bluuebunny/crossref_metadata_2025 huggingface dataset:
OCT-based Visual Field Estimation Using Segmentation-free 3D CNN Shows Lower Variability than Subjective Standard Automated Perimetry
Authors: Koyama Makoto , Inoda Satoru , Ueno Yuta , Ito Yoshikazu , Oshika Tetsuro , Tanito Masaki
Published: August 2024

Purpose: To train and evaluate a segmentation-free 3D convolutional neural network (3DCNN) model for estimating visual field (VF) from optical coherence tomography (OCT) images and to compare the residual variability of OCT-based estimated VF (OCT-VF) with that of Humphrey Field Analyzer (HFA) measurements in a diverse clinical population. Design: Retrospective cross-sectional study. Participants: 5,351 patients (9,564 eyes) who underwent macular OCT imaging and Humphrey Field Analyzer (HFA) tests (24-2 or 10-2 test patterns) at a university hospital from 2006 to 2023. The dataset included 47,653 paired OCT-VF data points, including various ocular conditions. Methods: We trained a segmentation-free 3DCNN model based on the EfficientNet3D-b0 architecture on a comprehensive OCT dataset to estimate VF. We evaluated the model's performance using Pearson's correlation coefficient and Bland‒Altman analysis. We assessed residual variability using a jackknife resampling approach and compared OCT-VF and HFA datasets using generalized estimating equations (GEE), adjusting the number of VF tests, follow-up duration, age, and clustering by eye and patient. Main Outcome Measures: Correlations between estimated and measured VF thresholds and mean deviations (MDs), and residual variability of OCT-VF and HFA. Results: We observed strong correlations between the estimated and measured VF parameters (Pearson's r: 24-2 thresholds 0.893, MD 0.932; 10-2 thresholds 0.902, MD 0.945; all p < 0.001). Bland‒Altman analysis showed good agreement between the estimated and measured MD, with a slight proportional bias. GEE analysis demonstrated significantly lower residual variability for OCT-VF than for HFA (24-2 thresholds: 1.10 vs. 2.48 dB; 10-2 thresholds: 1.20 vs. 2.48 dB; all p < 0.001, Bonferroni-corrected), with lower variability across all test points, severities, and ages, thus highlighting the robustness of the segmentation-free 3DCNN approach in a heterogeneous clinical sample. Conclusions: A segmentation-free 3DCNN model objectively estimated VF from OCT images with high accuracy and significantly lower residual variability than subjective HFA measurements in a heterogeneous clinical sample, including patients with glaucoma and individuals with other ocular diseases. The improved reliability, lower variability, and objective nature of OCT-VF highlight its value for enhancing VF assessment and monitoring of various ocular conditions, potentially facilitating earlier detection of progression and more efficient disease management.
The CoREST complex is a therapeutic vulnerability in malignant peripheral nerve sheath tumors
Authors: Soukar Imad , Fisher Robert , Bhagavatula Sanjana , Collard Marianne , Cole Philip A. , Alani Rhoda M.
Published: August 2024

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma that may be seen in patients with neurofibromatosis type 1 (NF1) or occur sporadically. While surgery is the primary treatment for localized MPNST with a 61.9% overall survival rate, metastatic disease is often fatal due to resistance to systemic therapies which underscores the urgent need for effective treatments. MPNSTs frequently harbor inactivating driver mutations in the PRC2 epigenetic repressor complex suggesting epigenetic therapies may represent a specific vulnerability in these tumors. Here, we investigate the role of the LSD1-HDAC1-CoREST (LHC) repressor complex in mediating MPNST tumor growth and progression. Our findings demonstrate that the LHC small molecule inhibitor, corin, induces apoptosis and significantly inhibits proliferation in MPNST cells. Transcriptomic analysis of corin-treated MPNST cells demonstrates specific increases in genes associated with axonogenesis and neuronal differentiation as well as altered extracellular matrix; additionally, corin treatment is shown to inhibit MPNST invasion in vitro. These results underscore the critical role of the LHC complex in facilitating MPNST growth and progression and suggest that targeting the LHC complex represents a promising therapeutic approach for this aggressive malignancy.
Low-cost and highly efficient generation of near-complete bacterial pathogen genomes by TELL-Seq
Authors: Wu Zhuoying , Zhang Ting , Li Sheng , Shen Lingzhu , Yang Zhangnv , Yang Yunfeng , Chen Xuanheng , Li Bolin , Zhou Shicong , Zhou Xintian , Wu Beibei , Jiang Jianmin , Li Xiao
Published: August 2024

Recent evidences suggest that de novo genome assembly can provide additional insights into genomic variation landscape beyond short-read NGS analyses. Despite the advent of long-read sequencing technologies, generating high-quality bacterial genome assemblies remains expensive and requires high-quality and large quantities of DNA. TELL-Seq, an emerging linked-read technology, has been reported as a low-cost alternative for producing near-complete genome assembly in certain bacterial species. However, a systematic assessment of its performance and characteristics in de novo bacterial genome assembly has not yet been conducted. To address this, we benchmarked TELL-Seq using a set of clinical and standard bacterial pathogens with a wide range of genome size (2.0 - 6.4 Mbp), GC-content (32% - 68%), genome complexity (mappability from 0.15 to 0.60) and Gram types. Our findings indicate that, with 1/6 cost and 1/15,000 of DNA compared to PacBio HiFi, TELL-Seq could generate as high quality near-complete bacterial genome assemblies. The optimal depth for assembly is around 200x, as increased depth improves contiguity and completeness, though quality plateaus at 250x. In general, genome complexity was significantly correlated with assembly quality, but GC-content was not. Nevertheless, genomes with extreme GC-content may require higher depths for accurate assembly. Our study suggests that TELL-Seq could be a scalable method for large-scale bacterial genomic surveys. The data generated from this study could serve as a benchmark dataset for further algorithm development.
ROLE OF WORKING MEMORY IN INTERLIMB GENERALIZATION OF NEWLY LEARNED SKILLS
Authors: Yadav Goldy , Pal Rahul , Matkar Shraddha , Kumar Neeraj
Published: August 2024

Newly acquired skill memory can generalize/transfer to the untrained arm. Such interlimb generalization of a learned skill has been shown to be symmetric in nature and is thought to be mediated by cognitive processes that emerge during skill learning. However, it is unknown whether engaging in other cognitively demanding tasks following skill acquisition can influence skill generalization. Our research goal was to uncover how a secondary task, involving working memory, interacts with a newly formed skill memory and influences subsequent interlimb generalization. To test this idea, we conducted a set of three experiments by recruiting right-handed young healthy individuals (N=92) who learned a novel motor skill (long or short training on a skilled reaching task) followed by performing a working memory or control task with the right arm. Finally, all individuals were tested for immediate or delayed (after 24 hours) interlimb skill generalization to the untrained left arm. We found significant immediate as well as delayed generalization in individuals who received long training on the motor skill task, irrespective of whether they performed working memory or control task. On the other hand, performing the working memory but not control task following short skill training impaired generalization when the untrained arm was tested 24 hours later. These findings indicate that short training reflecting early stages of skill learning and the subsequent skill memory stabilization are dependent on working memory such that the underlying neural interactions mediating these processes can have implications for skill generalization.

NEW AND NOTEWORTHY

Skill learning is deemed successful if it can generalize to untrained conditions. Despite the potential clinical relevance of interlimb skill generalization for motor rehabilitation, such as in case of unilateral stroke, the underlying mechanisms that can influence such generalization are not fully understood. Specifically, whether interlimb skill memory generalization can be impacted by another memory system is unknown. Here, we show that engaging in a working memory task following short skill training is detrimental for interlimb skill generalization, and such interference caused by working memory is not evident when the skill training is longer. These behavioral findings bridge the link between traditionally distinct memory systems, i.e., procedural skill memory and working memory.
Macrophage WDFY3, a protector against autoimmunity
Authors: Wu Xun , Wang Ziyi , Croce Katherine R. , Li Fang , Cui Jian , D’Agati Vivette D. , Soni Rajesh K. , Khalid Shareef , Saleheen Danish , Tabas Ira , Yamamoto Ai , Zhang Hanrui
Published: August 2024

Efficient efferocytosis is essential for maintaining homeostasis. Excessive apoptotic cell (AC) death and impaired macrophage efferocytosis lead to autoantigen release and autoantibody production, immune activation, and organ damage. It remains unclear whether these immunogenic autoantigens are the sole cause of increased autoimmunity or if efferocytosis of ACs directly influences macrophage function, impacting their ability to activate T cells and potentially amplifying autoimmune responses. Additionally, it has not been established if enhancing macrophage efferocytosis or modulating macrophage responses to AC engulfment can be protective in autoimmune-like disorders. Our previous work showed WDFY3 is crucial for efficient macrophage efferocytosis. This study reveals that myeloid knockout ofWdfy3exacerbates autoimmunity in young mice with increased AC burden by systemic injections of ACs and in middle-aged mice developing spontaneous autoimmunity, whereas ectopic overexpression of WDFY3 suppresses autoimmunity in these models. Macrophages, as efferocytes, can activate T cells and the inflammasome upon engulfing ACs, which are suppressed by overexpressing WDFY3. This work uncovered the role of WDFY3 as a protector against autoimmunity by promoting macrophage efferocytosis thus limiting autoantigen production, as well as mitigating T cell activation and inflammasome activation.
Utilization of CoRDS Registry to Monitor Quality of Life in Patients with VCP Multisystem Proteinopathy
Authors: Abdoalsadig Eiman , Hamid Merwa , Peck Allison , Johar Leepakshi , Kimonis Virginia
Published: August 2024

Background

VCP disease, also known as multisystem proteinopathy (MSP1), is a rare, autosomal dominant, adult-onset, neuromuscular disease that is caused by variants in the valosin-containing protein (VCP) gene. VCP disease may exhibit one or more of the following primary features: Inclusion Body Myopathy (IBM), Paget’s disease of bone (PDB), Frontotemporal Dementia (IBMPFD), and Amyotrophic Lateral Sclerosis (ALS). Due to its progressive nature, death normally occurs in their sixties due to respiratory and cardiac failure. The purpose of this study is to utilize the Cure VCP Disease patient registry hosted by the Coordination of Rare Diseases at Sanford (CoRDS) to conduct a prospective natural history study.

Methods

Seventy-nine participants enrolled in the patient registry and answered demographic,VCPvariant type, Patient-Reported Outcome Measures (PROMs), and Quality of Life (QOL) questionnaires over the course of three years. We additionally investigated if any sex differences existed and if genotype-phenotype correlations affected the rate of progression of the varying clinical manifestations.

Results

Overall, participants’ mobility declined significantly as the disease progressed. Participants reported a 0.6% decline in upper extremity function, 1.2% decline in lower extremity function, and 0.3% decline in cognitive function per year of age. Furthermore, participants reported a 1.6% decline in upper and lower extremity function and a 0.1% decline in cognitive function per year of disease duration. The highest PROMs correlations between overall health and lower extremity function, upper extremity function, fatigue, and the ability to perform vigorous activities. Genotype-phenotype correlations revealed no significant differences except for the absense of PDB in thep.Arg159Cysgroup.

Conclusion

The VCP CoRDS Registry was found to be a valuable tool for monitoring the QOL in patients with VCP disease and capturing patient perspectives for future clinical trials.
Effectiveness of ongoing single dose Rifampicin post-exposure prophylaxis (SDR PEP) implementation under routine programme conditions – an observational study in Nepal Impact assessment of single dose Rifampicin post-exposure prophylaxis
Authors: Banstola Nand Lal , Banstola NL , Hasker E , Mieras L , Gurung D , Baral B , Mehata S , Prasai S , Ghimire Y , Napit P , van Brakel WH
Published: August 2024

Background/Introduction: Leprosy control remains a challenge in Nepal. Single-dose rifampicin post-exposure prophylaxis (SDR-PEP) shows promise in reducing leprosy incidence among contacts of index cases, contributing to reducing the transmission of Mycobacterium (M.) leprae. This study evaluates the effectiveness of routine SDR-PEP implementation in Nepal in addition to contact screening, focusing on its impact on reducing leprosy risk among contacts and potential population-level effects. Methodology: We conducted a retrospective cohort study to compare leprosy case notification rates and leprosy risk among close contacts. We compared two districts implementing SDR-PEP (the intervention group) and two without (the control group). Data from 2015 onwards included demographics, index case types, and contact relationships. Statistical analyses, including hazard ratios (HR) and Kaplan-Meier survival curves, assessed the impact of SDR-PEP implementation. Findings: All four districts showed a decrease in case notification rates since 2015, with the steepest decline in the intervention districts. The risk of developing leprosy among contacts was significantly lower in the intervention districts (HR 0.28, 95% CI 0.18-0.44). SDR-PEP offered 72% protection, consistent over time, as shown in Kaplan-Meier plots. The interaction between intervention and blood-related contact was non-significant (0.29 versus 0.27, p=0.32), and the proportion of MB cases among incident cases was not significantly different post-PEP (51.4% vs. 53.6%, p=0.82). Conclusions: This study demonstrates the substantial protective effect of integrating SDR-PEP in routine leprosy control programs with contact screening, significantly lowering leprosy risk among contacts. SDR-PEP is equally effective for blood-related contacts and does not preferentially prevent PB cases. While suggesting potential population-level impact, the study design does not allow for firm conclusions at this level. Further research is needed to fully assess SDR-PEP's effectiveness in diverse contexts and optimize its implementation. Integrating SDR-PEP within well-organized contact screening programs is effective and is expected to reduce leprosy transmission when applied as a rolling intervention.
Genetic Testing History in Adults with Autism Spectrum Disorder
Authors: Mierau Susanna B , Thom Robyn P , Ravichandran Caitlin T , Nagy Amanda , Rice Cashel , Macenski Christina , Keary Christopher J , Palumbo Michelle L , McDougle Christopher J , Neumeyer Ann M
Published: August 2024

Background & Objectives Many genes have been identified in autism spectrum disorder (ASD). Yet little is known about how many adults with ASD receive recommended genetic testing and their outcomes. We investigated the percentage of adults with ASD who received genetic testing using recommended methods in our ASD specialty clinic and the percentage with positive findings. Methods Potentially eligible adults were identified through search of our health system data repository and ASD diagnoses confirmed using review of relevant medical records by consensus of psychiatrists specializing in ASD. Patients were included (N=630) who had at least one visit with a qualifying clinician between 5/1/2010 and 12/15/2020 and demographic data available. Data were collected through manual retrospective review of the electronic health record. Results Only 41% of the adults with ASD (261/630) had a history of genetic testing documented in the medical record. Genetic testing was declined by patients or families for 11% (72) of records and not recorded in 47% (297). Mean (SD; range) age for the 261 adults with testing documented was 28.5 (5.3; 22-58) years. Sixty-seven (26%) were identified as female, 14 (6%) as Asian, 8 (3%) as Black or African American, 226 (89%) as White, 6 (2%) as other race, and 2 (1%) as Hispanic. 189 (73%) had intellectual disability. Ninety-one percent (236) had the genetic testing method recorded. Only 54% (95% CI: 46%, 61%) of patients had testing using a recommended method (chromosomal array, autism/intellectual disability sequencing panel, or exome sequencing). Few adults had received testing with sequencing technologies. A genetic cause of ASD was found in 28% (95% CI: 19%, 39%) of the 121 adults with results from ASD-related genetic testing recorded. Discussion Genetic testing can offer clinical and research insights. Yet it is underutilized in this population of adults with ASD. Nearly half of the adults in our sample lacked documentation of genetic testing. Thus, the percentage of adults with confirmed ASD who had any recommended genetic testing may be even lower than reported. Adults with ASD may benefit from having their genetic testing history reviewed in the clinic and the latest genetic testing performed.
Cardiovascular risk in aging adults with double deficits in social support: a gender-sensitive, cross-sectional analysis of the CLSA cohort
Authors: Conklin Annalijn I , Safari Abdollah , Veenstra Gerry , Khan Nadia A
Published: August 2024

Background: Synergistic effects of different forms of social support (informational, tangible, emotional and belonging) on cardiovascular disease risk factors (CVRF) in aging women versus men is unknown. Aim: To quantify gender differences in the additive and multiplicative associations of four different forms of social support (informational, tangible, emotional and belonging) with cardiovascular disease risk factors (CVRF) in aging adults. Methods: Baseline data from 28,779 adults (45-85 years) in the Canadian Longitudinal Study on Aging Comprehensive cohort (2012-15) with four self-reported social support measures and measured body mass index, waist circumference and blood pressure. We used stratified multivariable principal component regression (PCR) and then post-estimated calculation of adjusted means and 95% CIs. Results: Among women, reporting low availability of two types of social support was consistently associated with the highest adjusted mean levels of WC and BMI. However, lack of two types of support was less clearly or consistently associated with anthropometric measures among men. The highest adjusted mean SBP levels among women were seen for women with low availability of informational support. Among men, low-low combinations of two social supports did not consistently correspond to the highest adjusted mean SBP levels. Results for DBP were null and showed no gender differences. Sensitivity analyses revealed two significant interaction effects of tangible and belonging supports for SBP and WC among women. Conclusion: Findings showed women with two deficits in social supports had the worse CVRF profiles than one social support deficit. Women’s worse CVRF profiles were seen for deficit combinations that included low informational support. We did not, however, find antagonistic/synergistic effects of social support on CVRFs. Heart health care and prevention for aging women would benefit from ensuring informational support with other supports is available.
Learning to use landmarks for navigation amplifies their representation in retrosplenial cortex
Authors: Fischer Lukas F. , Xu Liane , Murray Keith T. , Harnett Mark T.
Published: August 2024

Visual landmarks provide powerful reference signals for efficient navigation by altering the activity of spatially tuned neurons, such as place cells, head direction cells, and grid cells. To understand the neural mechanism by which landmarks exert such strong influence, it is necessary to identify how these visual features gain spatial meaning. In this study, we characterized visual landmark representations in mouse retrosplenial cortex (RSC) using chronic two-photon imaging of the same neuronal ensembles over the course of spatial learning. We found a pronounced increase in landmark-referenced activity in RSC neurons that, once established, remained stable across days. Changing behavioral context by uncoupling treadmill motion from visual feedback systematically altered neuronal responses associated with the coherence between visual scene flow speed and self-motion. To explore potential underlying mechanisms, we modeled how burst firing, mediated by supralinear somatodendritic interactions, could efficiently mediate context- and coherence-dependent integration of landmark information. Our results show that visual encoding shifts to landmark-referenced and context-dependent codes as these cues take on spatial meaning during learning.
Deep Learning and 3D Imaging Reveal Whole-Body Alterations in Obesity
Authors: Kaltenecker Doris , Horvath Izabela , Al-Maskari Rami , Kolabas Zeynep Ilgin , Chen Ying , Hoeher Luciano , Todorov Mihail , Kapoor Saketh , Ali Mayar , Kofler Florian , Morigny Pauline , Geppert Julia , Jeridi Denise , Cigankova Carolina , Kolenic Victor Miro , Gur Nilsu , Pan Chenchen , Piraud Marie , Rueckert Daniel , Rohm Maria , Hellal Farida , Elsner Markus , Bhatia Harsharan Singh , Menze Bjorn H , Herzig Stephan , Paetzold Johannes Christian , Diaz Mauricio Berriel , Erturk Ali
Published: August 2024

Many diseases, such as obesity, have systemic effects that impact multiple organ systems throughout the body. However, tools for comprehensive, high-resolution analysis of disease-associated changes at the whole-body scale have been lacking. Here, we developed a suite of deep learning-based image analysis algorithms (MouseMapper) and integrated it with tissue clearing and light-sheet microscopy to enable a comprehensive analysis of diseases impacting diverse systems across the mouse body. This approach enables the quantitative analysis of cellular and structural changes across the entire mouse body at unprecedented resolution and scale, including tracking nerves over several centimeters in whole animal bodies. To demonstrate its power, we applied MouseMapper to study nervous and immune systems in high-fat diet induced obesity. We uncovered widespread changes in both immune cell distribution and nerve structures, including alterations in the trigeminal nerve characterized by a reduced number of nerve endings in obese mice. These structural abnormalities were associated with functional deficits of whisker sensing and proteomic changes in the trigeminal ganglion, primarily affecting pathways related to axon growth and the complement system. Additionally, we found heterogeneity in obesity-induced whole-body inflammation across different tissues and organs. Our study demonstrates MouseMapper's capability to discover and quantify pathological alterations at the whole-body level, offering a powerful approach for investigating the systemic impacts of various diseases.
Identifying drug-resistant individual cells within tumors by semi-supervised transfer learning from bulk to single-cell transcriptome
Authors: Huang Kaishun , Liu Hui
Published: August 2024

The presence of pre-existing or acquired drug-resistant cells within the tumor often leads to tumor relapse and metastasis. Single-cell RNA sequencing (scRNA-seq) enables elucidation of the subtle differences in drug responsiveness among distinct cell subpopulations within tumors. A few methods have employed scRNA-seq data to predict the drug response of individual cells to date, but their performance is far from satisfactory. In this study, we propose SSDA4Drug, a semi-supervised few-shot transfer learning method for inferring drug-resistant cancer cells. SSDA4Drug extracts pharmacogenomic features from both bulk and single-cell transcriptomic data using semi-supervised adversarial domain adaptation. This allows us to transfer knowledge of drug sensitivity from bulk-level cell lines to single cells. We conduct extensive performance evaluation experiments across multiple independent scRNA-seq datasets, demonstrating SSDA4Drug’s superior performance over current state-of-the-art methods. Remarkably, with only one or two labeled target-domain samples, SSDA4Drug significantly boosts the predictive performance of single-cell drug responses. Moreover, SSDA4Drug accurately recapitulates the temporally dynamic changes of drug responses during continuous drug exposure of tumor cells, and successfully identifies reversible drug-responsive states in lung cancer cells, which initially acquire resistance through drug exposure but later restore sensitivity during drug holidays. Also, our predicted drug responses consistently align with the developmental patterns of drug sensitivity observed along the evolutionary trajectory of oral squamous cell carcinoma cells. In addition, our derived SHAP values and integrated gradients effectively pinpoint the key genes involved in drug resistance in prostate cancer cells. These findings highlight the exceptional performance of our method in determining single-cell drug responses. This powerful tool holds the potential for identifying drug-resistant tumor cell subpopulations, paving the way for advancements in precision medicine and novel drug development.
DNA polymerase kappa stabilized by PTBP2 interacts with MRE11 and promotes genomic instability in leukemia cells
Authors: Lama Shristi , Barik Bibhudev , IS Sajitha , Sarkar Tannistha , Chanda Sayantan , Behera Monalisa , Behera Subhankar Priyadarshi , Biswas Sutapa , Mohapatra Sonali , Biswas Ghanashyam , Chakraborty Soumen
Published: August 2024

Polypyrimidine tract binding protein 2 (PTBP2) is an RNA-binding protein that controls alternative splicing in neuronal, muscle, and Sertoli cells. Our study unveils a novel role of PTBP2 in promoting the excessive production of the DNA polymerase kappa (Polκ) by stabilizing its 3’UTR. We observed an association between its increased expression and the upregulation of PTBP2 in clinical samples of Chronic Myeloid Leukemia (CML).Ptbp2knock-out CML cell lines and patient samples treated with hydroxyurea presented with increased DNA damage, as evidenced by long comet tails and higher levels of the DNA damage marker, γH2AX foci, however overexpression ofPolκin thePtbp2-KO cells restored normal phenotype. The deregulation of the DNA repair pathway is a defining feature of malignancies and is closely associated with genomic instability. POLK was found to interact with MRE11 of the MRN complex, thereby governing the activation of ATM-CHK2. Cells with elevated levels ofPtbp2andPolκdemonstrated increased sister chromatid exchange and BrdU incorporation inex-vivoassays, while multinucleated cells with multipolar spindles were observed inin-vivoassays. Our findings confirm the critical role of the PTBP2-POLK axis in driving genomic instability and bolstering the viability of cells with increased malignancy.
Flower bud cooling protects pollen development and improves fertility during heatwaves
Authors: Jansen Martijn J. , Jansma Stuart Y. , Kuipers Klaske M. , Vriezen Wim H. , Millenaar Frank F. , Montoro Teresa , de Kovel Carolien G.F. , van Eeuwijk Fred A. , Visser Eric J.W. , Rieu Ivo
Published: August 2024

Early pollen development is a bottleneck for plant fertility in heatwave conditions, thus affecting yield stability. Mechanisms that protect this process and explain variation in tolerance level between genotypes are poorly understood. Here we show that sepal transpiration in young, still closed, flower buds reduces the impact of heat on developing tomato pollen and that this mechanism is enhanced by the major tomato pollen thermotolerance QTL, qPV11. By direct measurement of the flower bud core temperature and transpiration we show this process, which we term ‘flower bud cooling’, depends on heat-induced opening of sepal stomata and that the transpiration enhancing effect of qPV11 requires functional stomatal regulation and is specific to the sepals. Large-scale evaluation of populations in both a production field and greenhouse showed that qPV11 improves pollen viability and fruit set in heatwave-affected complex cultivation environments. These findings highlight enhanced flower bud cooling as a naturally evolved protection mechanism against heatwaves and qPV11 as genetic component in the differential regulation of transpiration between reproductive and vegetative tissues and candidate variant for the breeding of climate-resilient tomato cultivars.
Dissecting contributions of pulmonary arterial remodeling to right ventricular afterload in pulmonary hypertension
Authors: Neelakantan Sunder , Mendiola Emilio A , Vang Alexander , Myers Kyle J , Zhang Peng , Choudhary Gaurav , Avazmohammadi Reza
Published: August 2024

Pulmonary hypertension (PH) is defined as an elevation in the right ventricle (RV) afterload, characterized by increased hemodynamic pressure in the main pulmonary artery (PA). Elevations in RV afterload increase RV wall stress, resulting in RV remodeling and potentially RV failure. From a biomechanical standpoint, the primary drivers for RV afterload elevations include increases in pulmonary vascular resistance (PVR) in the distal vasculature and decreases in vessel compliance in the proximal PA. However, the individual contributions of the various vascular remodeling events toward the progression of PA pressure elevations and altered vascular hemodynamics remain elusive. In this study, we used a subject-specific one-dimensional (1D) fluid-structure interaction (FSI) model to investigate the alteration of pulmonary hemodynamics in PH and to quantify the contributions of vascular stiffening and increased resistance towards increased main pulmonary artery (MPA) pressure. We used a combination of subject-specific hemodynamic measurements, ex-vivo mechanical testing of arterial tissue specimens, and ex-vivo X-ray micro-tomography imaging to develop the 1D-FSI model and dissect the contribution of PA remodeling events towards alterations in the MPA pressure waveform. Both the amplitude and pulsatility of the MPA pressure waveform were analyzed. Our results indicated that increased distal resistance has the greatest effect on the increase in maximum MPA pressure, while increased stiffness caused significant elevations in the characteristic impedance. The method presented in this study will serve as an essential step toward understanding the complex interplay between PA remodeling events that leads to the most severe adverse effect on RV dysfunction.
ADAM interact with large protein complexes to regulate Histone modification, gene expression and splicing
Authors: Pandey Ankit , Cousin Helene , Kumar Shiv , Taylor Louis , Chander Ashmita , Coppenrath Kelsey , Shaidani Nikko-Ideen , Horb Marko , Alfandari Dominique
Published: August 2024

Cranial neural crest (CNC) cells are key stem cells that contribute to most of the facial structures in vertebrates. ADAM (A DisintegrinAndMetalloprotease) proteins are essential for the induction and migration of the CNC. We have shown that Adam13 associates with the transcription factor Arid3a to regulate gene expression. Here we show that Adam13 modulates Histone modifications in the CNC. We show that Arid3a binding to thetfap2αpromoter depends on the presence of Adam13. This association promotes the expression of onetfap2αvariant expressed in the CNC that uniquely activates the expression of gene critical for CNC migration. We show that both Adam13 and human ADAM9 associate with proteins involved in histone modification and RNA splicing, a function critically affected by the loss of Adam13. We propose that ADAMs may act as extracellular sensors to modulate chromatin availability, leading to changes in gene expression and splicing.
Gut microbiota dysbiosis induced by brain tumor modulates the efficacy of immunotherapy
Authors: Kim Hyeon Cheol , Kim Hyun-Jin , La Jeongwoo , Park Won Hyung , Park Sang Hee , Kang Byeong Hoon , Kim Yumin , Lee Heung Kyu
Published: August 2024

Background Although the influence of gut microbiota on various tumors has gained recognition, the intricate mechanisms underlying their effects on brain tumors remain largely unexplored. In this study, our objective was to unveil pivotal gut microbiota that contribute significantly to the anti-tumor immune response against brain tumors. Results During the progression of brain tumors, our research uncovered a notable shift in the gut microbiome, as revealed through comprehensive 16S rRNA sequencing analysis. This shift coincided with a substantial decrease in the concentration of tryptophan in fecal samples, indicating a potential link between tryptophan levels and microbiome composition. Intriguingly, dietary supplementation with tryptophan significantly mitigated these microbial alterations, suggesting a restorative effect on the gut microbiota composition. This intervention not only reversed the changes observed in the gut microbiome but also markedly improved survival rates, a phenomenon that was determined to be dependent on the gut microbiota. The mechanism underlying this improvement appears to involve an enhancement in T cell circulation, which in turn boosts the efficacy of immunotherapeutic approaches. Upon further investigation into the specific microbial species that were positively influenced by tryptophan supplementation, some candidates were screened. Among several gut microbiota strains restored by tryptophan supplementation, the most significant is Duncaniella dubosii. Through sole colonization into germ-free mice, we found that the presence of Duncaniella dubosii alone was able to replicate the beneficial effects observed with tryptophan supplementation. Conclusions This study highlights Duncaniella dubosii's crucial role in linking tryptophan supplementation to positive shifts in the gut microbiome, immune modulation, and enhanced survival during brain tumor progression. It underscores the complex interaction between diet, microbiota, and immune responses, offering novel insights for boosting cancer immunotherapy's success.
Is there a right place? The effect of oviposition site selection on offspring survival in a glassfrog
Authors: Angiolani Larrea Francesca N , Valencia-Aguilar Anyelet , Garrido-Priego Marina , Culebras Jaime , Peignier Mélissa , Jindiachi Lelis , Tinajero-Romero José G. , Guayasamin Juan M. , Ringler Eva
Published: August 2024

The choice of where to breed can have fundamental consequences for offspring development and survival. In amphibians, desiccation is one of the biggest threats to survival, especially in species that deposit their clutches in terrestrial habitats. In several species, hydration of the clutch is ensured by a caregiving parent, but in species without extended care, it might be the selection of a suitable oviposition location that helps secure a constant external source of hydration. We used Teratohyla spinosa, a Neotropical glassfrog without extended parental care, to test the effect of oviposition site selection on offspring development and survival. Previous observations have revealed that this species preferentially deposits eggs on the underside of leaves close to their margins. We hypothesized that T. spinosa strategically chooses this position on the leaves to ensure clutch hydration during embryonic development. To this end, we performed a clutch translocation experiment where we manipulated the location of clutches and compared their level of hydration, hatching time, and mortality rate to control clutches. We found that clutch hydration and mortality were not affected by the location on the leaf. These findings suggest that the oviposition site selection in T. spinosa does not affect clutch survival – at least under high humidity conditions.
Antibiotic-mediated microbial community restructuring is dictated by variability in antibiotic susceptibility and population interactions
Authors: Kim Kyeri , Weiss Andrea , Ma Helena R , Son Hye-In , Zhou Zhengqing , You Lingchong
Published: August 2024

It is widely known that faster-growing bacterial cells are more susceptible to antibiotics. Given this notion, it appears intuitive that antibiotic treatment would enrich slower-growing cells in a clonal population or slower-growing populations in a microbial community, which has been commonly observed. However, experimental observations also show the enrichment of faster-growing subpopulations under certain conditions. Does this apparent discrepancy suggest uniqueness about different growth environments or the role of additional confounding factors? If so, what could be the major determinant in antibiotic-mediated community restructuring? Combining modeling and quantitative measurements using a barcoded heterogeneous E. coli library, we show that the outcome of antibiotic-mediated community restructuring can be driven by two major factors. One is the variability among the clonal responses of different subpopulations to the antibiotic; the other is their interactions. Our results suggest the importance of quantitative measurements of antibiotic responses in individual clones in predicting community responses to antibiotics and addressing subpopulation interactions.
Awe is characterized as an ambivalent experience in the human behavior and cortex: integrated virtual reality-electroencephalogram study
Authors: Yi Jinwoo , Han Danny Dongyeop , Oh Seung-Yeop , Cha Jiook
Published: August 2024

Ambivalent feelings are a defining feature of awe, which has been understood as a possible source of its psychosocial benefits. However, due to the conventional unidimensional model of affective valence, behavior and neural representation of ambivalent feelings during awe remain elusive. To address this gap, we combined awe-inducing virtual reality clips, electroencephalogram, and a deep learning-based dimensionality reduction technique (N= 43). Behaviorally, awe ratings were precisely predicted by the duration and intensity of ambivalent feelings, not by single valence-related metrics. In the electrophysiological analysis, we identified latent neural space for each participant sharing valence representation structures across individuals and stimuli. In these spaces, ambivalent feelings during awe were distinctly represented from positive and negative ones, and the variability in their distinctiveness specifically predicted awe ratings. Additionally, frontal delta oscillations mainly engaged in differentiating valence representations. Our findings demonstrate that awe is fundamentally an ambivalent experience reflected in both behavior and electrophysiological activities. This work provides a new framework for understanding complex emotions and their neural underpinnings, with potential implications for affective neuroscience and relevant fields.
Percent of lung involved in disease on chest X-ray predicts unfavorable treatment outcome in pulmonary tuberculosis
Authors: Ghanem Marwan , Srivastava Ratnam , Ektefaie Yasha , Hoppes Drew , Rosenfeld Gabriel , Yaniv Ziv , Grinev Alina , Xu Ava Y. , Yang Eunsol , Velásquez Gustavo E. , Harrison Linda , Rosenthal Alex , Savic Radojka M. , Jacobson Karen R. , Farhat Maha R.
Published: August 2024

Radiology may better define tuberculosis (TB) severity and guide duration of treatment. We aimed to systematically study baseline chest X-rays (CXR) and their association with TB treatment outcome using real-world data. We used logistic regression to associate TB treatment outcomes with CXR findings, including percent of lung involved in disease (PLI), cavitation, and Timika score, alone or in combination with other clinical characteristics, stratifying by drug resistance status and HIV (n = 2,809). We fine-tuned convolutional neural nets (CNN) to automate PLI measurement from the CXR DICOM images (n = 5,261). PLI is the only CXR finding associated with unfavorable outcome across drug resistance and HIV subgroups [Rifampicin-susceptible disease without HIV, adjusted odds ratio (aOR) 1·11 (1·01, 1·22), P-value 0·025]. The most informed model of baseline characteristics tested predicts outcome with a validation mean area under the curve (AUC) of 0·769. PLI and Timika (AUC 0·656 and 0·655 respectively) predict unfavorable outcomes better than cavitary information (best AUC 0·591). The addition of PLI improves prediction compared to sex and age alone (AUC 0·680 and 0·627, respectively).PLI>25% provides a better separation of favorable and unfavorable outcomes compared to PLI>50%. The best performing ensemble of CNNs has an AUC 0·850 for PLI>25% and mean absolute error of 11·7% for the PLI value. PLI is better than cavitation for predicting unfavorable treatment outcome in pulmonary TB in non-clinical trial settings and it can be accurately and automatically predicted with CNNs.

One Sentence Summary

The percent of lung involved in disease improves prediction of unfavorable outcomes in pulmonary tuberculosis when added to clinical characteristics.
Clinical practice guidelines for the care of patients with a chronic subdural haematoma: multidisciplinary recommendations from presentation to recovery
Authors: Stubbs DJ , Davies BM , Edlmann E , Ansari A , Bashford TH , Braude P , Bulters D , Camp S , Carr G , Coles JP , DeMonteverde-Robb D , Dhesi J , Dinsmore J , Evans NR , Foster E , Fox E , Froom I , Gillespie CS , Gray N , Grieve K , Hartley P , Lecky F , Kolias A , Jeeves J , Joannides A , Minett T , Moppett I , Nathanson MH , Newcombe V , Outtrim JG , Owen N , Peterman L , Ralhan S , Shipway D , Sinha R , Thomas W , Whitfield P , Wilson SR , Zolnourian A , Dixon-Woods M , Menon DK , Hutchinson PJ
Published: August 2024

Introduction

A cSDH is an encapsulated collection of fluid and blood degradation products in the subdural space. It is increasingly common, affecting older people and those living with frailty. Currently, no guidance exists to define optimal care from onset of symptoms through to recovery. This paper presents the first consensus- built recommendations for best practice in the care of cSDH, co-designed to support each stage of the patient pathway.

Methods

Guideline development was led by a multidisciplinary Steering Committee with representation from diverse clinical groups, professional associations, patients, and carers. Literature searching to identify relevant evidence was guided by core clinical questions formulated through facilitated discussion with specially convened working groups. A modified Delphi exercise was undertaken to build consensus on draft statements for inclusion in the guideline using survey methodology and an in-person meeting. The proposed guideline was subsequently endorsed by the Society for British Neurological Surgeons, Neuroanaesthesia and Critical Care Society, Association of Anaesthetists, British Association of Neuroscience Nurses, British Geriatric Society, and Centre for Perioperative Care.

Results

We identified that high quality evidence was generally lacking in the literature, although randomised controlled trial (RCT) data were available to inform specific recommendations on aspects of surgical technique and use of corticosteroids. The final guideline represents the outcome of synthesising the available evidence as well as consensus-built expert opinion and patient involvement. The guideline comprises 67 recommendations across 8 major themes, covering: presentation and diagnosis, neurosurgical triage and shared decision-making, non-operative management, perioperative management (including of anticoagulation), timing of surgery, intraoperative care, postoperative care, rehabilitation and recovery.

Conclusions

We present the first multidisciplinary guideline for the care of patients with cSDH. The recommendations reflect a paradigm shift in the care of cSDH, recognising and formalising the need for multidisciplinary and collaborative clinical management and communication and decision-making with patients delivered effectively across secondary and tertiary care.
DNA methylation patterns contribute to changes of cellular differentiation pathways in leukocytes with LOY from patients with Alzheimer’s disease
Authors: Jąkalski Marcin , Bruhn-Olszewska Bożena , Rychlicka-Buniowska Edyta , Davies Hanna , Sarkisyan Daniil , Siedlar Maciej , Baran Jarosław , Węglarczyk Kazimierz , Jaszczynski Janusz , Ryś Janusz , Gedraitis Vilmantas , Filipowicz Natalia , Klich-Rączka Alicja , Kilander Lena , Ingelsson Martin , Dumanski Jan P.
Published: August 2024

Alzheimer’s disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of chromosome Y (LOY) in leukocytes is strongly associated with AD. We studied here DNA methylation and RNA expression in sorted monocytes and granulocytes with and without LOY from male AD patients. Through multi-omic analysis, we identified new candidate genes and confirmed the involvement of numerous genes previously associated with AD. Our findings highlight LOY-related differences in DNA methylation that occur in gene regulatory regions and are predominantly accompanied by down-regulation of affected genes. Specifically, we observed alterations in key genes involved in leukocyte differentiation:FLI1, involved in early hematopoiesis;RUNX1, essential for blood cell development;RARA, regulating gene expression in response to retinoic acid;CANX, crucial for protein folding;CEBPB, a transcription factor important for immune responses; andMYADM, implicated in cell adhesion and migration. Moreover, protein-protein interaction analysis in granulocytes identified that products of two of these genes,CANXandCEBPB, are key hub proteins. Thus, LOY appears to dysregulate genes involved in leukocyte differentiation and induce higher-level epigenetic changes. This research underscores the potential of multi-omic approaches in pure cell populations to uncover the molecular underpinnings of AD and reinforces the significance of LOY as a pathogenic factor in this disease. Overall, results support the hypothesis that age-related immune cell dysfunction contributes to AD development. Finally, our results link previous analysis showing impact of LOY on leukocyte differentiation, LOY-associated transcriptional dysregulation and GWAS studies of LOY.