suggest a cellular account of associative memory, in which hippocampal ripples coordinate the activity of specialized cellular populations to facilitate links between stimuli.
Evaluating the Effectiveness of Point-of-Entry UV Treatment for Cistern Water Among Households in the US Virgin Islands
Authors: Voth-Gaeddert Lee , Momberg Douglas , Brathwaite Kela , Schranck Andrew , Lemley Mandy , Libbey Stephen
Published: October 2022

UV water treatment can be a viable option for point-of-entry applications among households utilizing private water sources. In the US Virgin Islands (USVI), the primary water source is roof-harvested rainwater, collected in large cisterns and supplied to household taps via a pump. While diversification of water sources provides increased resilience to climate change, literature suggests rainwater catchment systems are at high risk of microbial contamination. One option USVI households have is UV systems. However, limited data is available on UV system effectiveness for USVI installations while these systems can be expensive. Therefore, Love City Strong, a local NGO, piloted a multi-year UV access program which included free UV systems with prefiltration along with installation and monthly household visits for up to 12 months including water quality testing. In addition, due to the significant costs associated with the prefiltration portion of the system, a pilot study was conducted to evaluate the effectiveness of the UV systems without prefiltration.

The results from the UV system access program demonstrated thatE. coliwas not detected in 95.2% of tap samples (n=271). Among samples with detectable levels ofE. coliand total coliforms, turbidity was lower compared to samples with non-detections. Field teams reported user error was often identified in association withE. colidetections (e.g., bypass was opened). Among all samples from the pilot study of UV systems without prefiltration, noE. coliwas detected (n=24). Total first-year costs for locally available UV systems with and without prefiltration ranged from $1,059-$1,645 and $927-$1,183, respectively, while operation and maintenance (O& M) costs ranged from $166-$266 and $142-$146, respectively. Given these data, UV systems may be a viable option for generating potable water; however, clear purchasing and installation protocols are needed as well as simple O&M guidelines for households to reduce user error.

Synopsis

Point-of-entry UV systems were able to produce water for domestic use with no detectable E. coli in 95.2% of samples among USVI households using roof-harvested rainwater.
Macaque Brainnetome Atlas: A Multifaceted Brain Map with Parcellation, Connection, and Histology
Authors: Lu Yuheng , Cui Yue , Cao Long , Cheng Luqi , Dong Zhenwei , Wang Changshuo , Liu Youtong , Zhang Baogui , Wang Haiyan , Li Kaixin , Ma Liang , Shi Weiyang , Li Wen , Ma Yawei , Du Zongchang , Zhang Jiaqi , Xiong Hui , Luo Na , Liu Yanyan , Hou Xiaoxiao , Liu Xinyi , Sun Hongji , Wang Jiaojian , Paxinos George , Yang Zhengyi , Fan Lingzhong , Jiang Tianzi
Published: October 2022

The rhesus macaque (Macaca mulatta) is a crucial experimental animal that shares many genetic, brain organizational, and behavioral characteristics with humans. A macaque brain atlas that identifies anatomically and functionally distinct regions is fundamental to biomedical and evolutionary research. However, even though connectivity information is vital for understanding brain functions, a connectivity-based whole-brain atlas of the macaque has not previously been made. In this study, we created a new whole-brain map, the Macaque Brainnetome Atlas (MacBNA), based on the anatomical connectivity profiles provided by high angular and spatial resolution ex vivo diffusion MRI data. The new atlas consists of 248 cortical and 56 subcortical regions as well as their structural and functional connections. The parcellation and the diffusion-based tractography were comprehensively evaluated with multi-contrast MRI, invasive neuronal-tracing, and Nissl-stained images collected from a single subject and with open-access datasets from other cohorts. As a demonstrative application, the structural connectivity divergence between macaque and human brains was mapped using the Brainnetome atlases of those two species to uncover the genetic underpinnings of the evolutionary changes in brain structure. The resulting resource includes (1) the thoroughly delineated Macaque Brainnetome Atlas (MacBNA), (2) regional connectivity profiles, (3) the postmortem high resolution macaque diffusion and T2-weighted MRI dataset (Brainnetome-8), and (4) multi-contrast MRI, block-face, and section images collected from a single macaque. MacBNA can serve as a common reference frame for mapping multifaceted features across modalities and spatial scales and for integrative investigation and characterization of brain organization and function. Therefore, it will enrich the collaborative resource platform for nonhuman primates and facilitate translational and comparative neuroscience research.
Dynamic genome-based metabolic modeling of the predominant cellulolytic rumen bacteriumFibrobacter succinogenesS85
Authors: Fakih Ibrahim , Got Jeanne , Robles-Rodriguez Carlos Eduardo , Siegel Anne , Forano Evelyne , Muñoz-Tamayo Rafael
Published: October 2022

Fibrobacter succinogenesis a cellulolytic predominant bacterium that plays an essential role in the degradation of plant fibers in the rumen ecosystem. It converts cellulose polymers into intracellular glycogen and the fermentation metabolites succinate, acetate, and formate. We developed dynamic models ofF. succinogenesS85 metabolism on glucose, cellobiose, and cellulose on the basis of a network reconstruction done with the Automatic Reconstruction of metabolic models (AuReMe) workspace. The reconstruction was based on genome annotation, 5 templates-based orthology methods, gap-filling and manual curation. The metabolic network ofF. succinogenesS85 comprises 1565 reactions with 77% linked to 1317 genes, 1586 unique metabolites and 931 pathways. The network was reduced using the NetRed algorithm and analyzed for computation of Elementary Flux Modes (EFMs). A yield analysis was further performed to select a minimal set of macroscopic reactions for each substrate. The accuracy of the models was acceptable in simulatingF. succinogenescarbohydrate metabolism with an average coefficient of variation of the Root mean squared error of 19%. Resulting models are useful resources for investigating the metabolic capabilities ofF. succinogenesS85, including the dynamics of metabolite production. Such an approach is a key step towards the integration of omics microbial information into predictive models of the rumen metabolism.
Multi-histone ChIP-Seq Analysis with DecoDen
Authors: Narendra Tanmayee , Visonà Giovanni , de Jesus Cardona Crhistian , Schweikert Gabriele
Published: October 2022

Epigenetic mechanisms coordinate packaging, accessibility and read-out of the DNA sequence within the chromatin context. They significantly contribute to the regulation of gene expression. Thus, they play fundamental roles during differentiation on the one hand and maintenance and propagation of cell identity on the other. Epigenetic malfunctioning is associated with a large range of diseases, from neurodevelopmental disorders to cancer progression. In humans, hundreds of known epigenetic factors and complexes are involved in establishing covalent modifications on the DNA sequence itself and on associated histone proteins. Within the cellular context, the resulting combinatorial epigenomic patterns are neither established nor interpreted independently of each other and therefore exhibit high correlations in a region-specific manner. Post-translational modifications of histone proteins can be analysed using Chromatin Immunoprecipitation followed by sequencing (ChIP-Seq). Often, several assays for a number of different histone modifications are performed as part of the same experimental design. These measurements are, however, confounded by shared biases including chromatin accessibility and mappability. Existing computational methods analyse each histone modification separately. We introduce DecoDen, a new approach that leverages replicates and multi-histone ChIP-Seq experiments for a fixed cell type to learn and remove shared biases. DecoDen (Deconvolve and Denoise) consists of two major steps: We use non-negative matrix factorisation (NMF) to learn a joint cell-type specific background signal. Half-sibling regression (HSR) is then used to correct for these biases in the histone modification signals. We demonstrate that DecoDen is a robust and interpretable method that enables the unbiased discovery of subtle peaks, which are particularly important in an individual-specific context.
Mechanical management of weeds drops nymphal density ofXylella fastidiosavectors
Authors: López-Mercadal Júlia , Mercadal-Frontera Pau , Miranda Miguel Ángel
Published: October 2022

Xylella fastidiosaWells (1987) (Proteobacteria:Xanthomonadaceae) is a xylem pathogen bacterium transmitted by xylem feeder insects that causes several important plant diseases such as Pierce’s disease in grapes or leaf scorch in almond and olives trees. The bacterium was detected in the Balearic Islands in October 2016, including three subspecies:fastidiosa,multiplexandpauca. The major potential vectors described in the Balearics arePhilaenus spumariusL. andNeophilaenus campestrisFallen (1805). In order to interfere the life cycle of vectors, we tested the effect of mechanical control of the plant cover on the most vulnerable phases, such as nymphs and/or newly emerged adults. For this, we selected four organic orchards in Mallorca, three olive and one vineyard plots. Owners of each selected plot conducted mechanical control according to their common procedures and their own machinery, which in general included cut and tillage of the plant cover during March-April. Nymph abundance per surface (30 sampling points/treatment/orchard x 0,25 m2) was measured in each plot in a weekly basis before and after mechanical control. Our results indicated that either tillage and mowing decreased nymphal density ofX. fastidiosavectors in both types of crops. These results contribute to the integrated pest management of vectors by conducting feasible farm-based management of the regular plant cover.

Abstract Figure
Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins
Authors: Li Kexin , Huo Qingji , Dimmitt Nathan H. , Qu Guofan , Bao Junjie , Pandya Pankita H. , Saadatzadeh M. Reza , Bijangi-Vishehsaraei Khadijeh , Kacena Melissa A. , Pollok Karen E. , Lin Chien-Chi , Li Bai-Yan , Yokota Hiroki
Published: October 2022

Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and osteosarcoma-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with Cisplatin. CM was enriched with proteins such as Calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of Calr transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein (APP), a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.
Resistance exercise protects mice from protein-induced fat accretion
Authors: Trautman Michaela E. , Braucher Leah N. , Elliehausen Christian , Zhu Wenyuan G. , Zelenovskiy Esther , Green Madelyn , Sonsalla Michelle M. , Yeh Chung-Yang , Hornberger Troy A. , Konopka Adam R. , Lamming Dudley W.
Published: October 2022

Low protein (LP) diets extend the lifespan of diverse species, and are associated with improved metabolic health in both rodents and humans. Paradoxically, many athletes and bodybuilders consume high protein (HP) diets and protein supplements, yet are both fit and metabolically healthy. Here, we examine this paradox using weight pulling, a validated progressive resistance exercise training regimen, in mice fed either an LP diet or an isocaloric HP diet. We find that despite having lower food consumption than the LP group, HP-fed mice gain significantly more fat mass than LP-fed mice when not exercising, while weight pulling protected HP-fed mice from this excess fat accretion. The HP diet augmented exercise-induced hypertrophy of the forearm flexor complex, and weight pulling ability increased more rapidly in the exercised HP-fed mice. Surprisingly, exercise did not protect from HP-induced changes in glycemic control. Our results confirm that HP diets can augment muscle hypertrophy and accelerate strength gain induced by resistance exercise without negative effects on fat mass, and also demonstrate that LP diets may be advantageous in the sedentary. Our results highlight the need to consider both dietary composition and activity, not simply calories, when taking a precision nutrition approach to health.
Multi-trait genome-wide association analyses leveraging alcohol use disorder findings identify novel loci for smoking behaviors in the Million Veteran Program
Authors: Cheng Youshu , Dao Cecilia , Zhou Hang , Li Boyang , Kember Rachel L. , Toikumo Sylvanus , Zhao Hongyu , Gelernter Joel , Kranzler Henry R. , Justice Amy , Xu Ke
Published: October 2022

Smoking behaviors and alcohol use disorder (AUD), moderately heritable traits, commonly co-occur in the general population. Single-trait genome-wide association studies (GWAS) have identified multiple loci for smoking and AUD. However, GWASs that have aimed to identify loci contributing to comorbid smoking and AUD have used small samples and thus have not been highly informative. Applying multi-trait analysis of GWASs (MTAG), we conducted a joint GWAS of smoking and AUD with data from the Million Veteran Program (N=318,694). By leveraging GWAS summary statistics for AUD, MTAG identified 21 genome-wide significant (GWS) loci associated with smoking initiation and 18 loci associated with smoking cessation compared to 16 and 8 loci, respectively, identified by single-trait GWAS. The novel loci for smoking behaviors identified by MTAG included those previously associated with psychiatric or substance use traits. Colocalization analysis identified 10 loci shared by AUD and smoking status traits, all of which achieved GWS in MTAG, including variants onSIX3, NCAM1, and nearDRD2. Functional annotation of the MTAG variants highlighted biologically important regions onZBTB20, DRD2, PPP6C, andGCKRthat contribute to smoking behaviors. In contrast, MTAG of smoking behaviors and alcohol consumption (AC) did not enhance discovery compared with single-trait GWAS for smoking behaviors. We conclude that using MTAG to augment the power of GWAS enables the identification of novel genetic variants for commonly comorbid phenotypes, providing new insights into their pleiotropic effects on smoking behavior and AUD.
Deconstructing olfactory epithelium developmental pathways in esthesioneuroblastoma
Authors: Finlay John B. , Hachem Ralph Abi , Jang David , Osazuwa-Peters Nosayaba , Goldstein Bradley J.
Published: October 2022

Importance

Esthesioneuroblastoma (ENB) is a rare tumor arising from the olfactory cleft region of the nasal cavity. Due to the low incidence of this tumor, as well as an absence of established reagents such as cell lines or murine models, understanding the mechanisms driving ENB pathobiology has been challenging.

Objective

Here, we sought to apply advances from research on the human olfactory epithelial neurogenic niche, along with new biocomputational approaches, to better understand the cellular and molecular factors in low and high grade ENB and how specific transcriptomic markers may predict prognosis.

Design, Setting, and Participants

This was a retrospective biocomputational analysis utilizing human ENB and normal olfactory mucosal tissue and clinical outcomes data. The setting was a large academic medical center. Participants were selected based on available datasets, and included ENB patients across all four tumor grades, and patients with normal olfactory mucosa.

Main Outcomes and Measures

Outcomes include deconvolution analysis, differential gene expression analysis, overall survival, and immunohistochemistry. A machine learning model was used to predict cell-type proportion signatures in ENB, and Kaplan-Meier curves with associated log-rank tests were used to estimate differences in overall survival.

Results

We analyzed a total of 19 ENB samples (9 low grade I/II, 10 high grade III/IV) with available bulk RNA-Sequencing and survival data, along with 10 samples from normal olfactory mucosa (3 bulk RNA-Sequencing, 7 single cell RNA-Sequencing). The bulk RNA-Sequencing deconvolution model identified a significant increase in globose basal cell (GBC) and CD8 T cell identities in high grade tumors (GBC from approximately 0% to 8%, CD8 T cell from 0.7% to 2.2%), and significant decreases in mature neuronal, Bowman’s gland, and olfactory ensheathing programs, in high grade tumors (mature neuronal from 3.7% to approximately 0%, Bowman’s gland from 18.6% to 10.5%, olfactory ensheathing from 3.4% to 1.1%). Trajectory analysis identified potential regulatory pathways in proliferative ENB cells, including PRC2. Survival analysis guided by gene expression in bulk RNA-Sequencing data identified favorable prognostic markers such as SOX9, S100B, and PLP1 expression.

Conclusions and Relevance

Our analyses provide a basis for additional translational research on ENB management, as well as identification of potential new prognostic markers.
Actigraphic Correlates of Neuropsychiatric Disability in Adult Patients with Focal Epilepsy
Authors: Abboud Mark A. , Kamen Jessica L , Bass John S , Lin Lu , Gavvala Jay R. , Rao Sindhu , Smagula Stephen F , Krishnan Vaishnav
Published: October 2022

Disability in patients with epilepsy (PWE) is multifactorial: beyond seizure frequency/severity, PWE are prone to a range of neuropsychiatric, cognitive, and somatic comorbidities that significantly impact quality of life. In this study, we explored how variations in epilepsy severity and the burden of self-reported somatic/neuropsychiatric symptoms are associated with disruptions to 24h activity patterns (rest-activity rhythms, RARs), determined through wrist accelerometry/actigraphy. Continuous multiday recordings were obtained from 59 adult patients with focal epilepsy (44% male, ages 18-72), who contemporaneously provided responses to a range of validated psychometric instruments to measure the burden of anxiety, depression, sleepiness, and somatic symptoms. As a comparator, we conducted a similar psychometric-actigraphic correlation in 1761 subjects of Hispanic origin (35% male, ages 18-65) from the Study of Latinos (SOL) Sueño Ancillary Study. RARs were analyzed via a sigmoidally-transformed cosine model (quantifying RAR amplitude, steepness, acrophase and robustness) and non-parametric measures to estimate RAR stability, fragmentation, and sleep. Compared with age- and sex-matched SOL subjects, RARs from PWE subjects featured a significantly diminished amplitude, a wider rest phase and significantly more total daily sleep. Within PWE, similar RAR distortions were associated with seizure intractability and/or anticonvulsant polytherapy. In contrast, high anxiety, depression, and somatic symptom scores were associated with diminished RAR robustness and a delayed acrophase. We applied the complete SOL Sueño database to train logistic regression models to dichotomously classify anxiety, depression and sleepiness symptoms using age, sex, body mass index and a range of non-collinear RAR parameters. When tested on PWE, these models predicted prevalent anxiety and depression symptoms with modest success (accuracy ∼70%) but failed to predict subjective sleepiness. Together, these results demonstrate that RAR features may vary with depression and anxiety symptoms in ambulatory patients with focal epilepsy, potentially offering a set of objective wearable-derived endpoints to adjunct routine clinical care and drug/device treatment trials. With larger actigraphic-psychometric datasets in PWE, we may identify RAR signatures that can more precisely distinguish between variations in seizure risk, the burden of anticonvulsant therapy and prevalent mood/anxiety symptoms.
Residence time analysis on cerebral aneurysms treated with coils using planar-laser-induced fluorescence and computational fluid dynamics
Authors: Romero Bhathal Julia , Faisal Syed , Levitt Michael , Geindreau Christian , Aliseda Alberto
Published: October 2022

Biofidelic numerical models have been developed such as the coil-resolved model to study hemodynamics in the treated aneurysm. In this model, the geometry of the coils is recreated from high-resolution tomography scans of a phantom aneurysm treated with coils. However, this model hasn’t been validated. The purpose of this work is to validate the coil-resolved model. To achieve this, we used the planar-laser induced fluorescence technique on phantom aneurysm treated with coils and measured the residence time and the evolution of rhodamine concentration during the washout. We run passive scalar simulations with the coil-resolved model and measured the evolution of concentration over time. The comparison of the numerical and the experimental results shows that the coil-resolved model reproduces the hemodynamics of the experimental setup. Therefore it can be used as a reference to study hemodynamics in the treated aneurysm or to validate porous media models developed for treatment outcomes prediction.
Genetically modified IL-2 bone marrow-derived myeloid cells reprogram the glioma immunosuppressive tumor microenvironment
Authors: Canella Alessandro , Nazzaro Matthew , Rajendran Sakthi , Schmitt Claire , Haffey Abigail , Nigita Giovanni , Thomas Diana , Wrightnour Haley , Fadda Paolo , Mardis Elaine R. , Cripe Timothy P. , Rajappa Prajwal
Published: October 2022

Gliomas are the most prevalent type of brain tumors and one of the leading causes of cancer-related death in the adolescent and young adult population (AYA). Two-thirds of glioma AYA patients are affected by low-grade gliomas (LGGs), but there are no specific treatments. Therefore, a percentage of LGG patients experience tumor relapse and malignant progression to high-grade glioma which leads to fatal outcomes. In part, malignant progression is potentiated by the immunosuppressive stromal component of the tumor microenvironment (TME) underscored by M2-macrophages and a paucity of cytotoxic T cells. As a result, first-line immunotherapies have failed to improve outcomes for patients with progressive high-grade gliomas. Here, we report the efficacy of an in vivo approach that demonstrates the potential for a novel cell-mediated innate immunotherapy designed to abrogate immunosuppressive mechanisms within the glioma TME and enhance the recruitment of activated effector T cells. A single dose of engineered bone marrow-derived myeloid cells that release Interleukin-2 (GEMys-IL2) was used systemically to treat mice with LGG tumors systemically. Our results demonstrate that GEMys-IL2 efficiently crossed the blood brain barrier (BBB), infiltrated the glioma microenvironment, and reprogrammed the infiltrating immune cell composition and transcriptome. In addition, GEMys-IL2 impaired tumor progression and extended survival in a LGG immunocompetent mouse model. In conclusion, we demonstrated that GEMys-IL2 have a therapeutic effect in vivo, thus supporting its potential application as a novel immunotherapy that warrants further investigation.
Fiber enhancement and 3D orientation analysis in label-free two-photon fluorescence microscopy
Authors: Sorelli Michele , Costantini Irene , Bocchi Leonardo , Axer Markus , Pavone Francesco Saverio , Mazzamuto Giacomo
Published: October 2022

3D fluorescence microscopy can be profitably used in combination with tissue clearing and myelin labeling techniques for investigating the human brain myeloarchitectonics with sub-micrometric resolution, and for providing detailed histological reference data for the validation of diffusion magnetic resonance imaging (dMRI) tractography. Differently from state-of-the-art polarimetry-based neuroimaging modalities such as 3D polarized light imaging and 3D polarized-sensitive optical coherence tomography, the quantitative histological analysis of cortical and white matter fiber architectures from fluorescence microscopy images requires the estimation of fiber orientations via image processing techniques, as Fourier or structure tensor analysis. However, these can be error-prone as they are not able to detect myelinated fibers in surrounding brain tissue. Here we present a novel image processing pipeline built around a 3D Frangi filter able to enhance fiber structures of varying diameters in tiled brain section reconstructions of arbitrary size, and to produce accurate 3D fiber orientation maps in both grey and white matter regions, while preserving the native resolution of the employed microscopy system. The developed software tool also features the estimation of fiber orientation distribution functions which, in view of their widespread use in the neuroimaging community, may favor a multimodal comparison with brain connectivity data obtained from the aforementioned label-free optical modalities, and the validation of modern dMRI-based tractography. The proposed image processing pipeline was applied to brain samples treated according to a novel label-free preparation technique capable of enhancing the autofluorescence of myelinated fiber axons, thus demonstrating the feasibility of single fiber orientation analyses in fluorescence microscopy without the need for exogenous staining.
Genetic mapping revealsPou2af2-dependent tuning of tuft cell differentiation and intestinal type 2 immunity
Authors: Nadjsombati Marija S. , Niepoth Natalie , Webeck Lily M. , Kennedy Elizabeth A. , Jones Danielle L. , Baldridge Megan T. , Bendesky Andres , von Moltke Jakob
Published: October 2022

Chemosensory epithelial tuft cells contribute to innate immunity at barrier surfaces, but their differentiation from epithelial progenitors is not well understood. Here we exploited differences between inbred mouse strains to identify an epithelium-intrinsic mechanism that regulates tuft cell differentiation and tunes innate type 2 immunity in the small intestine. Balb/cJ (Balb) mice had fewer intestinal tuft cells than C57BL/6J (B6) mice and failed to respond to the tuft cell ligand succinate. A majority of this differential succinate response was determined by a single genetic locus from 50-67Mb on chromosome 9 (Chr9). Congenic Balb mice carrying the B6 Chr9 locus had elevated baseline numbers of tuft cells and responded to succinate. The Chr9 locus includesPou2af2, a transcriptional cofactor essential for tuft cell development. Epithelial crypts expressed a previously unannotated short isoform ofPou2af2that uses a novel transcriptional start site and encodes a non-functional protein. Low tuft cell numbers and the resulting lack of succinate response in Balb mice was explained by a preferential expression of the short isoform. Physiologically, differentialPou2af2isoform usage tuned innate type 2 immunity in the small intestine. Balb mice maintained responsiveness to helminth pathogens while ignoring commensalTritrichomonasprotists and reducing norovirus burdens.

One Sentence Summary

Genetic mapping identifiesPou2af2isoform usage as a novel regulator of tuft cell differentiation that tunes intestinal innate type 2 immunity.
The genetic basis of variation immune defense againstLysinibacillus fusiformisinfection inDrosophila melanogaster
Authors: Smith Brittny R. , Patch Kistie B. , Unckless Robert L.
Published: October 2022

The genetic causes of phenotypic variation often differ depending on the population examined, particularly if the populations were founded by relatively small numbers of genotypes. Similarly, the genetic causes of phenotypic variation among similar traits (resistance to different xenobiotic compounds or pathogens) may also be completely different or only partially overlapping. Differences in genetic causes for variation in the same trait among populations suggests considerable context dependence for how selection might act on those traits. Similarities in the genetic causes of variation for different traits, on the other hand, suggests pleiotropy which also would influence how natural selection would shape variation in a trait. We characterized immune defense against a naturalDrosophilapathogen, the Gram-positiveLysinibacillus fusiformis, in three different populations and found almost no overlap in the genetic architecture of variation in survival post infection. However, when comparing our results to a similar experiment with the fungal pathogen,B. bassiana, we found a convincing shared QTL peak for both pathogens. This peak contains theBomanincluster ofDrosophilaimmune effectors. RNAi knockdown experiments confirms a role of some of these genes in immune defense against both pathogens. This suggests that natural selection may act on the entire cluster ofBomaningenes (and the linked region under the QTL) or specific peptides for specific pathogens.

Author Summary

Like most traits, the way individuals respond to infection vary among individuals within a population. Some of this variation is caused by genetic differences in the host organism. Over the past decade, two prominent resources were developed to assess genetic variation for complex traits of the fruit fly,Drosophila melanogasterand map the genetic variants responsible. We recently described a strain ofLysinibacillus fusiformisbacteria, which was isolated from fruit flies and is moderately virulent when flies are infected. We mapped genetic variation in resistanceL. fusiformisusing these mapping resources. We find that among the resources, different changes were associated with immune defense. However, we also found that within a resource, the same region of the genome was associated with resistance to bothL. fusiformisand a fungal pathogen. These results suggest that different populations adapt differently to the same pathogens, but two distinct pathogens share similar causes of genetic variation within a single population.
Hidden endosymbionts: A male-killer concealed by another endosymbiont and a nuclear suppressor
Authors: Richardson Kelly M. , Ross Perran A. , Cooper Brandon S. , Conner William R. , Schmidt Tom , Hoffmann Ary A.
Published: October 2022

Maternally transmitted endosymbiotic bacteria that cause male killing (MK) have only been described from a few insects, but this may reflect challenges in their detection rather than a rarity of MK. Here we identify MKWolbachiain populations ofDrosophila pseudotakahashii, present at a low frequency (around 4%) in natural populations and previously undetected due to a different fixedWolbachiastrain in this species expressing a different reproductive manipulation, cytoplasmic incompatibility (CI). The MK phenotype was eliminated after tetracycline treatment that removedWolbachia. Molecular analyses indicated the MK phenotype to be expressed when a secondWolbachiastrain was present alongside the CIWolbachia. A genomic analysis highlightedWolbachiaregions diverged between the strains involving 17 genes and also identified theWolbachiaas representing an outgroup to a clade ofWolbachiainfectingmelanogaster-group species, includingwRi-like andwMel-like strains. Doubly infected males induced CI with uninfected females but not females singly infected with CI-causingWolbachia. The MK phenotype manifested at the larval stage and was transmitted maternally at a high fidelity but with occasional loss of the MKWolbachiastrain. A rapidly spreading dominant nuclear suppressor genetic element affecting MK was identified through backcrossing and subsequent analysis with ddRAD SNPs of theD. pseudotakahashiigenome. These findings highlight the complexity of nuclear and microbial components affecting MK endosymbiont detection and dynamics in populations, and the challenges of making connections between endosymbionts and the host phenotypes affected by them.
Multimodal mapping of cell types and projections in the central nucleus of the amygdala
Authors: Wang Yuhan , Krabbe Sabine , Eddison Mark , Henry Fredrick E. , Fleishman Greg , Lemire Andrew L. , Wang Lihua , Korff Wyatt , Tillberg Paul W. , Lüthi Andreas , Sternson Scott M.
Published: October 2022

The central nucleus of the amygdala (CEA) is a brain region that integrates external and internal sensory information and executes innate and adaptive behaviors through distinct output pathways. Despite its complex functions, the diversity of molecularly defined neuronal types in the CEA and their contributions to major axonal projection targets have not been examined systematically. Here, we performed single-cell RNA-sequencing (scRNA-Seq) to classify molecularly defined cell types in the CEA and identified marker-genes to map the location of these neuronal types usingexpansionassisted iterative fluorescence insituhybridization (EASI-FISH). We developed new methods to integrate EASI-FISH with 5-plex retrograde axonal labeling to determine the spatial, morphological, and connectivity properties of ∼30,000 molecularly defined CEA neurons. Our study revealed spatio-molecular organization of the CEA, with medial and lateral CEA associated with distinct cell families. We also found a long-range axon projection network from the CEA, where target regions receive inputs from multiple molecularly defined cell types. Axon collateralization was found primarily among projections to hindbrain targets, which are distinct from forebrain projections. This resource reports marker-gene combinations for molecularly defined cell types and axon-projection types, which will be useful for selective interrogation of these neuronal populations to study their contributions to the diverse functions of the CEA.