bluuebunny/crossref_metadata_2025 huggingface dataset:
In Situ Trace Elements in Quartz and K-Feldspar from Felsic Igneous Rocks: A Titanium-in-K-Feldspar Geothermometer for Natural Magmatic Systems
Authors: Zhang Yongmei , Gu Xuexiang , Rusk Brian , Mao Wei , Wang Jialin , Zheng Shaohua
Published: November 2022

Scanning electron microscope, cathodoluminescence (CL) imaging and laser ablation–inductively coupled plasma–mass spectrometry analyses were conducted on coexisting pairs of quartz and K-feldspar from 14 samples of various types of felsic igneous rocks. Difference of the concentration of trace elements in quartz and K-feldspar among plutonic, pegmatitic and volcanic rocks is closely related to the rock-forming process and P–T condition. In general, a decreasing Ti concentration and increasing Al, Li, and Ge concentrations from plutonic to pegmatitic quartz suggest a higher degree of magmatic fractionation and lower crystallization temperature. Sensitive elements to magma differentiation in K-feldspar such as Ba, Sr, and LREE show a decreasing trend from various granitic rocks to pegmatite, while Rb, Cs, Li, Ge, and P exhibit increasing trends. The K-feldspar from various types of felsic igneous rocks typically shows similar CL textures but relatively higher luminescence intensity compared with coexisting quartz. Both quartz and K-feldspar phenocrysts in the volcanic rhyolite have a bright rim and a dark core in CL images, corresponding to bimodal Ti concentrations. Among all samples, Ti concentrations in both quartz and coexisting K-feldspar positively correlate with their CL intensities, suggesting the activation of Ti-impurity in these minerals leads to increased CL intensity. Meanwhile, there is a good positive correlation between Ti concentrations in quartz and those in K-feldspar with an R2 value of 0.86. It is considered that Ti concentrations in the both minerals are mainly temperature dependent at relatively constant pressure on basis of a fair aTiO2 restriction. Here, for the first time, we calculated a titanium-in-K-feldspar (TitaniKfs) thermometer in the form of log (XTi, kfs/aTiO2) = −(3430 ± 268)/T(K) + (5.081 ± 0.298) for natural felsic magma systems. The Ti contents of K-feldspar (in ppm by weight) increase exponentially with reciprocal T at temperatures ranging from 500°C to 800°C, at 200–300 MPa. An application of this thermometer to granitic rocks from Xinjiang and Inner Mongolia in China fits well with other geothermometers. In addition, the present TitaniKfs thermometer is expected to be particularly useful in determining the temperature condition of K-feldspar-bearing extraterrestrial materials such as lunar rocks.
Degassing, Crystallization and Rheology of Hawaiitic Lava Flows: the Case of the 1669 AD Eruption of Mount Etna (Italy)
Authors: Lanzafame Gabriele , Giacomoni Pier Paolo , Casetta Federico , Mancini Lucia , Iezzi Gianluca , Coltorti Massimo , Ferlito Carmelo
Published: November 2022

Understanding lava flow dynamics during major effusive events is of paramount importance in volcanic areas characterized by a high risk of lava invasion. Mount Etna volcano (Sicily, Italy) has a long history of eruptions characterized by the emplacement of kilometer-wide lava fields, which have often reached the distal parts of the volcanic edifice, nowadays the location of numerous population centers. The 1669 eruption was one of the volcano’s most important events in historic times due to the low altitude of the eruptive vent and the high volume of emitted products (607 ± 105 × 106 m3), with lava flows that destroyed numerous villages located along their path. The flows reached the city of Catania, at a distance of >16 km from the emission point. In this work, we investigate the products of the 1669 eruption through geochemical, mineralogical, 2D and 3D textural analyses with the aim of reconstructing the degassing, crystallization and rheological history of the magma and lavas in pre- to post-eruptive conditions. Combining geothermobarometric and hygrometric models allowed us to estimate magmatic water content (4.1 wt.%) before the eruption, whereas the syn-eruptive crystal content (10 vol.% at the onset of flowing) was retrieved through the textural analysis of pyroclasts sampled from the near-vent fallout. Finally, crystallization and degassing occurring at surface conditions were reconstructed using the textural and mineralogical analysis of lavas. Results were integrated in a three-phase (melt + crystal + bubble) rheological model indicating that lava viscosity, at the onset of the eruption, was low enough (<3.51 log Pa s) to permit the development of a complex and extensive lava field. Flows reached numerous kilometers in length, thanks to the joint effects of lava tunneling, delayed crystal nucleation and growth, and the presence (up to 21.35 vol.%) of deformed bubbles. The combination of these processes maintained the high fluidity of the melt suspension, allowing the flow to arrive at considerable distances from the vent. Lastly, the results of this study highlight the necessity of an accurate real-time multi-analytical petrological characterization of active lavas during the monitoring of effusive eruptions, essential for reliable viscosity modeling of advancing flow units and therefore vital in predicting the direction of lava flows, especially in densely populated areas such as the southern flank of Mount Etna.
Redirecting Nonurgent Patients From the Pediatric Emergency Department to Their Pediatrician Office for a Same-Day Visit—A Quality Improvement Initiative
Authors: Wolski Thomas P. , Jamerino-Thrush Jennifer , Bigham Michael T. , Kline-Krammes Sarah , Patel Nirali , Lee Timothy J. , Pollauf Laura A. , Joyce Crystal N. , Kunka Sarah , McNinch Neil L. , Jacobs Michelle , White P. Cooper
Published: November 2022

Objectives

Providing high-quality care in the appropriate setting to optimize value is a worthy goal of an efficient health system. Consequences of managing nonurgent complaints in the emergency department (ED) have been described including inefficiency, loss of the primary care–patient relationship, and delayed care for other ED patients. The purpose of this initiative was to redirect nonurgent patients arriving in the ED to their primary care office for a same-day visit, and the SMART AIM was to increase redirected patients from 0% of those eligible to 30% in a 12-month period.

Methods

The setting was a pediatric ED (PED) and primary care office of a tertiary care pediatric medical system. The initiative utilized the electronic health record to identify and mediate the redirection of patients to the patient's primary care office after ED triage. The primary measurement was the percentage of eligible patients redirected. Additional measures included health benefits during the primary care visit (vaccines, well-visits) and a balancing measure of patients returned to the PED.

Results

The SMART AIM of >30% redirection was achieved and sustained with a final redirection rate of 46%. In total, 216 of 518 eligible patients were redirected, with zero untoward outcomes. The encounter time for redirected patients was similar for those who remained in the PED, and additional health benefits were appreciated for redirected patients.

Conclusions

This initiative redirected nonurgent patients efficiently from a PED setting to their primary care office. The process is beneficial to patients and families and supports the patient-centered medical home. The balancing measure of no harm done to patients who accepted redirect reinforced the reliability of PED triage. The benefits achieved through the project highlight the value of the primary care–patient relationship and the continued need to improve access for patients and families.
In silico method for predicting infectious strains of influenza A virus from its genome and protein sequences
Authors: Roy Trinita , Sharma Khushal , Dhall Anjali , Patiyal Sumeet , Raghava Gajendra Pal Singh
Published: November 2022

Influenza A is a contagious viral disease responsible for four pandemics in the past and a major public health concern. Being zoonotic in nature, the virus can cross the species barrier and transmit from wild aquatic bird reservoirs to humans via intermediate hosts. In this study, we have developed a computational method for the prediction of human-associated and non-human-associated influenza A virus sequences. The models were trained and validated on proteins and genome sequences of influenza A virus. Firstly, we have developed prediction models for 15 types of influenza A proteins using composition-based and one-hot-encoding features. We have achieved a highest AUC of 0.98 for HA protein on a validation dataset using dipeptide composition-based features. Of note, we obtained a maximum AUC of 0.99 using one-hot-encoding features for protein-based models on a validation dataset. Secondly, we built models using whole genome sequences which achieved an AUC of 0.98 on a validation dataset. In addition, we showed that our method outperforms a similarity-based approach (i.e., blast) on the same validation dataset. Finally, we integrated our best models into a user-friendly web server ‘FluSPred’ (https://webs.iiitd.edu.in/raghava/fluspred/index.html) and a standalone version (https://github.com/raghavagps/FluSPred) for the prediction of human-associated/non-human-associated influenza A virus strains.
Representation of Race and Ethnicity in a Contemporary US Health Cohort: TheAll of UsResearch Program
Authors: Kathiresan Nina , Cho So Mi Jemma , Bhattacharya Romit , Truong Buu , Hornsby Whitney , Natarajan Pradeep
Published: November 2022

Participation and inclusion in biomedical research remain disproportionate across sociodemographics limiting discoveries in genomic studies and contributing to systemic disparities in healthcare. To alleviate such inequities, the National Institute of Health initiated theAll of UsResearch Program (AoU), a prospective, population-based cohort to identify the root causes and consequences of health outcomes across diverse demographics. We quantify representation of key racial groups in the accruing AoU cohort of US adults aged ≥18 years and compare to their actual representation in the US. Of the 358,705 AoU participants to date, Hispanic or Latino participants were underrepresented by 0.85-fold, non-Hispanic Asian by 0.58-fold, non-Hispanic White by 0.98-fold, and Other by 0.43-fold. Meanwhile, individuals identifying as non-Hispanic Black or African American were overrepresented by 1.88-fold. While AoU representation better mirrors the US demographics compared to other cohorts, recruitment trends for the ongoing AoU underscore the need to further tailor participation initiatives for diverse populations.
Dual-mode near-infrared multispectral imaging system equipped with deep learning models improves the identification of cancer foci in breast cancer specimens
Authors: Liao Jun , Zhang Lingling , Wang Han , Bai Ziqi , Zhang Meng , Han Dandan , Jia Zhanli , Liu Yao , Qin Chenchen , Niu ShuYao , Bu Hong , Yao Jianhua , Liu Yueping
Published: November 2022

For surgically resected breast cancer samples, it is challenging to perform specimen sampling by visual inspection, especially when the tumor bed shrinks after neoadjuvant therapy in breast cancer. In this study, we developed a dual-mode near-infrared multispectral imaging system (DNMIS) to overcome the human visual perceptual limitations and obtain richer sample tissue information by acquiring reflection and transmission images covering visible to NIR-II spectrum range (400–1700 nm). Additionally, we used artificial intelligence (AI) for segmentation of the rich multispectral data. We compared DNMIS with the conventional sampling methods, regular visual inspection and a cabinet X-ray imaging system, using data from 80 breast cancer specimens. DNMIS demonstrated better tissue contrast and eliminated the interference of surgical inks on the breast tissue surface, helping pathologists find the tumor area which is easy to be overlooked with visual inspection. Statistically, AI-powered DNMIS provided a higher tumor sensitivity (95.9% vs visual inspection 88.4% and X-rays 92.8%), especially for breast samples after neoadjuvant therapy (90.3% vs visual inspection 68.6% and X-rays 81.8%). We infer that DNMIS can improve the breast tumor specimen sampling work by helping pathologists avoid missing out tumor foci.
In Silico, Brain Mesh Platform for Computing Topographic Dependent Internal Facets
Authors: Shaw Caleb , Riviere-Cazaux Cecile , Obrochta Dylan , Otto Stephanie , Ray Lawrence , Strother Lars , Burns Terry , Khan M. Rashed
Published: November 2022

Individualized and anatomically correct computational models of the brain can be leveraged to improve knowledge of drug dispersal following simulation of drug delivery. Using a patient’s magnetic resonance image (MRI) scans, we were able to reconstruct the pial surface of the brain of the left hemisphere with strong anatomic accuracy. We then established the major internal features, including the lateral ventricle, a tumor, and drug delivery catheters. These were able to include relevant tissue characteristics such as porosity and permeability in the Multiphysics platform COMSOL to create a platform for brain modeling. To test the performance of this platform, we simulated direct drug infusion in both a healthy patient brain and a diseased patient model, focusing on glioblastoma (GBM). Using this platform, we simulated perturbed convection enhanced delivery of a cancer medication (similar to temozolomide (TMZ) but modeled using methylene blue) to the tumor. Consequently, with our patient derived model, we are able to simulate solute dispersal and fluid flow representative ofin vivoconditions.
The power of geohistorical boundaries for modeling the genetic background of human populations: the case of the rural Catalan Pyrenees
Authors: Fibla Joan , Maceda Iago , Laplana Marina , Guerrero Montserrat , Álvarez Miguel Martín , Burgueño Jesús , Camps Agustí , Fàbrega Jordi , Felisart Josefina , Grané Joan , Luis Remón José , Serra Jordi , Moral Pedro , Lao Oscar
Published: November 2022

The genetic variation of the European population at a macro-geographic scale follows genetic gradients which reflect main migration events. However, less is known about factors affecting mating choices at a micro-geographic scale. In this study we have analyzed 726,718 autosomal SNPs in 435 individuals from the Catalan Pyrenees covering around 200 km of a vast and abrupt region in the north of the Iberian Peninsula, for which we have information about the geographic origin of all grand-parents and parents. At a macro-geographic scale, our analyses recapitulate the genetic gradient observed in Spain. However, we also identified the presence of micro-population substructure among the sampled individuals. Such micro-population substructure does not correlate with geographic barriers such as the expected by the orography of the considered region, but by the bishoprics present in the covered geographic area. These results support that, on top of main human migrations, long ongoing socio-cultural factors have also shaped the genetic diversity observed at rural populations.
Identifying endogenous peptide receptors by combining structure and transmembrane topology prediction
Authors: Teufel Felix , Refsgaard Jan C. , Kasimova Marina A. , Madsen Christian T. , Stahlhut Carsten , Grønborg Mads , Winther Ole , Madsen Dennis
Published: November 2022

Many secreted endogenous peptides rely on signalling pathways to exert their function in the body. While peptides can be discovered through high throughput technologies, their cognate receptors typically cannot, hindering the understanding of their mode of action. We investigate the use of AlphaFold-Multimer for identifying the cognate receptors of secreted endogenous peptides in human receptor libraries without any prior knowledge about likely candidates. We find that AlphaFold’s predicted confidence metrics have strong performance for prioritizing true peptide-receptor interactions. By applying transmembrane topology prediction using DeepTMHMM, we further improve performance by detecting and filtering biologically implausible predicted interactions. In a library of 1112 human receptors, the method ranks true receptors in the top percentile on average for 11 benchmark peptide-receptor pairs.
Physics of sliding on water predicts morphological and behavioral allometry across a wide range of body sizes in water striders (Gerridae)
Authors: Kim Woojoo , Lee Jae Hong , Pham Thai H. , Tran Anh D. , Ha Jungmoon , Bang Sang Yun , Jablonski Piotr G. , Kim Ho-Young , Lee Sang-im
Published: November 2022

Laws of physics shape morphological and behavioral adaptations to locomotion at different body sizes. Water striders serve as a model taxon to study how simple physical constraints of water-surface habitats affect their behavior and morphology, and hydrodynamics of rowing by midlegs on the surface is well understood. However, the physics of the subsequent passive sliding has been less explored. We created a model of sliding on the water surface to simulate the effect of body mass, striding type, and wetted leg lengths on an insect’s ability to float on the surface and on the sliding resistance. The model predicts that to support their weight on the surface during sliding, the heavy species should either develop long forelegs that support the frontal part of its body during symmetrical striding (when two midlegs thrust) or use asymmetrical striding (when one forward-extended midleg supports the body while the other midleg and contra-lateral hindleg thrust). These predictions are confirmed by the behavior and morphology of various Gerridae species. Hence, the results illustrate how simple physical processes specific to a certain habitat type have far-reaching consequences for the evolution of morphological and behavioral diversification associated with body size among biological organisms in these habitats.
Crystal ribcage: a platform for probing real-time lung function at cellular resolution in health and disease
Authors: Banerji Rohin , Grifno Gabrielle N. , Shi Linzheng , Smolen Dylan , LeBourdais Rob , Muhvich Johnathan , Eberman Cate , Hiller Bradley E. , Lee Jisu , Regan Kathryn , Zheng Siyi , Zhang Sue , Jiang John , Raslan Ahmed A. , Breda Julia C. , Pihl Riley , Traber Katrina , Mazzilli Sarah , Ligresti Giovanni , Mizgerd Joseph P. , Suki Béla , Nia Hadi T.
Published: November 2022

Understanding the dynamic pathogenesis and treatment response in pulmonary diseases requires probing the lung at cellular resolution in real-time. Despite recent progress in intravital imaging, optical imaging of the lung during active respiration and circulation has remained challenging. Here, we introduce the crystal ribcage: a transparent ribcage that (i) allows truly multiscale optical imaging of the lung in health and disease from whole-organ to single cell, (ii) enables the modulation of lung biophysics and immunity through intravascular, intrapulmonary, intraparenchymal, and optogenetic interventions, and (iii) preserves the 3-D architecture, air-liquid interface, cellular diversity, and respiratory-circulatory functions of the lung. Utilizing these unprecedented capabilities on murine models of primary and metastatic lung tumors, respiratory infection, pulmonary fibrosis, emphysema, and acute lung injury we probed how disease progression remodels the respiratory-circulatory functions at the single alveolus and capillary levels. In cancer, we identified the earliest stage of tumorigenesis that compromises alveolar and capillary functions, a key state with consequences on tumor progression and treatment response. In pneumonia, we mapped mutual links between the recruited immune cells and the alveolar-capillary functions. We found that neutrophil migration is strongly and reversibly responsive to vascular pressure with implications for understanding of how lung physiology, altered by disease and anatomical location, affects immune cell activities. The crystal ribcage and its broad applications presented here will facilitate further studies of real-time remodeling of the alveoli and capillaries during pathogenesis of nearly any pulmonary disease, leading to the identification of new targets for treatment strategies.
A divide-and-conquer method for analyzing high-dimensional noisy gene expression networks
Authors: Fang Zhou , Gupta Ankit , Kumar Sant , Khammash Mustafa
Published: November 2022

Intracellular gene expression systems are inevitably random due to low molecular counts. Consequently, mechanistic models for gene expression should be stochastic, and central to the analysis and inference of such models is solving the Chemical Master Equation (CME), which characterizes the probability evolution of the randomly evolving copy-numbers of the reacting species. While conventional methods such as Monte-Carlo simulations and finite state projections exist for estimating CME solutions, they suffer from the curse of dimensionality, significantly decreasing their efficacy for high-dimensional systems. Here, we propose a new computational method that resolves this issue through a novel divide-and-conquer approach. Our method divides the system into aleadersystem andseveralconditionally independentfollowersubsystems. The solution of the CME is then constructed by combining Monte Carlo estimation for the leader system with stochastic filtering procedures for the follower subsystems. We develop an optimized system decomposition, which ensures the low-dimensionality of the sub-problems, thereby allowing for improved scalability with increasing system dimension. The efficiency and accuracy of the method are demonstrated through several biologically relevant examples in high-dimensional estimation and inference problems. We demonstrate that our method can successfully identify a yeast transcription system at the single-cell resolution, leveraging mRNA time-course microscopy data, allowing us to rigorously examine the heterogeneity in rate parameters among isogenic cells cultured under identical conditions. Furthermore, we validate this finding using a novel noise decomposition technique introduced in this study. This technique exploits experimental time-course data to quantify intrinsic and extrinsic noise components, without requiring supplementary components, such as dual-reporter systems.
WEBNG: A templating tool for weighted ensemble sampling of rule-based models
Authors: Saglam Ali Sinan , Faeder James R.
Published: November 2022

Time scales for biological processes span many orders of magnitude, forcing modelers to tackle coupled processes that have large time scale gaps. This results in rare events, which take longer to occur than the fastest processes in the model. Efficient generation of rare events has been a focus of modelers for a long time and multiple software packages implement various rare event sampling algorithms. However, these packages frequently require expertise to get started with, making it harder for researchers to start using them. WEBNG (short for Weighted Ensemble–BioNetGen) is an open source software framwework that bridges the open source software packages WESTPA, which implements the weighted ensemble method for sampling rare events, and BioNetGen, which facilitates the specification and simulation of biochemical reaction network models following a rule-based approach. WEBNG simplifies rare event sampling in simulations of rule-based models by taking a model specified in the BioNetGen language (BNGL) and generating a WESTPA simulation folder ready to simulate with default parameters selected to match model observables. WEBNG is written in Python with dependencies only on proven, open-source packages that are in active development, which makes WEBNG easy to install and maintain. Here, we describe the architecture and features of WEBNG and demonstrate its capabilities through application to a two-gene model of cell fate transitions.
Mechanically manipulate glymphatic transportation by ultrasound combined with microbubbles
Authors: Ye Dezhuang , Chen Si , Liu Yajie , Weixel Charlotte , Hu Zhongtao , Chen Hong
Published: November 2022

The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transportation is believed to be driven by the perivascular pumping effect generated by arterial wall pulsation induced by the cardiac cycle. Ultrasound sonication of circulating microbubbles in the cerebral vasculature induces volumetric expansion and contraction of microbubbles that push and pull on the vessel wall to generate a microbubble pumping effect. The objective of this study was to evaluate whether glymphatic transportation can be mechanically manipulated by focused ultrasound (FUS) sonication of microbubbles. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as a fluid tracer followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected microbubbles. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the perivascular space into the interstitial space. This study revealed that ultrasound combined with circulating microbubbles could noninvasively enhance glymphatic transportation in the brain.

Significance Statement

The glymphatic system is a waste clearance system in the brain analogous to the lymphatic system in peripheral organs. Glymphatic system impairment might contribute to brain disease pathologies, including those in neurodegenerative diseases, traumatic brain injury, and stroke. This study revealed that ultrasound could mechanically enhance glymphatic transportation. This result opens opportunities for using ultrasound to probe the role of the glymphatic system in brain function and brain diseases. Findings from this study suggest that ultrasound can be utilized as a noninvasive/nonpharmacological approach to mitigate brain diseases caused by impaired glymphatic function.
Analyzing the covariance structure of plasma signaling proteins in relation to the diagnosis of dementia
Authors: Guan Calvin , Au Rhoda , Ang Alvin , Gangopadhyay Ashis
Published: November 2022

Numerous studies have shown that individuals with dementia have exhibited activation of inflammatory pathways in their brains. Typically, these studies use traditional and well-established regression methods for data analysis. In this paper, a new approach is introduced that utilizes the analysis of the covariance structure using methods related to the principal component analysis (PCA) theory. Eleven biomarkers related to neuroinflammation were used to determine the association with the onset of dementia. Various demographic covariates were adjusted to account for possible confounding effects of the covariance structure. Three hypothesis testing methods were considered to discern differences between partial covariance matrices for comparing power and Type I errors through simulation studies. Application of hypothesis testing methods using data from Framingham Heart Study (FHS) found significant differences in covariance matrices between the non-dementia and dementia groups.
Networks and genes modulated by posterior hypothalamic stimulation in patients with aggressive behaviours: Analysis of probabilistic mapping, normative connectomics, and atlas-derived transcriptomics of the largest international multi-centre dataset
Authors: Gouveia Flavia Venetucci , Germann Jürgen , Elias Gavin JB , Boutet Alexandre , Loh Aaron , Lopez Rios Adriana Lucia , Torres Diaz Cristina V , Contreras Lopez William Omar , Martinez Raquel CR , Fonoff Erich T , Benedetti-Isaac Juan C , Giacobbe Peter , Arango Pava Pablo M , Yan Han , Ibrahim George M , Lipsman Nir , Lozano Andres M , Hamani Clement
Published: November 2022

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as treatment for refractory aggressive behaviour, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. 91% of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral posterior hypothalamic area and normative connectomic analyses identified fiber tracts and interconnected brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and the amygdala – together with patient age – was highly predictive of treatment outcome. Finally, transcriptomic analysis showed that genes involved in mechanisms of aggressive behaviour, neuronal communication, plasticity and neuroinflammation may underlie this functional network.

SIGNIFICANCE STATEMENT

This study investigated the brain mechanisms associated with symptom improvement following deep brain stimulation of the posterior hypothalamus for severe and refractory aggressive behavior. Conducting an integrated imaging analysis of a large international multi-center dataset of patients treated with hypothalamic deep brain stimulation, we were able to show for the first time that treatment is highly efficacious across various patients with an average improvement greater than 70%. Leveraging this unique dataset allowed us to demonstrate that some patient characteristics are important for treatment success, describe the optimal target zone for maximal benefit, that engagement of distinct fiber tracts and networks within the emotional neurocircuitry are key for positive outcome, and - using imaging transcriptomics - elucidate some potential molecular underpinnings. The provided optimal stimulation site allows for direct clinical application.
Alveolar epithelial type 1 cells serve as a cell of origin for lung adenocarcinoma with distinct molecular and phenotypic presentation
Authors: Yang Minxiao , Shen Hua , Flodby Per , Koss Michael D. , Bassiouni Rania , Liu Yixin , Jashashvili Tea , Stueve Theresa R. , Mullen Daniel J. , Ryan Amy L. , Carpten John , Castaldi Alessandra , Wallace W. Dean , Zhou Beiyun , Borok Zea , Marconett Crystal N.
Published: November 2022

Lung adenocarcinoma (LUAD) is the most common subtype of cancer arising in the distal lung. LUAD encompasses several pathologic subtypes, each with differing clinical outcomes and biological behaviors. However, the molecular and cellular underpinnings of the different subtypes are largely unknown. Understanding which cell populations in the distal lung contribute to LUAD could provide insights into the marked heterogeneity in pathologic features, clinical presentation and responses to therapy of LUAD. Differential expression analysis of lung adenocarcinoma transcriptomes from The Cancer Genome Atlas revealed distinct alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell signatures within human LUAD with significantly different survival outcomes between tumors expressing AT2 and AT1 gene signatures, suggesting AT1 cells might contribute to a subset of LUAD cases. To address this, we tested the ability of AT1 cells to give rise to LUAD following induction of KrasG12D, a known oncogenic driver of human LUAD. Activation of KrasG12Din Gram-domain containing 2 (Gramd2)+AT1 cells gave rise to multiple LUAD lesions, primarily of papillary histology. In contrast, activation of KrasG12Din surfactant protein C (Sftpc+) AT2 cells resulted in LUAD lesions of lepidic histology. Immunohistochemistry established thatGramd2:KrasG12Dlesions were of primary lung origin and not metastatic events. Spatial transcriptomic profiling revealed distinct pathway alterations within Gramd2- and Sftpc-derived LUAD. Immunofluorescence confirmed differences observed in the spatial transcriptomic analysis in expression patterns and distribution of cell-specific markers depending on cell of origin, while universal upregulation of the Krt8 intermediate cell state marker was observed. Our results are consistent with Gramd2+AT1 cells serving as a putative cell of origin for LUAD and suggest that LUAD may be a collection of adenocarcinomas that share a common location within the distal lung but arise from different cells of origin.
The entry of pinewood nematode is linked to programmed tracheal development of vector beetles
Authors: Tang Xuan , Koski Tuuli-Marjaana , Sun Jianghua
Published: November 2022

The transmission of some pathogens by insect vectors often requires fine-tuned biological synchronization and communication between the two parties. However, the role of tissue development in mediating this pathogen-vector coordination remains elusive. Here we investigated the association between tracheal development ofMonochamus alternatusbeetle and a notorious plant parasitic pine wood nematodeBursaphelenchus xylophilus, which enter and inhabit inside the tracheal system after adult beetle eclosion and then were transmitted to pine trees (Pinusspp.) by the beetle. We found that the tracheal systems of newly emerged adult beetles underwent morphological changes during the adult sclerotization, characterized by a remarkable increase of diameter of thoracic tracheal dorsal tubes. Consistently, comparative transcriptomics further revealed dramatic changes in gene expression occurring within five days after eclosion, demonstrating sequential regulation of tracheal genes. Genes controlling primary branching were up-regulated soon after eclosion, whereas those controlling terminal branching and branch fusion were up-regulaed at the later stage. Interestingly, during tracheal maturation, genes involved in biosynthesis of Juvenile Hormone (JH) and ecdysteroids were activated. Nematode loading assay further revealed that the entry of nematodes to beetle tracheae was initiated earliest after three days post eclosion, implying that nematode entry is reliant on the formation of the vector’s primary tracheal branches and is perhaps stimulated by production of insect hormones or their precursors. In addition, specific regulation on secreted proteins, such as Defensin-1-like and membrane proteins, at later stages of tracheal maturation may further facilitate the entry of nematodes by improving their retention. Therefore, this study highlights vital role of programed tracheal development on nematode entry into its vector beetle, and suggests a potential roles of insect genes and metabolites in manipulation of interspecific biological developmental synchronization between parasites and their insect vectors.
Feasibility of Ultra-Short Term Analysis of Heart Rate and Systolic Arterial Pressure Variability at Rest and During Stress via Time-domain and Entropy-based Measures
Authors: Volpes Gabriele , Barà Chiara , Busacca Alessandro , Stivala Salvatore , Javorka Michal , Faes Luca , Pernice Riccardo
Published: November 2022

Heart Rate Variability (HRV) and Blood Pressure Variability (BPV) are widely employed tools for characterizing the complex behavior of cardiovascular dynamics. Usually, HRV and BPV analyses are carried out through short-term (ST) measurements, which exploit ∼5 minute-long recordings. Recent research efforts are focused on reducing the time series length, assessing whether and to what extent Ultra-Short Term (UST) analysis is capable of extracting information about cardiovascular variability from very short recordings. In this work, we compare ST and UST measures computed on electrocardiographic R-R intervals and systolic arterial pressure time series obtained at rest and during both postural and mental stress. Standard time-domain indices are computed, together with entropy-based measures able to assess regularity and complexity of cardiovascular dynamics, on time series lasting up to 60 samples, employing either a faster linear parametric estimator or a more reliable but time-consuming model-free method based on nearest neighbor estimates. Our results evidence that shorter time series up to 120 samples still exhibit an acceptable agreement with the ST reference, and can be exploited to discriminate between stress and rest as well. Moreover, although neglecting nonlinearities inherent to short-term cardiovascular dynamics, the faster linear estimator is still capable of detecting differences among the conditions, thus resulting suitable to be implemented on wearable devices.
Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology
Authors: Cadeddu Roberto , Van Zandt Meghan , Odeh Karen , Anderson Collin J , Flanagan Deirdre , Nordkild Peter , Pittenger Christopher J , Bortolato Marco
Published: November 2022

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of cholinergic interneurons (CINs) in the striatum seen inpostmortemstudies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement, a mild acute stressor that increases AP synthesis in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.
Cross-attractor modeling of resting-state functional connectivity in psychiatric disorders
Authors: Sun Yinming , Zhang Mengsen , Saggar Manish
Published: November 2022

Resting-state functional connectivity (RSFC) is altered across various psychiatric disorders. Brain network modeling (BNM) has the potential to reveal the neurobiological underpinnings of such abnormalities by dynamically modeling the structure-function relationship and examining biologically relevant parameters after fitting the models with real data. Although innovative BNM approaches have been developed, two main issues need to be further addressed. First, previous BNM approaches are primarily limited to simulating noise-driven dynamics near a chosen attractor (or a stable brain state). An alternative approach is to examine multi(or cross)-attractor dynamics, which can be used to better capture non-stationarity and switching between states in the resting brain. Second, previous BNM work is limited to characterizing one disorder at a time. Given the large degree of co-morbidity across psychiatric disorders, comparing BNMs across disorders might provide a novel avenue to generate insights regarding the dynamical features that are common across (vs. specific to) disorders. Here, we address these issues by (1) examining the layout of the attractor repertoire over the entire multi-attractor landscape using a recently developed cross-attractor BNM approach; and (2) characterizing and comparing multiple disorders (schizophrenia, bipolar, and ADHD) with healthy controls using an openly available and moderately large multimodal dataset from the UCLA Consortium for Neuropsychiatric Phenomics. Both global and local differences were observed across disorders. Specifically, the global coupling between regions was significantly decreased in schizophrenia patients relative to healthy controls. At the same time, the ratio between local excitation and inhibition was significantly higher in the schizophrenia group than the ADHD group. In line with these results, the schizophrenia group had the lowest switching costs (energy gaps) across groups for several networks including the default mode network. Paired comparison also showed that schizophrenia patients had significantly lower energy gaps than healthy controls for the somatomotor and visual networks. Overall, this study provides preliminary evidence supporting transdiagnostic multi-attractor BNM approaches to better understand psychiatric disorders’ pathophysiology.
A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma
Authors: Shojaei Shahla , Basso João , Amereh Meitham , Alizadeh Javad , Dehesh Tania , De Silva Rosa Simone , Clark Courtney , Hassan Misha , Tomczyk Mateuz , Cole Laura , Hatch Grant , Dolinsky Vern , Pasco Chris , Schibli David , Dhingra Sanjiv , Srivastava Abhay , Ravandi Amir , Vitorino Rui , Ghavami Saeid , Akbari Mohsen
Published: November 2022

Chemoresistance is a major clinical challenge in the management of glioblastoma (GBM) Temozolomide (TMZ) is the chemotherapeutic drug of choice for GBM; however, the therapeutic effect of TMZ is limited due to the development of resistance. Recapitulating GBM chemoresistance in a controlled environment is thus essential in understanding the mechanism of chemoresistance. Herein, we present a hybrid microphysiological model of chemoresistant GBM-on-a-chip (HGoC) by directly co-culturing TMZ-resistant GBM spheroids with healthy neurons to mimic the microenvironment of both the tumor and the surrounding healthy tissue. We characterized the model with proteomics, lipidomics, and secretome assays. The results showed that our artificial model recapitulated the molecular signatures of recurrent GBM in humans. Both showed alterations in vesicular transport and cholesterol pathways, mitotic quiescence, and a switch in metabolism to oxidative phosphorylation associated with a transition from mesenchymal to amoeboid. This is the first report to unravel the interplay of all these molecular changes as a mechanism of chemoresistance in glioblastoma. Moreover, we have shown that the acquisition of resistance increases invasiveness and the presence of neurons decreases this property.
Whole-brain modeling of the differential influences of Amyloid-Beta and Tau in Alzheimer’s Disease
Authors: Patow Gustavo , Stefanovski Leon , Ritter Petra , Deco Gustavo , Kobeleva Xenia ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2022

Background

Alzheimer’s Disease is a neurodegenerative condition associated with the accumulation of two misfolded proteins, amyloid-beta (Aβ) and tau. We study their effect on neuronal activity, with the aim of assessing their individual and combined impact.

Methods

We use a whole-brain dynamic model to find the optimal parameters that best describe the effects of Aβand tau on the excitation-inhibition balance of the local nodes.

Results

We found a clear dominance of Aβover tau in the early disease stages (MCI), while tau dominates over Aβin the latest stages (AD). We identify crucial roles for Aβand tau in complex neuronal dynamics and demonstrate the viability of using regional distributions to define models of large-scale brain function in AD.

Conclusions

Our study provides further insight into the dynamics and complex interplay between these two proteins, opening the path for further investigations on biomarkers and candidate therapeutic targets in-silico.
Instantaneous visual genotyping and facile site-specific transgenesis via CRISPR-Cas9 and phiC31 integrase
Authors: Ma Junyan , Zhang Weiting , Sun Zhengwang , Parvez Saba , Peterson Randall T. , Yeh Jing-Ruey Joanna
Published: November 2022

The zebrafishDanio reriohas become a popular model in functional genomics and genetic disease studies. However, when a zebrafish mutant line must be propagated as heterozygotes due to homozygous lethality, using standard genotyping methods to identify a population of homozygous mutant embryos is time-consuming and sometimes impractical due to downstream applications such as large-scale chemical screens. Here, we introduce ‘TICIT’,TargetedIntegration byCRISPR-Cas9 andIntegraseTechnologies, which utilizes the site-specific DNA recombinase – phiC31 integrase – to insert fluorescent markers into CRISPR-Cas9-generated mutant alleles. It allows instantaneous determination of a zebrafish’s genotype simply by examining its color. This technique, which relies on first knocking in a 39-basepair phiC31 landing site via CRISPR-Cas9, enables researchers to insert large DNA fragments at the same genomic location repeatedly and with high precision and efficiency. We demonstrated that TICIT could also be used to create reporter fish driven by an endogenous promoter. Additionally, we created a landing site located in thetyrosinasegene that could support transgene expression in a broad spectrum of tissue and cell types, acting as a putative safe harbor locus. Hence, TICIT can yield predictable and reproducible transgene expression, facilitate diverse applications in zebrafish, and may be applicable to cells in culture and other model organisms.
Hearing elliptic movements reveals the imprint of action on prototypical geometries
Authors: Thoret Etienne , Aramaki Mitsuko , Bringoux Lionel , Ystad Sølvi , Kronland-Martinet Richard
Published: November 2022

Within certain categories of geometric shapes, prototypical exemplars that best characterize the category have been evidenced. These geometric prototypes are classically identified through the visual and haptic perception or motor production and are usually characterized by their spatial dimension. However, whether prototypes can be recalled through the auditory channel has not been formally investigated. Here we address this question by using auditory cues issued from timbre-modulated friction sounds evoking human drawing elliptic movements. Since non-spatial auditory cues were previously found useful for discriminating distinct geometric shapes such as circles or ellipses, it is hypothesized that sound dynamics alone can evoke shapes such as an exemplary ellipse. Four experiments were conducted and altogether revealed that a common elliptic prototype emerges from auditory, visual, and motor modalities. This finding supports the hypothesis of a common coding of geometric shapes according to biological rules with a prominent role of sensory-motor contingencies in the emergence of such prototypical geometry.