bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivomulti-site electrophysiology enabled by flexible optrodes towards bi-directional spinal cord interrogation
Authors: Metuh Pietro , Meneghetti Marcello , Berg Rune W. , Markos Christos
Published: September 2023

Optical neural interfaces combining optogenetics and electrophysiology have been demonstrated as powerful tools for distinguishing the causal roles of neural circuits in the nervous system. Functional optrodes for multipoint stimulation and recording have already been demonstrated in the brain. However, soft and flexible multimodal optrodes for the purpose of probing the spinal cord have remained undeveloped. Here, we present the design and fabrication of a novel optrode for multi-site optical stimulation and electrical recording in the spinal cord by combining optical fiber drawing of polymer material, laser micromachining, and integration of tungsten microelectrodes in a monolithic fiber-based structure. The results from space-resolved scattering measurements, electrochemical impedance spectroscopy, and an acutein vivoelectrophysiology experiment in an anesthetized rodent suggest this probe as a potential novel interface, which can serve as a part of therapeutic strategies against neurological conditions and injury in the spinal cord.
Grain Utilization by the Gut Microbiome as a Human Health Phenotype to Identify Multiple Effect Loci in Genome-Wide Association Studies ofSorghum bicolor
Authors: Korth Nate , Yang Qinnan , Van Haute Mallory J. , Tross Michael C. , Peng Bo , Shrestha Nikee , Zwiener Mackenzie , Mural Ravi V. , Schnable James C. , Benson Andrew K.
Published: September 2023

A growing epidemic of complex lifestyle diseases such as obesity and metabolic diseases are explained in part by dysbiosis of the human gut microbiome. The gut microbiome, comprising trillions of microorganisms, contributes to functions ranging from digestion to the immune system. Diet plays a critical role in determining the species composition and functionality of the gut microbiome. Substantial functional metabolic diversity exists within the cultivated grain crops which directly or indirectly provide more than half of all calories consumed by humans around the globe, however much of this diversity is poorly characterized and the effects of such diversity on the human gut microbiome is not well studied. We employed a quantitative genetics approach to identify genetic variants in sorghum that alter the composition and function of human gut microbes. Using an automated high-throughput phenotyping method based onin vitromicrobiome fermentation of grain from a diverse population ofSorghum bicolorcultivars, we demonstrate sorghum genetics can explain effects of grain variation on fermentation patterns of bacterial taxa across multiple human microbiomes. In a genome-wide analysis using a sorghum association panel, we identified fifteen multiple-effect loci (MEL) where different alleles in the sorghum genome produced changes in seed that affect the abundance of multiple bacterial taxa across two human microbiomes in automated in vitro fermentations. In a number of cases parallel genome-wide association studies conducted for biochemical and agronomic traits identified seed traits potentially causal for the link between sorghum genetics and human microbiome outcomes. This work demonstrates that genetic factors affecting sorghum seed can drive significant effects on human gut microbes, particularly bacterial taxa considered beneficial. Understanding these relationships will enable targeted crop breeding strategies to improve human health through gut microbiome modulation.
Accurate somatic variant calling performance using Avidity Sequencing with Burning Rock’s OncoScreenTMPlus panel
Authors: Zhang Guangliang , Liu Yangyang , Luo Yilun , Han Yusheng , Zhang Zhihong
Published: September 2023

Background

Next-generation sequencing (NGS) comprehensive genomic profiling panels provide targeted genome-wide detection of the somatic variant landscape of various cancer types. Recently, an innovative sequencing technology, Avidity Sequencing from Element Biosciences, has emerged to provide economical option for mid-throughput sequencing, with high quality (Q40).

Aims

The aim of this study was to evaluate the performance characteristics of AVITI sequencing by avidity on detection of somatic variants from reference samples, and to compare the variant detection concordance between AVITI and NovaSeq sequencing platforms by evaluating the variant callings of 518 cancer-related genes using Burning Rock’s OncoScreenTMPlus panel.

Methods

Contrived commercial reference control samples (harboring known variants) and clinical Formalin-Fixed Paraffin-Embedded tissue (FFPE) samples were examined to evaluate the variant detection performance of two sequencing platforms, with respects to Single Nucleotide Variant (SNV), Insertion-Deletion (Indel), Structure Variant (SV/Fusion), Copy Number Variation (CNV), Microsatellite Instability (MSI), and Tumor Mutation Burden (TMB). Variant specific QC metrics were developed to evaluate sequencing-level and variant calling level accuracy. All samples were processed utilizing the OncoScreenTMPlus assay, including library preparation and bioinformatics post sequencing data analysis.

Results

The OncoScreenTMPlus assay is compatible with the AVITI system. Samples prepared with the OncoScreenTMPlus panel and sequenced on the AVITI system has successfully detected cancer related variants including SNV/Indels, SV/Fusion, CNVs, MSIs, and TMB, which were highly concordant with reference controls. In addition, the AVITI system produced a higher overall quality score, index assignment rate, mean target coverage, and lower optical duplication rate AVITI than NovaSeq system.

Conclusion

The new sequencing technology Avidity from AVITI system can be applied seamlessly to current high-performance targeted oncology assays to reliably identify somatic variants in a flexible and cost-effective manner.
Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in rodent and swine photoreceptors
Authors: Cheng Shun-Yun , Caiazzi Jillian , Biscans Annabelle , Alterman Julia F. , Echeverria Dimas , McHugh Nicholas , Hassler Matthew , Jolly Samson , Giguere Delaney , Cipi Joris , Khvorova Anastasia , Punzo Claudio
Published: September 2023

Inherited retinal dystrophies caused by dominant mutations in photoreceptor-expressed genes, are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery. Thus, an unmet need exists to identify siRNA chemistry that targets photoreceptor-expressed genes. Here we evaluated 12 different fully chemically modified siRNA configurations, where the valency and conjugate structure were systematically altered. The impact on retinal distribution following intravitreal delivery was examined. We found that the increase in valency (tetravalent siRNA) supports the best photoreceptor accumulation. A single intravitreal administration induces multi-months efficacy in rodent and porcine retinas while showing a good safety profile. The data suggest that this configuration can treat retinal diseases caused by photoreceptor-expressed genes with 1-2 intravitreal injections per year.
GammaGateR: semi-automated marker gating for single-cell multiplexed imaging
Authors: Xiong Jiangmei , Kaur Harsimran , Heiser Cody N , McKinley Eliot T , Roland Joseph T , Coffey Robert J , Shrubsole Martha J , Wrobel Julia , Ma Siyuan , Lau Ken S , Vandekar Simon
Published: September 2023

Motivation

Multiplexed immunofluorescence (mIF) is an emerging assay for multichannel protein imaging that can decipher cell-level spatial features in tissues. However, existing automated cell phenotyping methods, such as clustering, face challenges in achieving consistency across experiments and often require subjective evaluation. As a result, mIF analyses often revert to marker gating based on manual thresholding of raw imaging data.

Results

To address the need for an evaluable semi-automated algorithm, we developed GammaGateR, an R package for interactive marker gating designed specifically for segmented cell-level data from mIF images. Based on a novel closed-form gamma mixture model, GammaGateR provides estimates of marker-positive cell proportions and soft clustering of marker-positive cells. The model incorporates user-specified constraints that provide a consistent but slide-specific model fit. We compared GammaGateR against the newest unsupervised approach for annotating mIF data, employing two colon datasets and one ovarian cancer dataset for the evaluation. We showed that GammaGateR produces highly similar results to a silver standard established through manual annotation. Furthermore, we demonstrated its effectiveness in identifying biological signals, achieved by mapping known spatial interactions between CD68 and MUC5AC cells in the colon and by accurately predicting survival in ovarian cancer patients using the phenotype probabilities as input for machine learning methods. GammaGateR is a highly efficient tool that can improve the replicability of marker gating results, while reducing the time of manual segmentation.

Availability and Implementation

The R package is available athttps://github.com/JiangmeiRubyXiong/GammaGateR.

Contact

Please address correspondence tojiangmei.xiong@vanderbilt.eduandsimon.vandekar@vumc.org.

Key Points

GammaGateR is the first semi-automated marker gating tool for mIF image, and it will help to diminish the inconsistency with manual marker gating.

With novel cfGMM, GammaGateR can fit flexibly across slides with different distributions and incorporate biology priors.

GammaGateR is proven to reveal credible prognostic information, and it can quantify known findings in tumor cell populations.
Combination of memantine and alpha7 nicotinic acetylcholine receptor ligands exerts superior efficacy over monotreatments to improve cognitive performance of aged rats
Authors: Bruszt Nóra , Bali Zsolt Kristóf , Nagy Lili Veronika , Bodó Kornélia , Engelmann Péter , Ledneczki István , Némethy Zsolt , Lendvai Balázs , Hernádi István
Published: September 2023

Combination treatments based on pharmacological interactions at α7 nAChRs are promising therapeutic approaches for neurocognitive disorders (NCDs). Memantine, an already approved medication in some NCDs, may not only act as an antagonist of the glutamatergic NMDA receptors (NMDAR) but also serve as an antagonist of the cholinergic α7 nAChRs. Here we set out to utilize a combination treatment regime with an α7 nAChR-selective agonist (PHA-543613) and a novel proprietary α7 nAChR ligand with marked positive allosteric modulator (PAM) activity (CompoundX). The cognitive efficacy of combination treatments was tested in a naturally aged rat model. Naturally aged rats showed marked cognitive decline in the novel object recognition (NOR) test, and they displayed pathological changes at the molecular level in terms of various inflammatory markers. In addition, aged rats also exhibited cholinergic changes such as mRNA upregulation of α7 nAChRs. Memantine-PHA-543613 and memantine-CompoundX combination treatments successfully alleviated the age-related decline of recognition memory of rats by exceeding the null-effects of the corresponding subtherapeutic levels of monotreatments. Results indicate a positive interaction between memantine and α7-nAChR agonists and PAMs, which reflects a prominent role of α7 nAChRs in the cognitive enhancement of combination treatments especially in age-related cognitive decline. Moreover, the putative direct action of memantine on α7 nAChRs may also contribute to the observed synergistic interaction between memantine and other selective α7 nAChR compounds.
Patterns and drivers of pollen co-transport networks vary across pollinator groups
Authors: Carneiro Liedson Tavares , Williams Jessica Nicole , Barker Daniel A , Anderson Joseph W , Martel Carlos , Arceo-Gomez Gerardo
Published: September 2023

Pollen transport is an understudied process with consequences for plant reproductive success and floral evolution. Recently, pollinator bodies have been described as pollen competition arenas, with implications for plant community assembly. However, the identity, strength, and diversity of pollen competitive interactions and how they vary across pollinator groups is unknown. Evaluating patterns and drivers of the pollen competition landscape across different pollinator groups is central to further our understanding of plant coexistence mechanisms. Here, we integrate information on insect pollen loads with network analyses to uncover novel pollen co-transport networks and how these vary across pollinators. We evaluate differences in pollen load size, diversity and their phenological and phylogenetic attributes among insect groups and how these relate to body size and sex. Pollen co-transport networks revealed differences in the number and identity of competitors that pollen species encounter across pollinator groups. These networks were highly modular, with groups of pollen species interacting more often on pollinator bodies. Pollen load size and richness were shaped by bee size and sex. Sex also influenced the pollen phylogenetical diversity. Pollinators can impose vastly different competitive landscapes during pollen transport, with so far unknown consequences for plant reproductive success, floral evolution and community assembly.
Preconfigured cortico-thalamic neural dynamics constrain movement-associated thalamic activity
Authors: González-Pereyra Perla , Martínez-Montalvo Mario G. , Ortega-Romero Diana I. , Pérez-Díaz Claudia I. , Merchant Hugo , Tellez Luis A. , Rueda-Orozco Pavel E.
Published: September 2023

Neural preconfigured activity patterns (nPAPs) have been proposed as building blocks for cognitive and sensory processing. However, their existence and function in motor networks have not been explicitly studied. Here, we explore the possibility that nPAPs are present in the motor thalamus (VL/VM) and their potential contribution to motor-related activity. To this end, we developed a preparation where VL/VM multiunitary activity could be robustly recorded in mouse behavior evoked by primary motor cortex (M1) optogenetic stimulation and forelimb movements. VL/VM-evoked activity was organized as rigid stereotypical activity patterns at the single and population levels. These activity patterns were unable to dynamically adapt to different temporal architectures of M1 stimulation. Moreover, they were experience-independent and present in virtually all animals, confirming their preconfigured nature. Finally, subpopulations expressing specific M1-evoked patterns also displayed specific movement-related patterns. Our data demonstrate that the behaviorally related identity of specific neural subpopulations is tightly linked to nPAPs.
Individual Differences Elucidate the Perceptual Benefits Associated with Robust Temporal Fine-Structure Processing
Authors: Borjigin Agudemu , Bharadwaj Hari M.
Published: September 2023

The auditory system is unique among sensory systems in its ability to phase lock to and precisely follow very fast cycle-by-cycle fluctuations in the phase of sound-driven cochlear vibrations. Yet, the perceptual role of this temporal fine structure (TFS) code is debated. This fundamental gap is attributable to our inability to experimentally manipulate TFS cues without altering other perceptually relevant cues. Here, we circumnavigated this limitation by leveraging individual differences across 200 participants to systematically compare variations in TFS sensitivity to performance in a range of speech perception tasks. TFS sensitivity was assessed through detection of interaural time/phase differences, while speech perception was evaluated by word identification under noise interference. Results suggest that greater TFS sensitivity is not associated with greater masking release from fundamental-frequency or spatial cues, but appears to contribute to resilience against the effects of reverberation. We also found that greater TFS sensitivity is associated with faster response times, indicating reduced listening effort. These findings highlight the perceptual significance of TFS coding for everyday hearing.

Significance Statement

Neural phase-locking to fast temporal fluctuations in sounds–temporal fine structure (TFS) in particular– is a unique mechanism by which acoustic information is encoded by the auditory system. However, despite decades of intensive research, the perceptual relevance of this metabolically expensive mechanism, especially in challenging listening settings, is debated. Here, we leveraged an individual-difference approach to circumnavigate the limitations plaguing conventional approaches and found that robust TFS sensitivity is associated with greater resilience against the effects of reverberation and is associated with reduced listening effort for speech understanding in noise.
Molecular Photoswitches Regulating the Activity of the Human Serotonin Transporter
Authors: Singer Nadja K. , González Leticia , Monari Antonio
Published: September 2023

Serotonin is an essential mediator regulating diverse neural processes, and its deregulation is related to debilitating neurological diseases. In particular, the human serotonin transporter (hSERT) is fundamental in completing the synaptic neural cycle by allowing the reuptake of serotonin. Its inhibition is particularly attractive, especially as a pharmacological target against depressive syndrome. Here, we analyze, by using long-range molecular dynamic simulations, the behavior of a molecular photoswitch whosecis- andtrans-isomers inhibit the hSERT differently. In particular, we evidence the structural and molecular basis behind the higher inhibiting capacity of thecis-isomer, which blocks more efficiently the hSERT conformational cycle leading to serotonin uptake.

TOC Graphic
Deactivation of ligand-receptor interactions enhancing lymphocyte infiltration drives melanoma resistance to Immune Checkpoint Blockade
Authors: Sahni Sahil , Wang Binbin , Wu Di , Dhruba Saugato Rahman , Nagy Matthew , Patkar Sushant , Ferreira Ingrid , Wang Kun , Ruppin Eytan
Published: September 2023

Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance often develops. To learn more about ICB resistance mechanisms, we developed IRIS (ImmunotherapyResistance cell-cellInteractionScanner), a machine learning model aimed at identifying candidate ligand-receptor interactions (LRI) that are likely to mediate ICB resistance in the tumor microenvironment (TME). We developed and applied IRIS to identify resistance-mediating cell-type-specific ligand-receptor interactions by analyzing deconvolved transcriptomics data of the five largest melanoma ICB therapy cohorts. This analysis identifies a set of specific ligand-receptor pairs that are deactivated as tumors develop resistance, which we refer to asresistance deactivated interactions (RDI).Quite strikingly, the activity of these RDIs in pre-treatment samples offers a markedly stronger predictive signal for ICB therapy response compared to those that are activated as tumors develop resistance. Their predictive accuracy surpasses the state-of-the-art published transcriptomics biomarker signatures across an array of melanoma ICB datasets. Many of these RDIs are involved in chemokine signaling. Indeed, we further validate on an independent large melanoma patient cohort that their activity is associated with CD8+ T cell infiltration and enriched in hot/brisk tumors. Taken together, this study presents a new strongly predictive ICB response biomarker signature, showing that following ICB treatment resistant tumors turn inhibit lymphocyte infiltration by deactivating specific key ligand-receptor interactions.
Increased LPS-Induced Fever and Sickness Behavior in Adult Male and Female Rats Perinatally Exposed to Morphine
Authors: Harder Hannah J. , Gomez Morgan G. , Searles Christopher T. , Vogt Meghan E. , Murphy Anne Z.
Published: September 2023

As a result of the current opioid crisis, the rate of children born exposed to opioids has skyrocketed. Later in life, these children have an increased risk for hospitalization and infection, raising concerns about potential immunocompromise, as is common with chronic opioid use. Opioids can act directly on immune cells or indirectly via the central nervous system to decrease immune system activity, leading to increased susceptibility, morbidity, and mortality to infection. However, it is currently unknown how perinatal opioid exposure (POE) alters immune function. Using a clinically relevant and translatable model of POE, we have investigated how baseline immune function and the reaction to an immune stimulator, lipopolysaccharide, is influenced byin uteroopioid exposure in adult male and female rats. We report here that POE potentiates the febrile and neuroinflammatory response to lipopolysaccharide, likely as a consequence of suppressed immune function at baseline (including reduced antibody production). This suggests that POE increases susceptibility to infection by manipulating immune system development, consistent with the clinical literature. Investigation of the mechanisms whereby POE increases susceptibility to pathogens is critical for the development of potential interventions for immunosuppressed children exposed to opioidsin utero.

Highlights

Perinatal exposure to morphine leads to increased fever and sickness post-LPS

Perinatal exposure to morphine alters peripheral immunity

Perinatal exposure to morphine increases microglial activation
Transgenic tools targeting striatal and pallidal subpopulations revealed evolutionary conservation and specialization of the cortico-basal ganglia circuit in zebrafish
Authors: Tanimoto Yuki , Kakinuma Hisaya , Aoki Ryo , Shiraki Toshiyuki , Higashijima Shin-ichi , Okamoto Hitoshi
Published: September 2023

The cortico-basal ganglia circuit mediates decision-making. Here, we generated transgenic tools for adult zebrafish targeting specific subpopulations of the components of this circuit and utilized them to identify evolutionary homologs of the mammalian direct- and indirect-pathway striatal neurons which respectively project to the homologs of the internal and external segment of the globus pallidus (dEN and Vl) as in mammals. Unlike in mammals, the Vl mainly projected to the dEN directly, not by way of the subthalamic nucleus. Further single-cell RNA sequencing analysis revealed two pallidal output pathways: a major shortcut pathway directly connecting the dEN with the pallium and the evolutionarily conserved closed loop by way of the thalamus. Our resources and circuit map provide the common basis for the functional study of the basal ganglia in a small and optically tractable zebrafish brain for the comprehensive mechanistic understanding of the cortico-basal ganglia circuit.
NuFold: A Novel Tertiary RNA Structure Prediction Method Using Deep Learning with Flexible Nucleobase Center Representation
Authors: Kagaya Yuki , Zhang Zicong , Ibtehaz Nabil , Wang Xiao , Nakamura Tsukasa , Huang David , Kihara Daisuke
Published: September 2023

RNA is not only playing a core role in the central dogma as mRNA between DNA and protein, but also many non-coding RNAs have been discovered to have unique and diverse biological functions. As genome sequences become increasingly available and our knowledge of RNA sequences grows, the study of RNA’s structure and function has become more demanding. However, experimental determination of three-dimensional RNA structures is both costly and time-consuming, resulting in a substantial disparity between RNA sequence data and structural insights. In response to this challenge, we propose a novel computational approach that harnesses state-of-the-art deep learning architecture NuFold to accurately predict RNA tertiary structures. This approach aims to offer a cost-effective and efficient means of bridging the gap between RNA sequence information and structural comprehension. NuFold implements a nucleobase center representation, which allows it to reproduce all possible nucleotide conformations accurately.
MLDAAPP: Machine Learning Data Acquisition for Assessing Population Phenotypes
Authors: Gabidulin Amir R. , Rudman Seth M.
Published: September 2023

Collecting phenotypic data from many individuals is critical to numerous biological disciplines. Yet, organismal phenotypic or trait data are still often collected manually, limiting the scale of data collection, precluding reproducible workflows, and creating the potential for human bias. Computer vision could largely ameliorate these issues, but currently available packages only operate with specific inputs and hence are not scalable or accessible for many biologists. We present Machine Learning Data Acquisition for Assessing Population Phenotypes (MLDAAPP), a package of tools for collecting phenotypic data from groups of individuals. We demonstrate that MLDAAPP is both accurate and uniquely effective at measuring phenotypes in challenging conditions - particularly images and videos of varying quality derived from both lab and field environments. Employing MLDAAPP solves key issues of reproducibility, increases both the scale and scope of data generation, and reduces the potential for human bias.
Division of labor among H3K4 Methyltransferases Defines Distinct Facets of Homeostatic Plasticity
Authors: Tsukahara Takao , Kethireddy Saini , Bonefas Katherine , Chen Alex , Sutton Brendan LM , Dou Yali , Iwase Shigeki , Sutton Michael A.
Published: September 2023

Heterozygous mutations in any of the six H3K4 methyltransferases (KMT2s) result in monogenic neurodevelopmental disorders, indicating nonredundant yet poorly understood roles of this enzyme family in neurodevelopment. Recent evidence suggests that histone methyltransferase activity may not be central to KMT2 functions; however, the enzymatic activity is evolutionarily conserved, implicating the presence of selective pressure to maintain the catalytic activity. Here, we show that H3K4 methylation is dynamically regulated during prolonged alteration of neuronal activity. The perturbation of H3K4me by the H3.3K4M mutant blocks synaptic scaling, a form of homeostatic plasticity that buffers the impact of prolonged reductions or increases in network activity. Unexpectedly, we found that the six individual enzymes are all necessary for synaptic scaling and that the roles of KMT2 enzymes segregate into evolutionary-defined subfamilies: KMT2A and KMT2B (fly-Trx homologs) for synaptic downscaling, KMT2C and KMT2D (Trr homologs) for upscaling, and KMT2F and KMT2G (dSet homologs) for both directions. Selective blocking of KMT2A enzymatic activity by a small molecule and targeted disruption of the enzymatic domain both blocked the synaptic downscaling and interfered with the activity-dependent transcriptional program. Furthermore, our study revealed specific phases of synaptic downscaling, i.e., induction and maintenance, in which KMT2A and KMT2B play distinct roles. These results suggest that mammalian brains have co-opted intricate H3K4me installation to achieve stability of the expanding neuronal circuits.
Contraceptive congruence: acknowledging pregnancy ambivalence in a novel measure of contraceptive use
Authors: Nelson Hallie N. , Lehman Erik , Horvath Sarah , Chuang Cynthia H.
Published: September 2023

Background

The historical view that pregnancy intention is dichotomous (i.e., intending or not intending pregnancy), and the notion that all individuals not intending pregnancy should be using highly effective contraceptive methods, oversimplifies how we view contraceptive decision-making. To better understand this, we studied contraceptive congruence as an alternative, 3-level measure describing methods as very congruent, somewhat congruent, or incongruent with one’s individual attitudes about becoming pregnant.

Methods

Secondary data analysis included 982 MyNewOptions study participants who were not intending pregnancy within the next year. The cross-sectional survey assessed attitudes about how important it is to avoid pregnancy, how pleased/upset one would be if pregnant, and current contraceptive method use. Participant answers to attitudinal questions and effectiveness of current contraceptive method were used to determine congruence categories.

Results

Contraceptive methods included LARC (8%), other prescription methods (50%), non-prescription methods (30%), and no method (12%). Methods for 23% of participants were very congruent, 48% somewhat congruent, and 29% incongruent with attitudes about becoming pregnant. Contraceptive congruence was significantly associated with contraceptive satisfaction in bivariate analysis. Predictors of contraceptive congruence included being married or living with partner, full-time employment, and intending future pregnancy in the next 1-5 years.

Conclusion

Contraceptive congruence is a novel measure that acknowledges pregnancy ambivalence and is associated with higher contraceptive satisfaction scores. Future contraception research should strive for robust, patient-centered measures of contraceptive use that acknowledge the complex attitudes affecting individual contraceptive behavior and satisfaction.
A Wearable Fiber-Free Optical Sensor for Continuous Monitoring of Neonatal Cerebral Blood Flow and Oxygenation
Authors: Liu Xuhui , Mohtasebi Mehrana , Safavi Pegah , Fathi Faraneh , Haratbar Samaneh Rabienia , Chen Li , Chen Jin , Bada Henrietta S. , Chen Lei , Abu Jawdeh Elie G. , Yu Guoqiang
Published: September 2023

Impact

The innovative DSCFO technology may serve as a low-cost wearable sensor for continuous bedside monitoring of multiple cerebral hemodynamic parameters in neonatal intensive care units.

Concurrent DSCFO and DCS measurements of CBF variations in neonatal piglet models generated consistent results.

No consistent correlation patterns were observed among peripheral and cerebral monitoring parameters in preterm neonates, suggesting the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations during IH events.

Integrating and correlating multiple cerebral functional parameters with clinical outcomes may identify biomarkers for prediction and management of IH associated brain injury.

Background

Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants.

Methods

DSCFO uses two small laser diodes as focused-point and a tiny CMOS camera as a high-density two-dimensional detector to detect spontaneous spatial fluctuation of diffuse laser speckles for CBF measurement, and light intensity attenuations for cerebral oxygenation measurement. The DSCFO was first validated against the established diffuse correlation spectroscopy (DCS) in neonatal piglets and then utilized for continuous CBF and oxygenation monitoring in preterm infants during intermittent hypoxemia (IH) events.

Results

Consistent results between the DSCFO and DCS measurements of CBF variations in neonatal piglets were observed. IH events induced fluctuations in CBF, cerebral oxygenation, and peripheral cardiorespiratory vitals in preterm infants. However, no consistent correlation patterns were observed among peripheral and cerebral monitoring parameters.

Conclusions

This pilot study demonstrated the feasibility of DSCFO technology to serve as a low-cost wearable sensor for continuous monitoring of multiple cerebral hemodynamic parameters. The results suggested the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations.
Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis
Authors: Liao Zian , Tang Suni , Jiang Peixin , Geng Ting , Cope Dominique I. , Dunn Timothy N. , Guner Joie , Alpuing Radilla Linda , Guan Xiaoming , Monsivais Diana
Published: September 2023

It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in individuals with endometriosis. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from individuals with or without endometriosis to time coursein vitrodecidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified differences in key pathways between the two groups, including defective bone morphogenetic protein (BMP)/SMAD4 signaling (ID2, ID3, FST), oxidate stress response (NFE2L2, ALOX15, SLC40A1), and retinoic acid signaling pathways (RARRES, RARB, ALDH1B1). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 and H3K27Ac in the decidualized stromal cells from individuals without endometriosis relative to those with endometriosis, with target genes enriched in pathways related to signaling by transforming growth factor β (TGFβ), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation in endometriosis patient-derived assembloids elevated the expression of decidualization markers. In summary, transcriptomic and genome-wide binding analyses of patient-derived endometrial cells and assembloids identified that a functional BMP/SMAD1/5/4 signaling program is crucial for engaging decidualization.
Germline-targeting chimpanzee SIV Envelopes induce V2-apex broadly neutralizing-like B cell precursors in a rhesus macaque infection model
Authors: Musharrafieh Rami , Safonova Yana , Song Ge , Roark Ryan S. , Lee Fang-Hua , Zhang Shiyu , Hurtado Jonathan , Yong Peter , Wang Shuyi , Russell Ronnie M. , Ding Wenge , Li Yingying , Rando Juliette , Murphy Alexander I. , Lindemuth Emily , Zhao Chengyan , Connell Andrew Jesse , Lee Wen-Hsin , Mishra Nitesh , Avillion Gabriel , He Wanting , Callaghan Sean , Dueker Katharina , Vo Anh L. , Li Xuduo , Capozzola Tazio , Joyce Collin , Zhao Fangzhu , Anzanello Fabio , Liu Weimin , Bibollet-Ruche Frederic , Ramos Alejandra , Li Hui , Lewis Mark G. , Ozorowski Gabriel , Landais Elise , Foley Brian T. , Wagh Kshitij , Sok Devin , Briney Bryan , Ward Andrew B. , Hahn Beatrice H. , Burton Dennis R. , Shaw George M. , Andrabi Raiees
Published: September 2023

Eliciting broadly neutralizing antibodies-(bnAbs) remains a major goal of HIV-1 vaccine research. Previously, we showed that a soluble chimpanzee SIV Envelope-(Env) trimer, MT145K, bound several human V2-apex bnAb-precursors and stimulated an appropriate response in V2-apex bnAb precursor-expressing knock-in mice. Here, we tested the immunogenicity of three MT145 variants (MT145, MT145K, MT145K.dV5) expressed as chimeric simian-chimpanzee-immunodeficiency-viruses-(SCIVs) in rhesus macaques-(RMs). All three viruses established productive infections with high setpoint vRNA titers. RMs infected with the germline-targeting SCIV_MT145K and SCIV_MT145K.dV5 exhibited larger and more clonally expanded B cell lineages featuring long anionic heavy chain complementary-determining-regions-(HCDR3s) compared with wildtype SCIV_MT145. Moreover, antigen-specific B cell analysis revealed enrichment for long-CDHR3-bearing antibodies in SCIV_MT145K.dV5 infected animals with paratope features resembling prototypic V2-apex bnAbs and their precursors. Although none of the animals developed bnAbs, these results show that germline-targeting SCIVs can activate and preferentially expand B cells expressing V2-apex bnAb-like precursors, the first step in bnAb elicitation.

Graphical Abstract
The effect of common paralytic agents used for fluorescence imaging on redox tone and ATP levels inCaenorhabditis elegans
Authors: Morton Katherine S , Wahl Ashlyn K , Meyer Joel N
Published: September 2023

One aspect ofCaenorhabditis elegansthat makes it a highly valuable model organism is the ease of use ofin vivogenetic reporters, facilitated by its transparent cuticle and highly tractable genetics. Despite the rapid advancement of these technologies, worms must be paralyzed for most imaging applications, and few investigations have characterized the impacts of common chemical anesthetic methods on the parameters measured, in particular biochemical measurements such as cellular energetics and redox tone. Using two dynamic reporters, QUEEN-2m for relative ATP levels and reduction-oxidation sensitive GFP (roGFP) for redox tone, we assess the impact of commonly used chemical paralytics. We report that no chemical anesthetic is entirely effective at doses required for full paralysis without altering redox tone or ATP levels, though 100 mM 2,3-Butadione monoxime appears to be the least problematic. We also assess the use of cold shock, commonly used in combination with physical restraint methods, and find that cold shock does not alter either ATP levels or redox tone. In addition to informing which paralytics are most appropriate for research in these topics, we highlight the need for tailoring the use of anesthetics to different endpoints and experimental questions. Further, we reinforce the need for developing less disruptive paralytic methods for optimal imaging of dynamicin vivoreporters.
The influence of birthweight, socioeconomic status, and adult health on brain volumes during aging
Authors: McNeil Christopher J , Habota Tina , Sandu Anca-Larisa , Waiter Gordon , Whalley Heather , Murray Alison D.
Published: September 2023

Preserved late-life brain volume is associated with resilience to dementia. We examined relationships between birthweight, socioeconomic status and adult health with late-life brain volumes. We hypothesised that early-life factors have direct and indirect effects on the aging brain. Neurotypical adults aged 61-67y underwent MRI and brain volumes measured. Birthweight, health and socioeconomic status were assessed by historical data or contemporary assessment. Measures of health and socioeconomic status were extracted using principal component analysis. Relationships between variables were explored by linear regression and structural equation models. Birthweight (β=0.095, p=0.017, n=280) and childhood socioeconomic status (β=0.091, p=0.033, n=280) were directly associated with late-life brain volume. Childhood socioeconomic status was associated with additional increase in grey matter volume (β=0.04, p=0.047, n=280). Better adult health was linked to increased late-life brain volume (β=0.15, p=0.003, n=280). Birthweight and childhood socioeconomic status are associated with whole and regional brain volume through direct and indirect mechanisms. Optimal fetal development, good adult health and reduced poverty, may prevent brain atrophy and decrease dementia risk in late-life.
Gcm alleviates the inflammatory phenotype induced by Toll activation inDrosophilahemocytes
Authors: Bazzi Wael , Monticelli Sara , Delaporte Claude , Riet Céline , Giangrande Angela , Cattenoz Pierre B.
Published: September 2023

Hemocytes, the myeloid-like immune cells ofDrosophila, fulfil a variety of functions that are not completely understood, ranging from phagocytosis to transduction of inflammatory signals. We here show that downregulating the hemocyte-specific Glide/Gcm transcription factor enhances the inflammatory response to the constitutive activation of the Toll pathway. This correlates with lower levels of glutathione S transferase, suggesting an implication of Glide/Gcm in ROS signaling and calling for a widespread anti-inflammatory potential of Glide/Gcm. We show the expression of neurotransmitter receptors in hemocytes and that Toll activation affects their expressions, disclosing a novel aspect of the inflammatory response mediated by neurotransmitters. Finally, we provide evidence for acetylcholine receptor nAchRalpha6 regulating hemocyte proliferation. Altogether, this study provides new insights on the molecular pathways involved in the inflammatory response.
Intestinal microbiota programming of alveolar macrophages influences severity of respiratory viral infection
Authors: Ngo Vu L. , Lieber Carolin M. , Kang Hae-ji , Sakamoto Kaori , Kuczma Michal , Plemper Richard K. , Gewirtz Andrew T.
Published: September 2023

Susceptibility to respiratory virus infections (RVIs) varies widely across individuals. Because the gut microbiome impacts immune function, we investigated the influence of intestinal microbiota composition on RVI and determined that segmented filamentous bacteria (SFB), naturally acquired or exogenously administered, protected mice against influenza virus (IAV) infection. Such protection, which also applied to respiratory syncytial virus and SARS-CoV-2, was independent of interferon and adaptive immunity but required basally resident alveolar macrophages (AM). In SFB-negative mice, AM were quickly depleted as RVI progressed. In contrast, AM from SFB-colonized mice were intrinsically altered to resist IAV-induced depletion and inflammatory signaling. Yet, AM from SFB-colonized mice were not quiescent. Rather, they directly disabled IAV via enhanced complement production and phagocytosis. Accordingly, transfer of SFB-transformed AM into SFB-free hosts recapitulated SFB-mediated protection against IAV. These findings uncover complex interactions that mechanistically link the intestinal microbiota with AM functionality and RVI severity.

One sentence summary

Intestinal segmented filamentous bacteria reprogram alveolar macrophages promoting nonphlogistic defense against respiratory viruses.
Phenotypic divergence and genomic architecture between parallel ecotypes at two different points on the speciation continuum in a marine snail
Authors: Raffini Francesca , De Jode Aurélien , Johannesson Kerstin , Faria Rui , Zagrodzka Zuzanna B. , Westram Anja M. , Galindo Juan , Rolán-Alvarez Emilio , Butlin Roger K.
Published: September 2023

Speciation typically occurs over too long a time frame to be observed directly. A way forward is to compare pairs of ecotypes that evolved in parallel in similar contexts but have reached different degrees of reproductive isolation. Such comparisons are possible in the marine snailLittorina saxatilisby contrasting barriers to gene flow between parallel ecotypes in Spain and Sweden. In both countries, divergent ecotypes have evolved to withstand either crab predation or wave action. Here, we explore transects spanning contact zones between the Crab and the Wave ecotypes using low-coverage whole-genome sequencing, morphological and behavioural traits. Despite parallel phenotypic divergence, distinct patterns of differentiation between the ecotypes emerged: a continuous cline in Sweden indicating a weak barrier to gene flow, but two highly genetically and phenotypically divergent, and partly spatially-overlapping clusters in Spain suggesting a much stronger barrier to gene flow. Absence of Spanish early-generation hybrids supported strong isolation, but a low level of gene flow is evident from molecular data. In both countries, highly differentiated loci were located in both shared and private chromosomal inversions but were also present in collinear regions. Despite being considered the same species and showing similar levels of phenotypic divergence, the Spanish ecotypes are much closer to full reproductive isolation than the Swedish ones. Barriers to gene flow of very different strengths between ecotypes within the same species might be explained by dissimilarities in the spatial arrangement of habitats, the selection gradients or the ages of the systems.

Abstract Figure

Graphical abstract.

Distinct patterns of divergence between parallel ecotypes in Sweden and Spain.
Placebo treatment affects brain systems related to affective and cognitive processes, but not nociceptive pain
Authors: Botvinik-Nezer Rotem , Petre Bogdan , Ceko Marta , Lindquist Martin A. , Friedman Naomi P. , Wager Tor D.
Published: September 2023

Placebo analgesia is a replicable and well-studied phenomenon, yet it remains unclear to what degree it includes modulation of nociceptive processes. Some studies find effects consistent with nociceptive effects, but meta-analyses show that these effects are often small. We analyzed placebo analgesia in a large fMRI study (N = 392), including placebo effects on brain responses to noxious stimuli. Placebo treatment caused robust analgesia in both conditioned thermal and unconditioned mechanical pain. Placebo did not decrease fMRI activity in nociceptive pain regions, including the Neurologic Pain Signature (NPS) and pre-registered spinothalamic pathway regions, with strong support from Bayes Factor analyses. However, placebo treatment affected activity in pre-registered analyses of a second neuromarker, the Stimulus Intensity Independent Pain Signature (SIIPS), and several associated a priori brain regions related to motivation and value, in both thermal and mechanical pain. Individual differences in behavioral analgesia were correlated with neural changes in both thermal and mechanical pain. Our results indicate that processes related to affective and cognitive aspects of pain primarily drive placebo analgesia.
Periodic and aperiodic changes to cortical EEG in response to pharmacological manipulation
Authors: Salvatore Sofia V. , Lambert Peter M. , Benz Ann , Rensing Nicholas R. , Wong Michael , Zorumski Charles F. , Mennerick Steven
Published: September 2023

Cortical electroencephalograms (EEG) may help understanding of neuropsychiatric illness and new treatment mechanisms. The aperiodic component (1/f) of EEG power spectra is often treated as noise, but recent studies suggest that changes to the aperiodic exponent of power spectra may reflect changes in excitation/inhibition (E/I) balance, a concept linked to antidepressant effects, epilepsy, autism, and other clinical conditions. One confound of previous studies is behavioral state, because factors associated with behavioral state other than E/I ratio may alter EEG parameters. Thus, to test the robustness of the aperiodic exponent as a predictor of E/I ratio, we analyzed active exploration in mice using video EEG following various pharmacological manipulations with the Fitting Oscillations & One Over F (FOOOF) algorithm. We found that GABAAreceptor (GABAAR) positive allosteric modulators increased the aperiodic exponent, consistent with the hypothesis that an increased exponent signals enhanced cortical inhibition, but other drugs (ketamine and GABAAR antagonists at sub-convulsive doses) did not follow the prediction. To tilt E/I ratio more selectively toward excitation, we suppressed the activity of parvalbumin (PV) interneurons with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Contrary to our expectations and studies demonstrating increased cortical activity following PV suppression, circuit disinhibition with the DREADD increased the aperiodic exponent. We conclude that the aperiodic exponent of EEG power spectra does not yield a universally reliable marker of E/I ratio. Alternatively, the concept of E/I state may be sufficiently oversimplified that it cannot be mapped readily onto an EEG parameter.

Significance StateBment

Neuropsychiatric illness is widely prevalent and debilitating. Causes are not well understood, but some hypotheses point toward altered excitation/inhibition (E/I) balance. Here, we use cortical electroencephalograms (EEG) in mice, given applicability of cortical EEG across species, and evaluate the impact of validated drugs, including anxiolytics (pentobarbital and diazepam), along with novel rapid-acting antidepressants (ketamine and allopregnanolone). We focus on analyzing the aperiodic component of EEG power spectra, which may be associated with changes in E/I ratio. We show that aperiodic exponent of EEG power spectra is not a reliable marker of E/I ratio. Moreover, the concept of E/I ratio may be too broad and complex to be defined by an EEG parameter.