bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond physical sensations: investigating empathy and prosocial behavior in vicarious pain responders
Authors: Ben Adiva Yoad , Genzer Shir , Perry Anat
Published: June 2024

Empathy, the capacity to share others’ emotional experiences, has been proposed as a key motivation for altruistic behavior in both humans and animals. Sharing another’s emotional experience may generate a self-embodied simulation of their emotional state, fostering understanding and promoting prosocial behavior. Vicarious pain responders report sensing physical pain when observing others in pain. Whether this ability extends to emotional experiences remains unexplored. Using both questionnaires and ecologically valid behavioral tasks, we explored whether vicarious pain responders differ from nonresponders in empathic abilities and prosocial behavior. Participants watched video clips of people describing a negative emotional life event. We operationalized several empathic abilities and responses (empathic accuracy, affective synchrony, emotional reaction, and empathic motivation) based on participants’ and targets’ responses during and after watching the videos. Participants were also engaged in a donation task measuring tendency for prosocial behavior. Findings reveal that compared to nonresponders, vicarious pain responders exhibit enhanced empathic accuracy, intensified emotional reactions to others’ emotional pain, and a greater motivation to communicate with the target. This study marks the first behavioral evidence showcasing vicarious pain responders’ empathic abilities, reactions, and motivation in response to nonphysical pain of others, expanding our knowledge of this phenomenon and its association with broader empathic abilities.
Perceived dissimilarity and knowledge sharing with younger workers: the role of generativity striving and knowledge receiving from younger workers
Authors: Lu Yunyan , Zhou Hao
Published: June 2024

Drawing on self-categorization theory, this study examined the impacts of perceived age and deep-level dissimilarities with younger workers on older workers’ tacit and explicit knowledge sharing (KS) with younger workers via generativity striving (GS), and extended the theory by proposing the moderating role of knowledge receiving (KR) from younger workers. This study used a three-wave online survey of 570 older workers in a large Chinese aircraft maintenance company. The results showed that GS mediated both the positive relationships between perceived age dissimilarity with younger workers and older workers’ tacit and explicit KS with younger workers, as well as the negative relationships between perceived deep-level dissimilarity (PDD) with younger workers and older workers’ tacit and explicit KS with younger workers. Moreover, the positive direct impact of GS and the negative indirect impact of PDD with younger workers on older workers’ explicit KS with younger workers were found to be relatively weaker when older workers’ KR from younger workers was high. The findings suggest that perceived age and deep-level dissimilarities with younger workers present both opportunities and challenges for older workers to share knowledge with younger workers.
Topographically selective motor inhibition under threat of pain
Authors: Betti Sonia , Badioli Marco , Dalbagno Daniela , Garofalo Sara , di Pellegrino Giuseppe , Starita Francesca
Published: June 2024

Pain-related motor adaptations may be enacted predictively at the mere threat of pain, before pain occurrence. Yet, in humans, the neurophysiological mechanisms underlying motor adaptations in anticipation of pain remain poorly understood. We tracked the evolution of changes in corticospinal excitability (CSE) as healthy adults learned to anticipate the occurrence of lateralized, muscle-specific pain to the upper limb. Using a Pavlovian threat conditioning task, different visual stimuli predicted pain to the right or left forearm (experiment 1) or hand (experiment 2). During stimuli presentation before pain occurrence, single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex to probe CSE and elicit motor evoked potentials from target right forearm and hand muscles. The correlation between participants' trait anxiety and CSE was also assessed. Results showed that threat of pain triggered corticospinal inhibition specifically in the limb where pain was expected. In addition, corticospinal inhibition was modulated relative to the threatened muscle, with threat of pain to the forearm inhibiting the forearm and hand muscles, whereas threat of pain to the hand inhibited the hand muscle only. Finally, stronger corticospinal inhibition correlated with greater trait anxiety. These results advance the mechanistic understanding of pain processes showing that pain-related motor adaptations are enacted at the mere threat of pain, as sets of anticipatory, topographically organized motor changes that are associated with the expected pain and are shaped by individual anxiety levels. Including such anticipatory motor changes into models of pain may lead to new treatments for pain-related disorders.
Association Between Corticosteroid Dose and Pain Reduction After Sacroiliac Joint Injections
Authors: Naber William J. , Scribner Darin , Kalpakjian Claire Z. , Bakshi Rishi
Published: June 2024

Objective

Sacroiliac joint–mediated back pain has proven therapeutic benefit from fluoroscopically guided sacroiliac joint corticosteroid injections. We examined corticosteroid dose and pain relief after fluoroscopically guided sacroiliac joint injections to better understand their relationship.

Design

This is a retrospective observational cohort analysis of electronic health record data on 661 patients who received unilateral fluoroscopically guided sacroiliac joint intraarticular corticosteroid injection with 40 mg versus 80 mg of methylprednisolone from 2012 and 2019. Patients were injected by fellowship trained proceduralists after diagnosis by board-certified physiatrists in an academic physiatry practice. Absolute change in pain scores (postprocedure and first follow-up) was modeled using linear regression of methylprednisolone dosage (40 mg vs. 80 mg) controlling for age, sex, body mass index, baseline pain scores, and follow-up time.

Results

Linear regression indicated that dosage of methylprednisolone, age, and body mass index were not statistically significantly associated with change in pain scores. Sex approached significance (P = 0.0501) indicating that females may have a lower degree of pain resolution than males.

Conclusions

Practitioners should consider corticosteroid dose when performing these beneficial procedures. This could reduce cost and potential side effects associated with larger doses, while still providing therapeutic benefit. This pilot study can guide future research and dosing guidelines for fluoroscopic spine injections.
For the Love of the Game
Authors: Grimsley Emily A. , Anderson David O. , Kendall Melissa A. , Zander Tyler , Parikh Rajavi , Weigel Ronald J. , Kuo Paul C.
Published: June 2024

Objective:

We sought to determine the premium associated with a career in academic surgery, as measured by compensation normalized to the work relative value unit (wRVU).

Background:

An academic surgical career embodying innovation and mentorship offers intrinsic rewards but is not well monetized. We know compensation for academic surgeons is less than their nonacademic counterparts, but the value of clinical effort, as normalized to the wRVU, between academic and nonacademic surgeons has not been well characterized. Thus, we analyzed the variations in the valuation of academic and nonacademic surgical work from 2010 to 2022.

Methods:

We utilized Medical Group Management Association Provider Compensation data from 2010, 2014, 2018, and 2022 to compare academic and nonacademic surgeons. We analyzed raw total cash compensation (TCC), wRVU, TCC per wRVU (TCC/wRVU), and TCC to collections (TCCtColl). We calculated collections per wRVU (Coll/wRVU). We adjusted TCC and TCCtColl for inflation using the Consumer Price Index. Linear modeling for trend analysis was performed.

Results:

Compared with nonacademic, academic surgeons had lower TCC (2010: $500,415.0±23,666 vs $631,515.5±23,948.2, −21%; 2022: $564,789.8±23,993.9 vs $628,247.4±15,753.2, −10%), despite higher wRVUs (2022: 9109.4±474.9 vs 8062.7±252.7) and higher Coll/wRVU (2022: 76.68±8.15 vs 71.80±6.10). Trend analysis indicated that TCC will converge in 2038 at an estimated $660,931.

Conclusions:

In 2022, academic surgeons had more clinical activity and superior organizational revenue capture, despite less total and normalized clinical compensation. On the basis of TCC/wRVUs, academia charges a premium of 16% over nonacademic surgery. However, trend analysis suggests that TCC will converge within the next 20 years.
antiCD49d Ab treatment ameliorates age-associated inflammatory response and mitigates CD8+ T-cell cytotoxicity after traumatic brain injury
Authors: Chen Zhangying , Ford Kacie P. , Islam Mecca B.A.R , Wan Hanxiao , Han Hyebin , Ramakrishnan Abhirami , Brown Ryan J. , Villanueva Veronica , Wang Yidan , Davis Booker T. , Weiss Craig , Cui Weiguo , Gate David , Schwulst Steven J.
Published: June 2024

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people.

Graphic abstract

Aged brains after TBI comprise two pools of CD8+T cells. The aged brain has long been resided by a population of CD8+T cells that’s exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8+T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8+T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.
Before the brink: sublethal impacts of climate change on stingless bee flight performance
Authors: da Silva Carmen R. B. , Macnaughtan Lachlan D. , Griffith Oliver W , Narendra Ajay
Published: June 2024

Aim: We aimed to understand the sublethal impacts of climate change on native bee ecology. We evaluated how flight performance, a key trait for predator escape, dispersal, and pollination, is impacted by temperature. We aimed to understand how species geographic ranges shape species thermal performance curves (TPCs), and estimate species vulnerability to further warming. Location: Australia. Time period: Present. Major taxa studied: Stingless bees. Methods: We tested the flight speed and acceleration of two species of stingless bees, Austroplebeia australis and Tetragonula carbonaria at seven test temperatures. We examined how the climate experienced by species throughout their range shapes their TPCs. By estimating the extent of species geographic ranges that experience temperatures that exceed their thermal optima we made inferences on how sublethal increase in temperature will likely impact key ecological activities associated with flight. Results: Species TPCs reflected the thermal environments they inhabit. A. australis, which experiences greater thermal variation and hotter temperatures throughout their range, had a broader TPC curve, higher thermal optima, and faster flight performance than T. carbonaria, rejecting the jack-of-all-trades master-of-none hypothesis. Further increases in temperature will reduce flight performance of T. carbonaria at a faster rate than A. australis, however, a larger proportion of A. australis range is currently exposed to temperatures above their thermal optima. Main conclusions: Climates will impact species ecology before they reach their lethal limits. Our study supports the idea that species fundamental niche breadths are linked to their geographic ranges, but that trade-offs are not associated with flight performance and ability to perform across a broad range of temperatures. When assessing vulnerability to climate change, it is important to consider how temperature impacts species traits, but also the climates that species experience throughout their unique geographic ranges.
Long-term perceptual priors drive confidence bias which favors prior-congruent evidence
Authors: Constant Marika , Filevich Elisa , Mamassian Pascal
Published: June 2024

Within a Bayesian framework, both our perceptual decisions and confidence about those decisions are based on the precision-weighted integration of prior expectations and incoming sensory information. This assumes priors to influence both decisions and confidence in the same way. Against this assumption, asymmetries have been found in the influence that priors have on confidence compared to discrimination decisions. However, these patterns were found for high-level probabilistic expectations that are flexibly induced in the task context. It remains unclear whether this generalizes to low-level perceptual priors that are naturally formed through long term exposure. Here we investigated human participants’ confidence in decisions made under the influence of a long-term perceptual prior: the slow-motion prior. Participants viewed moving line stimuli for which the slow-motion prior biases the perceived motion direction. On each trial, they made two consecutive motion direction decisions followed by a confidence decision. We contrasted two conditions – one in which the prior biased perceptual decisions and one in which decisions were driven by the sensory information alone. We found a confidence bias favoring the condition in which the prior influenced decisions, even when accounting for performance differences. Computational modeling revealed this effect to best be explained by confidence using the prior-congruent evidence as an additional cue, beyond the posterior evidence used in the perceptual decision. This suggests a confirmatory confidence bias favoring evidence congruent with low-level perceptual priors, revealing that, in line with high-level expectations, even long-term priors have a particularly strong influence at the metacognitive level.
Embracing naturalistic paradigms: substituting GPT predictions for human judgments
Authors: Yang Xuan , O’Reilly Christian , Shinkareva Svetlana V.
Published: June 2024

Naturalistic paradigms can assure ecological validity and yield novel insights in psychology and neuroscience. However, using behavioral experiments to obtain the human ratings necessary to analyze data collected with these paradigms is usually costly and time-consuming. Large language models like GPT have great potential for predicting human-like behavioral judgments. The current study evaluates the performance of GPT as a substitute for human judgments for affective dynamics in narratives. Our results revealed that GPT’s inference of hedonic valence dynamics is highly correlated with human affective perception. Moreover, the inferred neural activity based on GPT-derived valence ratings is similar to inferred neural activity based on human judgments, suggesting the potential of using GPT’s prediction as a reliable substitute for human judgments.
Loss of cell junctional components and matrix alterations drive cell desquamation and fibrotic changes in Idiopathic Pulmonary Fibrosis
Authors: Chandran Rachana R. , Vijayaraj Preethi , Garcia-Milian Rolando , King Jade , Castillo Kristen , Chen Liang , Kwon Yumi , William Sarai , Rickabaugh Tammy M. , Langerman Justin , Choi Woosuk , Sen Chandani , Lever Jacelyn E.P , Li Qian , Pavelkova Nikoleta , Plosa Erin J. , Rowe Steven M. , Plath Kathrin , Clair Geremy , Gomperts Brigitte N.
Published: June 2024

The distal bronchioles in Idiopathic Pulmonary Fibrosis (IPF) exhibit histopathological abnormalities such as bronchiolization, peribronchiolar fibrosis and honeycomb cysts that contribute to the overall architectural remodeling of lung tissue seen in the disease. Here we describe an additional histopathologic finding of epithelial desquamation in patients with IPF, wherein epithelial cells detach from the basement membrane of the distal bronchioles. To understand the mechanism driving this pathology, we performed spatial transcriptomics of the epithelial cells and spatial proteomics of the basement membrane of the distal bronchioles from IPF patients and patients with no prior history of lung disease. Our findings reveal a downregulation of cell junctional components, upregulation of epithelial-mesenchymal transition signatures and dysregulated basement membrane matrix in IPF distal bronchioles, facilitating epithelial desquamation. Further, functional assays identified regulation between Collagen IV in the matrix, and the junctional genesJUPandPLEC, that is crucial for maintaining distal bronchiolar homeostasis. In IPF, this balanced regulation between matrix and cell-junctions is disrupted, leading to loss of epithelial adhesion, peribronchiolar fibrosis and epithelial desquamation. Overall, our study suggests that in IPF the interplay between the loss of cell junctions and a dysregulated matrix results in desquamation of distal bronchiolar epithelium and lung remodeling, exacerbating the disease.

One Sentence Summary

Two-way regulation of cell junctional proteins and matrix proteins drives cellular desquamation and fibrosis in the distal bronchioles of patients with Idiopathic Pulmonary Fibrosis.
Cell type-specific expression of angiotensin receptors in the human lung with implications for health, aging, and chronic disease
Authors: Benjamin Kynon JM , Sauler Maor , Poonyagariyagorn Hataya , Neptune Enid R
Published: June 2024

The renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung,AGTR1andAGTR2, using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes forAGTR1and a subtype of alveolar epithelial type 2 cells forAGTR2. In the context of disease, we further pinpointAGTR2localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2B) andAGTR1localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, findingAGTR2associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway’s role in lung homeostasis and constructing rational approaches for targeting specific lung disorders.
Distinct functions of three Wnt proteins control mirror-symmetric organogenesis in theC. elegansgonad
Authors: So Shuhei , Asakawa Masayo , Sawa Hitoshi
Published: June 2024

Organogenesis requires the proper production of diverse cell types and their positioning/migration. However, the coordination of these processes during development remains poorly understood. The gonad inC. elegansexhibits a mirror-symmetric structure guided by the migration of distal tip cells (DTCs), which result from asymmetric divisions of somatic gonadal precursors (SGPs; Z1 and Z4). We found that the polarity of Z1 and Z4, which possess mirror-symmetric orientation, is controlled by the redundant functions of the LIN-17/Frizzled receptor and three Wnt proteins (CWN-1, CWN-2, and EGL-20) with distinct functions. Inlin-17mutants, CWN-2 promotes normal polarity in both Z1 and Z4, while CWN-1 promotes reverse and normal polarity in Z1 and Z4, respectively. In contrast, EGL-20 inhibits the polarization of both Z1 and Z4. Inlin-17;egl-20 cwn-2triple mutants with a polarity reversal of Z1, DTCs from Z1 frequently miss-migrate to the posterior side. Our further analysis demonstrates that the mis-positioning of DTCs in the gonad due to the polarity reversal of Z1 leads to mis-migration. Similar mis-migration was also observed incki-1(RNAi)animals producing ectopic DTCs. These results highlight the role of Wnt signaling in coordinating the production and migration of DTCs to establish a mirror-symmetric organ.
Decoding the Centromeric Region with a Near Complete Genome Assembly of the Oshima CherryCerasus speciosa
Authors: Fujiwara Kazumichi , Toyoda Atsushi , Biswa Bhim B. , Kishida Takushi , Tsuruta Momi , Nakamura Yasukazu , Kimura Noriko , Kawamoto Shoko , Sato Yutaka , Katsuki Toshio ,   Sakura 100 Genome Consortium, Koide Tsuyoshi
Published: June 2024

The Oshima cherry (Cerasus speciosa), which is endemic to Japan, has significant cultural and horticultural value. In this study, we present a near complete telomere-to-telomere genome assembly forC. speciosa, derived from the old growth "Sakurakkabu" tree on Izu Oshima Island. Using Illumina short-read, PacBio long-read, and Hi-C sequencing, we constructed a 269.3 Mbp genome assembly with a contig N50 of 32.0 Mbp. We examined the distribution of repetitive sequences in the assembled genome and identified regions that appeared to be centromeric. Detailed structural analysis of these putative centromeric regions revealed that the centromeric regions ofC. speciosacomprised repetitive sequences with monomer lengths of 166 or 167 bp. Comparative genomic analysis withPrunus sensu latogenome revealed structural variations and conserved syntenic regions. This high-quality reference genome provides a crucial tool for studying the genetic diversity and evolutionary history ofCerasusspecies, facilitating advancements in horticultural research and the preservation of this iconic species.
Identification of BiP as a temperature sensor mediating temperature-induced germline sex reversal
Authors: Shi Jing , Sheng Danli , Guo Jie , Zhou Fangyuan , Wu Shaofeng , Tang Hongyun
Published: June 2024

Besides regulation by karyotype, sex determination is also modulated by environmental cues like temperature, but the involving temperature-transduction mechanism remains elusive. Moreover, while sex determination was traditionally seen as dictated exclusively by either karyotype or temperature, recent observations suggest these factors can co-regulate sex, posing a mechanistic mystery. Here, we discovered that certain wild-isolated and mutantC. elegansstrains displayed genotypic-germline-sex-determination (GGSD) but with a temperature override. We found that ER chaperone BiP transduces temperature into germline-sex-governing signal and enables the co-existence of GGSD and temperature-dependent-germline-sex-determination (TGSD). Mechanistically, BiP availability is reduced at warmer temperatures through detecting increased ER-protein-folding burden, which promotes male-germline-fate through ERAD-mediated downregulation of the oocyte-fate driving factor, TRA-2. Remarkably, we can induce a switch between GGSD and TGSD by manipulating this newly-discovered process. Functionally, TGSD facilitatesC. eleganshermaphrodites in maintaining brood size at warmer temperatures. Moreover, BiP also acts in germline-sex-determination in a dioecious nematode. Collectively, our findings identify thermosensitive BiP as a conserved temperature sensor in TGSD and provide mechanistic insights into the fascinating transition of GGSD and TGSD.
SpatialQPFs: An R package for deciphering cell-cell spatial relationship
Authors: Li Xiao
Published: June 2024

Understanding spatial dynamics within tissue microenvironments is crucial for deciphering cellular interactions and molecular signaling in living systems. These spatial characteristics govern cell distribution, extracellular matrix components, and signaling molecules, influencing local biochemical and biophysical conditions. Despite significant progress in analyzing digital pathology images, current methods for capturing spatial relationships are limited. They often rely on specific spatial features that only partially describe the complex spatial distributions of cells and are frequently tied to particular outcomes within predefined model frameworks. To address these limitations, we presentSpatialQPFs, an R package designed to extract interpretable spatial features from cell imaging data using spatial statistical methodologies. Leveraging segmented cell information, our package offers a comprehensive toolkit for applying a range of spatial statistical methods within a stochastic process framework, including analyses of point process data, areal data, and geostatistical data. By decoupling feature extraction from specific outcome models,SpatialQPFsenables thorough large-scale spatial analyses applicable across diverse clinical and biological contexts. This approach enhances the depth and accuracy of spatial insights derived from tissue data, empowering researchers to conduct comprehensive spatial analyses efficiently and reproducibly. By providing a flexible and robust framework for spatial feature extraction,SpatialQPFsfacilitates advanced spatial analyses, paving the way for new discoveries in tissue biology and pathology.
Integration of Kinetic Data into Affinity-Driven Models for Improved T Cell-Antigen Specificity Prediction
Authors: Ghoreyshi Zahra S. , Teimouri Hamid , Kolomeisky Anatoly B. , George Jason T.
Published: June 2024

T cell receptor (TCR) and peptide-major histocompatibility complex (pMHC) interactions that result in T cell activation are complex and have been distinguished by their equilibrium affinity and kinetic profiles. While prior affinity-based models can successfully predict meaningful TCR-pMHC interactions in many cases, they occasionally fail at identifying TCR-pMHC interactions with low binding affinity. This study analyzes TCR-pMHC systems for which empirical kinetic and affinity data exist and prior affinity-based predictions fail. We identify a criteria for TCR-pMHC systems with available kinetic information where the introduction of a correction factor improves energybased model predictions. This kinetic correction factor offers a means to refine existing models with additional data and offers molecular insights to help reconcile previously conflicting reports concerning the influence of TCR-pMHC binding kinetics and affinity on T cell activation.
PINK1 deficiency rewires early immune responses in a mouse model of Parkinson’s disease triggered by intestinal infection
Authors: Recinto Sherilyn Junelle , Kazanova Alexandra , Bessaiah Hicham , Cordeiro Brendan , Mukherjee Sriparna , Premachandran Shobina , MacDonald Adam , Pei Jessica , Allot Alexis , Afanasiev Elia , Yaqubi Moein , McBride Heidi M , Trudeau Louis-Eric , Gruenheid Samantha , Stratton Jo Anne
Published: June 2024

Parkinson’s disease (PD) is characterized by a protracted period of non-motor symptoms, including gastrointestinal (GI) dysfunction, which can precede the development of the cardinal motor deficits by decades. This long prodrome of disease is highly suggestive of immune cell involvement in the initiation of disease, but currently the field lacks robust model systems to study such mechanisms. It has been hypothesized that pathology may be first initiated in the periphery due to environmental triggers, such as pathogens that enter the GI tract. We further speculate that the impact of such pathogens on the immune system could be exacerbated in genetically predisposed individuals. Our group has developed a GI-targeted pathogen-induced PD mouse model system in PINK1 KO mice with Gram-negative bacterial infections and found that T cells are a major player in driving PD-like motor symptoms at late stages following infection. Herein, we now map the initiating immune events at the site of infection at the earliest stages with the goal of shedding light on the earliest mechanisms triggering immune-mediated pathological processes relevant to PD. Using unbiased single cell sequencing, we demonstrate that myeloid cells are the earliest dysregulated immune cell type in PINK1 KO infected mice at 1-week post-infection, followed by a dysregulated T cell response shortly after, at 2 weeks post-infection. We find that these myeloid cells have an enhanced proinflammatory profile, are more mature, and develop enhanced capacity for antigen presentation. Using unbiased prediction analysis, our data suggest that cytotoxic T cells and myeloid cells are particularly poised for interacting with each other, and we identify possible direct cell-cell interaction pathways that might be implicated. Taken together, deciphering the earliest immune mechanisms in the periphery underpinning PD autoimmunity will be instrumental in the development of effective therapeutic targeting strategies before irrevocable neuronal damage ensues.
Advanced Cardiovascular Toxicity Screening: Integrating Human iPSC-Derived Cardiomyocytes with In Silico Models
Authors: Berezhnoy Andrey , Sinitsyna Anastasiya , Semidetnov Ivan , Naumov Vadim , Sergeeva Tatyana , Bakumenko Sergey , Slotvitsky Mikhail , Tsvelaya Valeriya , Agladze Konstantin
Published: June 2024

The pharmaceutical industry is evolving with the use of hiPSC-derived cardiomyocytes (hiPSC-CM) for in vitro cardiac safety screening. Traditional reliance on QT interval prolongation as a main cardiotoxicity marker is being challenged. In addition, Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative recommends using computer modeling and in silico platforms as more comprehensive approach for cardiotoxicity testing in conjunction with hiPSC-CM in vitro screening. Our study presents such an innovative platform that integrates in vitro hiPSC-CM propagation test with in silico models to assess cardiotoxicity. Utilizing the electrophysiological and morphological characteristics of hiPSC-CM, we offer a thorough evaluation of potential drug-induced cardiac risks by computer modelling. We show, using the example of lidocaine and other antiarrhythmics, that using a integrative experimental and computer platform, the possibility to correctly display the clinical manifestations of side effects in advance.
Decoupling shear stress and pressure effects in the biomechanics of autosomal dominant polycystic kidney disease using a perfused kidney-on-chip
Authors: Lapin Brice , Gropplero Giacomo , Vandensteen Jessica , Mazloum Manal , Bienaimé Frank , Descroix Stéphanie , Coscoy Sylvie
Published: June 2024

Kidney tubular cells are submitted to two distinct mechanical forces generated by the urine flow: shear stress and hydrostatic pressure. In addition, the mechanical properties of the surrounding extracellular matrix modulate tubule deformation under constraints. These mechanical factors likely play a role in the pathophysiology of kidney diseases as exemplified by autosomal dominant polycystic kidney disease, in which pressure, flow and matrix stiffness have been proposed to modulate the cystic dilation of tubules withPKD1mutations. The lack ofin vitrosystems recapitulating the mechanical environment of kidney tubules impedes our ability to dissect the role of these mechanical factors. Here we describe a perfused kidney-on-chip with tunable extracellular matrix mechanical properties and hydrodynamic constraints, that allows a decoupling of shear stress and flow. We used this system to dissect how these mechanical cues affectPkd1-/-tubule dilation. Our results show two distinct mechanisms leading to tubular dilation. For PCT cells (proximal tubule), overproliferation mechanically leads to tubular dilation, regardless of the mechanical context. For mIMCD-3 cells (collecting duct), tube dilation is associated with a squamous cell morphology but not with overproliferation and is highly sensitive to extracellular matrix properties and hydrodynamic constraints. Surprisingly, flow alone suppressedPkd1-/-mIMCD-3 tubule dilation observed in static conditions, while the addition of luminal pressure restored it. Ourin vitromodel emulating nephron geometrical and mechanical organization sheds light on the roles of mechanical constraints in ADPKD and demonstrates the importance of controlling intraluminal pressure in kidney tubule models.
Harmonic imaging for nonlinear detection of acoustic biomolecules
Authors: Nayak Rohit , Duan Mengtong , Ling Bill , Jin Zhiyang , Malounda Dina , Shapiro Mikhail G.
Published: June 2024

Gas vesicles (GVs) based on acoustic reporter genes have emerged as potent contrast agents for cellular and molecular ultrasound imaging. These air-filled, genetically encoded protein nanostructures can be expressed in a variety of cell typesin vivoto visualize cell location and activity or injected systemically to label and monitor tissue function. Distinguishing GVs from tissue signal deep inside intact organisms requires imaging approaches such as amplitude modulation (AM) or collapse-based pulse sequences, however they have limitations in sensitivity or require irreversible collapse of the GVs that restricts its scope for imaging dynamic cellular processes. To address these limitations, this study explores the utility of harmonic imaging to enhance the sensitivity of non-destructive imaging of GVs and cellular processes. Traditional fundamental-frequency imaging utilizing cross-wave AM (xAM) sequences has been deemed optimal for GV imaging. Contrary to this, we hypothesize that harmonic imaging, integrated with xAM could significantly elevate GV detection sensitivity. To verify our hypothesis, we conducted imaging on tissue-mimicking phantoms embedded with purified GVs, mammalian cells genetically modified to express GVs, and live mice after systemic GV infusion. Our findings reveal that harmonic xAM (HxAM) imaging markedly surpasses traditional xAM in isolating GVs’ nonlinear acoustic signature, showcasing significant enhancements in signal-to-background and contrast-to-background ratios across all tested samples. Further investigation into the backscattered spectra elucidates the efficacy of harmonic imaging in conjunction with xAM. HxAM imaging enables the detection of lower concentrations of GVs and cells with ultrasound and extends the imaging depthin vivoby up to 20% and imaging performance metrics by up to 10dB. These advancements bolster the capabilities of ultrasound for molecular and cellular imaging, underscoring the potential of using harmonic signals to amplify GV detection.
AEon: A global genetic ancestry estimation tool
Authors: Warren Naomi M , Pinese Mark
Published: June 2024

Genetic ancestry is a significant confounding factor in genetic association studies. It is therefore essential to estimate and account for ancestry if we hope to translate genomic research into equitable clinical utility for ethnically diverse populations. Despite this importance, accurate ancestry information is difficult to obtain, and existing methods to estimate ancestry are not designed for modern sequencing data. This methodological gap hinders the integration of genetic ancestry information in modern research, and limits progress in finding the genetic determinants of disease in diverse populations. To address this gap we present AEon, a probabilistic model-based global ancestry estimation tool, ready for use on modern genomic data. AEon predicts fractional population membership, accounting for possible admixture. Unlike previous global ancestry estimation tools such as EIGENSTRAT and ADMIXTURE, AEon takes input directly from a VCF/BCF, includes default training data based on the 26 reference populations of the 1000 Genomes Project, and produces visualisation aids and diagnostics to complement data output. AEon’s turnkey design significantly reduces the time taken to estimate ancestry from VCFs, without compromising on accuracy compared to ADMIXTURE analysis. AEon is available atgithub.com/GenomicRisk/aeon.
The expanded immunoregulatory protease network in mosquitoes is governed by gene co-expression
Authors: Morejon Bianca , Michel Kristin
Published: June 2024

Serine protease cascades regulate key innate immune responses. In mosquitoes, these cascades involve clip-domain serine proteases and their non-catalytic homologs (CLIPs), forming a complex network whose make-up and structural organization is not fully understood. This study assessed the impact of 85 CLIPs on humoral immunity inAnopheles gambiae. By coupling RNAi with assays measuring antimicrobial activity and melanization, we identified 27 CLIPs as immunoregulators that together form two distinct subnetworks. CLIPs regulating antimicrobial activity were found to control infection resistance, as knockdowns reduced bacterial load and improved survival. Furthermore, our analysis of CLIP gene expression unveiled a novel immunoregulatory mechanism reliant on protease baseline co-expression rather than infection-induced upregulation. These findings underscore that despite its complexity mosquito immune regulation may be targeted for malaria interventions.
SMARCA4mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy
Authors: Wang Yawen , Meraz Ismail M , Qudratullah Md , Kotagiri Sasikumar , Han Yanyan , Xi Yuanxin , Wang Jing , Lissanu Yonathan
Published: June 2024

Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex includingSMARCA4andARID1A. Importantly, clinical reports indicate thatSMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboringSMARCA4deficiency. Specifically, we show thatSMARCA4loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show thatSMARCA4loss in tumor cells led to profound downregulation ofSTING, IL1βand other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such asSTING, IL1β,type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-κB binding motif was highly enriched in enhancers that lose accessibility uponSMARCA4deficiency. Finally, we confirmed that SMARCA4 and NF-κB co-occupy the same genomic loci on enhancers associated withSTINGandIL1β,indicating a functional interplay between SMARCA4 and NF-κB. Taken together, our findings provide the mechanistic basis for the poor response ofSMARCA4-mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-κB on innate immune and inflammatory gene expression regulation.
Transgenerational transmission of post-zygotic mutations suggests symmetric contribution of first two blastomeres to human germline
Authors: Jang Yeongjun , Tomasini Livia , Bae Taejeong , Szekely Anna , Vaccarino Flora M. , Abyzov Alexej
Published: June 2024

Little is known about the origin of germ cells in humans. We previously leveraged post-zygotic mutations to reconstruct zygote-rooted cell lineage ancestry trees in a phenotypically normal woman, termed NC0. Here, by sequencing the genome of her children and their father, we analyzed the transmission of early pre-gastrulation lineages and corresponding mutations across human generations. We found that the germline in NC0 is polyclonal and is founded by at least two cells likely descending from the two blastomeres arising from the first zygotic cleavage. Analyses of public data from several multi-children families and from 1,934 familial quads confirmed this finding in larger cohorts, revealing that known imbalances of up to 90:10 in early lineages allocation in somatic tissues are not reflected in transmission to offspring, establishing a fundamental difference in lineage allocation between the soma and the germline. Analyses of all the data consistently suggest that germline has a balanced 50:50 lineage allocation from the first two blastomeres.
Glutamate, GABA, and dense-core vesicle secretion regulate predatory feeding in the nematodePristionchus pacificus
Authors: Onodera Ageha , Zhang Andrew , Chihara Takahiro , Sommer Ralf J. , Okumura Misako
Published: June 2024

Nematodes are one of the most diverse groups of organisms, found in various environments, and exhibit various feeding behaviours.Pristionchus pacificusdisplays two types of feeding behaviours: predatory and bacterial feeding. Previously, we showed that the neurotransmitter serotonin plays important roles in regulating predatory feeding inP. pacificus.However, the role of other neurotransmitters in predatory feeding remains unclear. Using the CRISPR/Cas9 system, we generated mutants of the dense-core vesicle (DCV)-based neuropeptide secretion system and genes related to seven neurotransmitters. Predatory assays revealed that the vesicular glutamate transporterPpa-EAT-4, glutamic acid decarboxylasePpa-UNC-25 which is involved in GABA synthesis, and the calcium-dependent activator protein for DCV secretionPpa-UNC-31, play roles in predatory feeding behaviour. We assessed the pharyngeal movement necessary for predation as well as locomotion rate in these mutants. While thePpa-eat-4andPpa-unc-31mutants decreased predation movement, thePpa-unc-25mutant showed a reduction only in bacterial events compared to wild type animals. Additionally,Ppa-unc-25andPpa-unc-31decreased in motor movement, potentially reducing predation efficiency. Together, these results suggest that glutamate, GABA and DCV secretion modulate feeding behaviours inP. pacificus. Our mutant collection of neurotransmitter-related genes will be useful for future analysis of neurobiology and behavioural evolution.
Identification of Multi-landscape and Cell Interactions in the Tumor Microenvironment through High-Coverage Single-Cell Sequencing
Authors: Zhong Wenlong , Wang Ligang , Guo Tonglei , Zhao Lihua , Wu Daqin , Xie Fei , Wang Xiao , Li Xiuxin , Wang FangXiao , Gu Weiyue , Lin Tianxin , Chen Xu
Published: June 2024

Single-cell RNA sequencing (scRNA-seq) is a widely used method for classifying cell types and states and revealing disease mechanisms. However, most contemporary scRNA-seq platforms fail to explore the multi-landscape of RNA. Here, we designed a microfluidic chip combined oligo-dT primers and Random Bridging Co-labeling (RBCL) RNA sequencing to develop an innovative Chigene scRNA-seq technology that can identify gene expression, mutations, and RNA splicing landscapes at the single-cell level. The Chigene scRNA-seq platform demonstrated exceptional performance, with minimal doublet rates of 0.94% (Chigene V1) and 1.93% (Chigene V2). Both versions exhibit high sensitivity, with Chigene V2 achieving nearly 100% RNA coverage and detecting over 1800 genes per cell on average. Targeted capture of single-cell gene mutations enhances mutation detection sensitivity. Moreover, this Chigene V2 platform has been validated in clinical samples for its ability to detect mutations, gene fusions and alternative splicing. The reliability of the platform was further corroborated using known functional gene mutation (CDKN1A) and fusion (FGFR3-TACC). To validate this method’s potential for discovering novel gene mutations in clinical samples, our investigation revealed an intriguing cell subpopulation carrying an ARHGAP5 mutation in urothelial carcinoma. These cells exhibited high-frequency mRNA splicing and exhibited specific crosstalk with T cells, distinguishing them from the subpopulation with the ARHGAP5 wild-type phenotype. Overall, this method provides a robust scRNA-seq platform suitable for comprehensive analyses of clinical specimens at different genetic information levels, thereby offering significant potential in the discovery of novel genes and interactions at the single-cell level.
Post-encoding administration of oxytocin selectively enhances memory consolidation of male faces in females
Authors: Li Jiashen , Chen Zhengyue , Liu Wei
Published: June 2024

Oxytocin plays a critical role in modulating social cognition and enhancing human memory for faces. However, it remains unclear which stage of memory oxytocin affects to enhance face memory. Our study explored oxytocin’s potential to selectively enhance the consolidation of social memories, specifically human faces, and whether this effect varies between genders. In two preregistered, randomized, double-blind, placebo-controlled trials with heterosexual participants (total N=294, comprising 149 males and 145 females), we explored how oxytocin affects memory consolidation. We administered oxytocin immediately after encoding (i.e., Study1) and 30 minutes before retrieval in a parallel study (i.e., Study2). This design allowed us to confirm that oxytocin’s effects were indeed due to consolidation rather than retrieval. We found that administering oxytocin post-encoding, but not before-retrieval, significantly improved female participants’ ability to recognize male faces 24 hours later, with no similar enhancement observed in males recognizing opposite-gender faces. Together with our analyses of social placebo effects and approachability rating during encoding, we concluded that oxytocin enhanced consolidation of long-term social memories in humans. Our results not only advance the understanding of the neurobiological mechanisms underlying social memory consolidation but also highlight oxytocin as a pharmacological tool for selectively enhancing human memory consolidation.

Highlights

Oxytocin selectively enhances memory consolidation of human faces, with gender-specific effects.

In females, oxytocin after encoding improves recognition of male faces after 24 hours.

Oxytocin-induced enhancement of social memory is due to enhanced consolidation, not retrieval or encoding.

Oxytocin shows potential for selectively modulating memory consolidation in humans.