bluuebunny/crossref_metadata_2025 huggingface dataset:
Impairment of autophagy-lysosomal activity near the chronically implanted microelectrodes
Authors: Chen Keying , Padilla Camila Garcia , Kiselyov Kirill , Kozai Takashi
Published: June 2023

Intracortical microelectrodes that can record and stimulate brain activity have become a valuable technique for basic science research and clinical applications. However, long-term implantation of these microelectrodes can lead to progressive neurodegeneration in the surrounding microenvironment, characterized by elevation in disease-associated markers. Dysregulation of autophagy-lysosomal degradation, a major intracellular waste removal process, is considered a key factor in the onset and progression of neurodegenerative diseases. It is plausible that similar dysfunctions in autophagy-lysosomal degradation contribute to tissue degeneration following implantation-induced focal brain injury, ultimately impacting recording performance. To understand how the focal, persistent brain injury caused by long-term microelectrode implantation impairs the autophagy-lysosomal pathway, we employed two-photon microscopy and immunohistology. This investigation focused on the spatiotemporal characterization of autophagy-lysosomal activity near the chronically implanted microelectrode. We observed an aberrant accumulation of immature autophagy vesicles near the microelectrode over the chronic implantation period. Additionally, we found deficits in autophagy-lysosomal clearance proximal to the chronic implant, which was associated with an accumulation of autophagy cargo and a reduction in lysosomal protease level during the chronic period. Furthermore, our evidence suggests astrocytes contribute to the clearance of myelin debris via autophagy-lysosomal degradation near the implanted microelectrode. Together, this study sheds light on the process of brain tissue degeneration caused by long-term microelectrode implantation, with a specific focus on impaired intracellular waste degradation.
Machine Learning Classification of Alzheimer’s Disease Pathology Reveals Diffuse Amyloid as a Major Predictor of Cognitive Impairment in Human Hippocampal Subregions
Authors: Stephen T.L. , Korobkova L. , Breningstall B. , Nguyen K. , Mehta S. , Pachicano M. , Jones K.T. , Hawes D. , Cabeen R.P. , Bienkowski M.S.
Published: June 2023

Analyzing Alzheimer’s disease (AD) pathology within anatomical subregions is a significant challenge, often carried out by pathologists using a standardized, semi-quantitative approach. To augment traditional methods, a high-throughput, high-resolution pipeline was created to classify the distribution of AD pathology within hippocampal subregions. USC ADRC post-mortem tissue sections from 51 patients were stained with 4G8 for amyloid, Gallyas for neurofibrillary tangles (NFTs) and Iba1 for microglia. Machine learning (ML) techniques were utilized to identify and classify amyloid pathology (dense, diffuse and APP (amyloid precursor protein)), NFTs, neuritic plaques and microglia. These classifications were overlaid within manually segmented regions (aligned with the Allen Human Brain Atlas) to create detailed pathology maps. Cases were separated into low, intermediate, or high AD stages. Further data extraction enabled quantification of plaque size and pathology density alongside ApoE genotype, sex, and cognitive status.

Our findings revealed that the increase in pathology burden across AD stages was driven mainly by diffuse amyloid. The pre and para-subiculum had the highest levels of diffuse amyloid while NFTs were highest in the A36 region in high AD cases. Moreover, different pathology types had distinct trajectories across disease stages. In a subset of AD cases, microglia were elevated in intermediate and high compared to low AD. Microglia also correlated with amyloid pathology in the Dentate Gyrus. The size of dense plaques, which may represent microglial function, was lower in ApoE4 carriers. In addition, individuals with memory impairment had higher levels of both dense and diffuse amyloid.

Taken together, our findings integrating ML classification approaches with anatomical segmentation maps provide new insights on the complexity of disease pathology in AD progression. Specifically, we identified diffuse amyloid pathology as being a major driver of AD in our cohort, regions of interest and microglial responses that might advance AD diagnosis and treatment.
Cortical high-frequency oscillations (≈ 110 Hz) in cats are state-dependent and enhanced by a subanesthetic dose of ketamine
Authors: Castro-Zaballa Santiago , González Joaquín , Cavelli Matías , Mateos Diego , Pascovich Claudia , Tort Adriano , Hunt Mark Jeremy , Torterolo Pablo
Published: June 2023

Ketamine is an NMDA receptor antagonist that has both antidepressant and anesthetic properties. At subanesthetic doses, ketamine can cause transient psychosis in humans, and is used to model psychosis in experimental animals. In rodents, subanesthetic doses of ketamine increase the power of high-frequency oscillations (HFO, 100-180 Hz) in the electroencephalogram and field potentials, a frequency band linked to cognitive functions. However, the effects of ketamine in higher mammals, with more translatable relevance, are poorly investigated. Here, we have examined cortical HFO during wakefulness, sleep, and after administering a sub-anesthetic dose of ketamine (15 mg/kg), utilizing the cat as an animal model. Four cats were implanted with cortical electrodes for chronic polysomnographic recordings. HFO power, connectivity, information flow directionality, and their relationships with respiratory activity were analyzed. During wakefulness, but not during sleep, we found that HFO were coupled with the inspiratory phase of the respiration. After ketamine administration, HFO were enhanced significantly and remained associated with the inspiratory phase. The analysis of the information flow after ketamine suggest that HFO originate from the olfactory bulb and stream towards the prefrontal cortex. Accordingly, occluding the nostrils significantly reduced HFO power in both the olfactory bulb and prefrontal cortex. In contrast, auditory stimulation did not affect HFO. In conclusion, spontaneous cortical HFO show certain state-dependent features in cats, and enhancement of this rhythm by ketamine may disrupt cortical information processing, which could contribute to some of the neuropsychiatric manifestations associated with ketamine.

Highlights

Ketamine is used to model psychosis in humans and experimental animals

Subanesthetic doses of ketamine increase the power of high-frequency oscillations

High-frequency oscillations are coupled with the inspiratory phase of respiration

These oscillations originate in the olfactory bulb and stream to the neocortex

Nostril occlusion lowers high-frequency activity in the olfactory bulb and neocortex

Graphical abstract
Home food procurement associated with improved food security during the COVID-19 pandemic
Authors: Niles Meredith T. , McCarthy Ashley C. , Malacarne Jonathan , Bliss Sam , Belarmino Emily H. , Laurent Jennifer , Merrill Scott C. , Nowak Sarah A. , Schattman Rachel E.
Published: June 2023

Home food procurement (HFP), including gardening, is associated with food security and improved health behaviors and outcomes. In the beginning of the COVID-19 pandemic, HFP increased in many high-income countries; yet little evidence has demonstrated what impact HFP had on food security. Furthermore, existing HFP studies are largely qualitative from unrepresentative samples, limiting population-level understanding of HFP engagement and impact. Using data from a representative sample of residents (n=988) in northern New England in the United States conducted in Spring/Summer 2021, we explore the relationship between HFP engagement in the first year of the pandemic and changes in food security status. We employ matching techniques to compare food security outcomes in households with observably similar demographic and social characteristics, and examine food security outcomes in three periods among households who do and do not participate in HFP. Our results show that nearly 60% of respondents engaged in at least one kind of HFP in the first year of the COVID-19 pandemic, with food insecure households being more likely to do HFP. Food insecure households (both newly and chronically food insecure) were also more likely to do HFP activities for the first time or more intensely than they had previously. Newly food insecure households were the most likely to engage in HFP overall, especially gardening. Furthermore, HFP engagement early in the COVID-19 pandemic is associated with improved food security for food insecure households in the 9-12 months after the start of the pandemic, though these improvements were primarily associated with newly, not chronically, food insecure households. Future research about HFP should continue to explore multiple HFP strategies and their potentially myriad relationships to food security, diet, and health outcomes.
Caregiving burden and associated factors among family caregivers of individuals with schizophrenia in Bangladesh: A cross-sectional study
Authors: Tabassum Tahsin Tasneem , Rahman Nur-A-Safrina , Shakhawat Hossain S M , Abdullah Faisal , Nawar Lubaba Tasneem , Lima Fahmida Islam , Gupta Mridul , Kona Suraiya Parveen , Podder Vivek
Published: June 2023

Background

Schizophrenia is a severe mental disorder affecting millions worldwide. Family caregivers play a vital role in patient treatment and recovery, but their responsibilities can be physically and emotionally exhausting. There is limited research on caregiver burden in Bangladesh.

Purpose

This study to identify factors associated with the burden among caregivers of schizophrenic individuals.

Methods

This cross-sectional study collected data from 175 caregivers from January to December 2020 in Dhaka, Bangladesh. A semi-structured questionnaire and validated Bangla version of the Zarit Interview Burden scale were used to assess the burden of primary caregivers and associated factors in caring for patients with schizophrenia.

Results

Participants’ mean age was 34.02±10.45 years, with 26.9% in the 34-41 age group. 49.1% were housewives, with most earning 5000 to 15000 taka monthly. Spouses accounted for 28.6% of caregivers. Most patients had an illness duration of less than five years (66.3%). Mean ZBI score was 49.49±12.06, indicating moderate to severe burden. Factors significantly associated with caregiver burden included age, gender, occupation, income, marital status, house condition, relationship with patients, illness stage, and duration.

Conclusion

This study highlights the burden experienced by caregivers of schizophrenic patients in Bangladesh and identifies factors associated with the burden. It recommends community interventions and psychosocial provisions to address this issue and inform targeted interventions to reduce caregiver burden. These findings provide insights for a comprehensive plan to manage such cases in the future.
Octopamine integrates the status of internal energy supply into the formation of food-related memories
Authors: Berger Michael , Fraatz Michèle , Auweiler Katrin , Dorn Katharina , Khadrawe Tanna El , Scholz Henrike
Published: June 2023

The brain regulates food intake in response to internal energy demands and food availability. However, can internal energy storage influence the type of memory that is formed? We show that the duration of starvation determines whetherDrosophila melanogasterforms appetitive short-term or longer-lasting intermediate memories. The internal glycogen storage in the muscles and adipose tissue influences how intensely sucrose associated information is stored. Insulin-like signaling in octopaminergic reward neurons integrates internal energy storage into memory formation. Octopamine, in turn, suppresses the formation of long-term memory. Octopamine is not required for short-term memory, because octopamine-deficient mutants can form appetitive short-term memory for sucrose and to other nutrients depending on the internal energy status. The reduced positive reinforcing effect of sucrose at high internal glycogen levels combined with the increased stability of food-related memories due to prolonged periods of starvation could lead to increased food intake.
Aberrant functional brain network organization is associated with relapse during 1-year follow-up in alcohol-dependent patients
Authors: Böhmer Justin , Reinhardt Pablo , Garbusow Maria , Marxen Michael , Smolka Michael N. , Zimmermann Ulrich S. , Heinz Andreas , Bzdok Danilo , Friedel Eva , Kruschwitz Johann D. , Walter Henrik
Published: June 2023

Alcohol dependence (AD) is a debilitating disease associated with high relapse rates even after long periods of abstinence. Thus, elucidating neurobiological substrates of relapse risk is fundamental for the development of novel targeted interventions that could promote long-lasting abstinence. In the present study, we analyzed resting-state functional magnetic resonance imaging (rsfMRI) data from a sample of recently detoxified AD patients (n= 93) who were followed-up for 12 months after rsfMRI assessment. Specifically, we employed graph theoretic analyses to compare functional brain network topology and functional connectivity between future relapsers (REL,n= 59), future abstainers (ABS,n= 28) and age and gender matched controls (CON,n= 83). Our results suggest increased whole-brain network segregation, decreased global network integration and overall blunted connectivity strength in REL compared to CON. Conversely, we found evidence for a comparable network architecture in ABS relative to CON. At the nodal level, REL exhibited decreased integration and decoupling between multiple brain systems compared to CON, encompassing regions associated with higher-order executive functions, sensory and reward processing. Among AD patients, increased coupling between nodes implicated in reward valuation and salience attribution constitutes a particular risk factor for future relapse. Importantly, aberrant network organization in REL was consistently associated with shorter abstinence duration during follow-up, portending to a putative neural signature of relapse risk in AD. Future research should further evaluate the potential diagnostic value of the identified changes in network topology and functional connectivity for relapse prediction at the individual subject level.
Calretinin-expressing islet cells: a source of pre- and post-synaptic inhibition of non-peptidergic nociceptor input to the mouse spinal cord
Authors: Davis Olivia C. , Dickie Allen C. , Mustapa Marami B. , Boyle Kieran A. , Browne Tyler J. , Gradwell Mark A. , Smith Kelly M. , Polgár Erika , Bell Andrew M. , Kókai Éva , Watanabe Masahiko , Wildner Hendrik , Zeilhofer Hanns Ulrich , Ginty David D. , Callister Robert J. , Graham Brett A. , Todd Andrew J. , Hughes David I.
Published: June 2023

Unmyelinated non-peptidergic nociceptors (NP afferents) arborise in lamina II of the spinal cord and receive GABAergic axoaxonic synapses, which mediate presynaptic inhibition. However, until now the source of this axoaxonic synaptic input was not known. Here we provide evidence that it originates from a population of inhibitory calretinin-expressing interneurons (iCRs), which correspond to lamina II islet cells. The NP afferents can be assigned to 3 functionally distinct classes (NP1-3). NP1 afferents have been implicated in pathological pain states, while NP2 and NP3 afferents also function as pruritoceptors. Our findings suggest that all 3 of these afferent types innervate iCRs and receive axoaxonic synapses from them, providing feedback inhibition of NP input. The iCRs also form axodendritic synapses, and their targets include cells that are themselves innervated by the NP afferents, thus allowing for feedforward inhibition. The iCRs are therefore ideally placed to control the input from non-peptidergic nociceptors and pruritoceptors to other dorsal horn neurons, and thus represent a potential therapeutic target for the treatment of chronic pain and itch.
Environmental life cycle assessment of recombinant growth factor production for cultivated meat applications
Authors: Trinidad Kirsten , Ashizawa Reina , Nikkhah Amin , Semper Cameron , Casolaro Christian , Kaplan David L. , Savchenko Alexei , Blackstone Nicole Tichenor
Published: June 2023

Growth factors are critical components of current serum-supplemented and serum-free media formulations for cultivated meat production. However, growth factors have been excluded, estimated using proxies, or modeled using proprietary data in existing environmental assessments of cultivated meat products. Cell culture media has been identified as a hotspot in such studies, therefore it is important to accurately quantify the environmental impacts of growth factor supplementation. To address this gap, this study applied life cycle assessment (LCA) methodology to comparatively assess the environmental impacts of recombinant growth factor production for cultivated meat applications. Life cycle inventories were developed for four recombinant growth factors (IGF-1, FGF, TGF-ß, and PDGF) produced using a novel bench- scale process. The functional unit of the product output was selected as 1 mg of produced growth factor. The results indicate that recombinant growth factors can have significant environmental impacts within cultivated meat systems, despite being used in very small quantities. For example, the global warming potential of production of 1 mg of IGF-1, FGF, TGF-ß, and PDGF was estimated to be 0.1, 0.04, 0.2 and 0.2 kg CO2eq, respectively. Future research should explore the sustainability of producing these growth factors at scale to meet the needs of the expanding cultivated meat industry or identifying alternatives to these growth factors that have a lower impact on the environment.

Nomenclature
Computational Studies of Human Sodium/glucose cotransporters: (SGLT1), (SGLT2) and investigation of Human Sirtuins together with Polydatin
Authors: Ferrari Ivan Vito , De Gregorio Alex , Fuggetta Maria Pia , Ravagnan Giampietro
Published: June 2023

For the first time, we investigated through molecular docking analysis with Autodock Vina and Autodock 4 the Polydatin, a derivative of resveratrol, with Sodium/glucose cotransporter 2 (SGLT1) and Sodium/glucose cotransporter 2(SGLT2) and with Sirtuins proteins, reporting excellent results both in terms of binding energies scores and inhibition constant Ki. In particular, from our analyses, Polydatin appears to have an excellent energetic affinity with human SGLT2 on the one hand, and with the human Sirtuin6, even though, comparing the binding energy values with all the investigated proteins, no significant differences were found in termins of binding energies scores. An important aspect that we want to underline is that our computational analyzes, although very accurate, require investigations in Vitro, in Vivo, and clinical studies to confirm that Polydatin has a key role with SGLT2, SGLT1, and with the Sirtuin family.
Species-Specific Responses Drive Browsing Impacts on Physiological and Functional Traits inQuercus agrifoliaandUmbellularia californica
Authors: Leonard Hugh E. , Ciambrone Mary , Pittermann Jarmila
Published: June 2023

Herbivory is a fundamental ecological force in the evolution of plant physiological, morphological, and chemical attributes. In this study, we explored how browsing pressure by local deer populations affected leaf form and function in two California native tree species, coast live oak (Quercus agrifolia) and bay laurel (Umbellularia californica). Specifically, we investigated how leaf and stem vascular attributes shifted between browsed and non-browsed zones of each species and tested for differences in trait coordination as well as stem-leaf function. Browsing significantly altered traits such as leaf to phloem ratios and leaf area, but we observed few meaningful differences in leaf and stem anatomy between browsed and non-browsed material. We discuss these results in the context of such additional ecological factors and explore future research considerations for investigating leaf and stem vascular trait development with herbivore presence.
Utilizing Aggregated Molecular Phenotype (AMP) Scores to Visualize Simultaneous Molecular Changes in Mass Spectrometry Imaging Data
Authors: Chappel Jessie R. , King Mary E. , Fleming Jonathon , Eberlin Livia S. , Reif David M. , Baker Erin S.
Published: June 2023

Mass spectrometry imaging (MSI) has gained increasing popularity for tissue-based diagnostics due to its ability to identify and visualize molecular characteristics unique to different phenotypes within heterogeneous samples. Data from MSI experiments are often visualized using single ion images and further analyzed using machine learning and multivariate statistics to identifym/z features of interest and create predictive models for phenotypic classification. However, often only a single molecule orm/zfeature is visualized per ion image, and mainly categorical classifications are provided from the predictive models. As an alternative approach, we developed an aggregated molecular phenotype (AMP) scoring system. AMP scores are generated using an ensemble machine learning approach to first select features differentiating phenotypes, weight the features using logistic regression, and combine the weights and feature abundances. AMP scores are then scaled between 0 and 1, with lower values generally corresponding to class 1 phenotypes (typically control) and higher scores relating to class 2 phenotypes. AMP scores therefore allow the evaluation of multiple features simultaneously and showcase the degree to which these features correlate with various phenotypes, leading to high diagnostic accuracy and interpretability of predictive models. Here, AMP score performance was evaluated using metabolomic data collected from desorption electrospray ionization (DESI) MSI. Initial comparisons of cancerous human tissues to normal or benign counterparts illustrated that AMP scores distinguished phenotypes with high accuracy, sensitivity, and specificity. Furthermore, when combined with spatial coordinates, AMP scores allow visualization of tissue sections in one map with distinguished phenotypic borders, highlighting their diagnostic utility.
A Novel Angiogenesis Role of GLP-1(32-36) to Rescue Diabetic Ischemic Lower Limbs via GLP-1R-Dependent Glycolysis
Authors: Zhang Yikai , Wang Shengyao , Zhou Qiao , Hu Yepeng , Xie Yi , Fang Weihuan , Yang Changxin , Wang Zhe , Ye Shu , Wang Xinyi , Zheng Chao
Published: June 2023

Glucagon-like peptide 1 (GLP-1) improves angiogenesis, but the mechanism remains unclear. To address this question, we conducted a metabolomics analysis in bone marrow-derived endothelial progenitor cells (EPCs) isolated from T1DM mice treated with or without GLP-1(32-36) amide, an end-product of GLP-1. GLP-1(32-36) treatment recovered glycolysis. In addition, GLP-1(32-36) treatment rescued diabetic ischemic lower limbs and EPCs dysfunction by regulating PFKFB3-driven glycolytic flux capacity and mitochondrial dynamics. The effects of GLP-1(32-36) were abolished in mice lacking a functional GLP-1 receptor (Glp1r-/-), which could be partially rescued in EPCs transiently expressing GLP-1R. GLP-1(32-36) treatment activated the eNOS/cGMP/PKG pathway, increased glycolysis, and enhanced EPCs angiogenesis. Taken together, these findings suggest that GLP-1(32-36) could be used as a monotherapy or add-on therapy with existing treatments for DPAD.

Graphical abstract
ENPP1 is an innate immune checkpoint of the anticancer cGAMP-STING pathway
Authors: Wang Songnan , Böhnert Volker , Joseph Alby J. , Sudaryo Valentino , Swinderman Jason , B.Yu Feiqiao , Lyu Xuchao , Skariah Gemini , Subramanyam Vishvak , Gilbert Luke A. , Goodarzi Hani , Li Lingyin
Published: June 2023

ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary breast tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 that restrains their response to tumor-derived cGAMP.Enpp1loss-of-function in both cancer cells and normal tissues slowed primary tumor initiation and growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Selectively abolishing the cGAMP hydrolysis activity of ENPP1 phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. Strikingly, we find that breast cancer patients with lowENPP1expression have significantly higher immune infiltration and improved response to therapeutics impacting cancer immunity upstream or downstream of the cGAMP-STING pathway, like PARP inhibitors and anti-PD1. Altogether, selective inhibition of ENPP1’s cGAMP hydrolase activity alleviates an innate immune checkpoint to boost cancer immunity and is therefore a promising therapeutic approach against breast cancer that may synergize with other cancer immunotherapies.
Gestational exposure to bisphenol S induces microvesicular steatosis by promoting lipogenesis and inflammation in male rat offspring
Authors: Molangiri Archana , Varma Saikanth , Hridayanka Kota Sri Naga , Srinivas Myadara , Kona Suryam Reddy , Ibrahim Ahamed , Duttaroy Asim K , Basak Sanjay
Published: June 2023

Fetal exposure to endocrine-disrupting bisphenol A (BPA) showed a long-lasting programming effect on organ development and predisposed to the metabolic risk of adult diseases. However, limited data on developmental exposure to BPA-substitute bisphenol S (BPS) in predisposing liver metabolic disease is available. Here, the effects of BPS exposure were assessed on hepatic metabolism by examining adiposity and inflammation in the adipose and liver of the 90-day male offspring. Pregnant Wistar rats were exposed to BPA and BPS (0.0, 0.4, 4.0 µg/kg bw) via gavage from gestational day 4 to 21. Prenatal BPS-exposed offspring exhibited a higher obesogenic effect than BPA, including changes in body weight, body fat, feed efficiency, and leptin signalling. The fasting blood glucose did not change, but BPS exposure elevated plasma corticosterone levels and adipocyte hypertrophy of the visceral adipose tissue (VAT) to a greater extent than BPA. Adipocyte hypertrophy was augmented by modulated expression of lipid uptake (PPARγ, FABP4), glucocorticoid (HSD11β1), inflammation (IL6, IL1β, CRP, COX2), oxidative stress (CHOP) and apoptotic (Caspase 3) mediators. Liver histology showed numerous lipid droplets, and hepatocyte ballooning, associated with upregulated expression of cholesterol, lipid biogenesis and glucocorticoid activators, indicating microvesicular steatosis in the prenatally BPS-exposed adult offspring. The upregulated PPARα, ADRP, and FGF21 expression and increased lipid peroxidation in the offspring’s liver suggest metaflammation due to fetal exposure to BPS. Fetal BPS exposure demonstrated a more significant disruption in metabolism involving adiposity, liver fat, inflammation in excess, and predisposition to hepatic steatosis in the male offspring.

Highlights

Fetal BPS exposure exhibited enlarged and inflamed adipocytes more than BPA

Prenatal BPS exposure induced excess lipid droplets & hepatocyte ballooning in liver

In utero exposure to BPS induces microvesicular steatosis in adult rats
Spatial redundancy transformer for self-supervised fluorescence image denoising
Authors: Li Xinyang , Hu Xiaowan , Chen Xingye , Fan Jiaqi , Zhao Zhifeng , Wu Jiamin , Wang Haoqian , Dai Qionghai
Published: June 2023

Fluorescence imaging with high signal-to-noise ratios has become the foundation of accurate visualization and analysis of biological phenomena. However, the inevitable photon shot noise poses a formidable challenge on imaging sensitivity. In this paper, we provide a spatial redundancy denoising transformer (SRDTrans) to remove noise from fluorescence images in a self-supervised manner. First, a sampling strategy based on spatial redundancy is proposed to extract adjacent orthogonal training pairs, which eliminates the dependence on high imaging speed. Secondly, to break the performance bottleneck of convolutional neural networks (CNNs), we designed a lightweight spatiotemporal transformer architecture to capture long-range dependencies and high-resolution features at a low computational cost. SRDTrans can overcome the inherent spectral bias of CNNs and restore high-frequency information without producing over-smoothed structures and distorted fluorescence traces. Finally, we demonstrate the state-of-the-art denoising performance of SRDTrans on single-molecule localization microscopy and two-photon volumetric calcium imaging. SRDTrans does not contain any assumptions about the imaging process and the sample, thus can be easily extended to a wide range of imaging modalities and biological applications.
Shared genetic risk factors and their implications for treatment of IPF and systemic hypertension
Authors: Parcesepe Gina , Allen Richard J , Guillen-Guio Beatriz , Moss Samuel , Jenkins R Gisli , Wain Louise V
Published: June 2023

More than 50% of individuals with idiopathic pulmonary fibrosis (IPF) have co-morbid hypertension. High blood pressure can lead to organ fibrosis or can be a consequence of artery stiffening due to fibrosis. Studies have implicated common processes, such as TGF-β signalling, in both traits’ regulation. Our goal is to identify shared genetic risk factors for IPF and hypertension.

We analysed the genome-wide genetic correlation using LD Score Regression and the largest available genome-wide association studies of clinically defined IPF, and systolic and diastolic blood pressure (SBP and DBP, respectively). We then conducted a genome-wide colocalisation analysis to identify regions with a shared signal at P<10−5between IPF and either SBP or DBP.

There was no genome-wide correlation between IPF and SBP (correlation (95% CI) -0.077(−0.142, -0.011), P=0.022) or DBP (correlation (95% CI) -0.027(−0.093, 0.039), P=0.427). The genome-wide colocalisation identified 8 shared signals, 3 (nearMAD1L1, GOLPH3L/HORMAD1, and at 17q21.31) had the same direction of effect on risk of IPF and hypertension and 5 (nearTERC, OBFC1, DEPTOR, and at 7q22.1 and 6p21.2) had opposite effects.

These findings support that there may be shared fibrotic mechanisms between IPF and hypertension. The opposite effects of variants at specific loci highlight the need for caution when considering therapeutic targeting of these shared pathways for either disease.
Circulating H3K27 Methylated Nucleosome plasma concentration: a synergistic information with ctDNA Molecular Profiling
Authors: Grolleau Emmanuel , Candiracci Julie , Lescuyer Gaelle , Barthelemy David , Benzerdjeb Nazim , Haon Christine , Geiguer Florence , Raffin Margaux , Hardat Nathalie , Balandier Julie , Rabeuf Rémi , Chalabreysse Lara , Wozny Anne-Sophie , Rommelaere Guillaume , Rodriguez-Lafrasse Claire , Subtil Fabien , Couraud Sébastien , Herzog Marielle , Payen-Gay Lea
Published: June 2023

Background

Molecular profiling of circulating tumor DNA (ctDNA) is a helpful tool for cancer treatment indication or for the early detection of relapse. A subset of patients with advanced lung adenocarcinoma cancers (NSCLC)can be cured by immunotherapy, radiotherapy, and/or chemotherapy combined regimens, or targeted therapies depending on their ctDNA molecular profile. However, clinical interpretation of ctDNA negative result remains challenging. Cell-free DNA (cfDNA) in association with nucleosomes are released into the bloodstream upon cell death therefore the characterization of both may provide useful information for patient management., Dysregulations of epigenetic modifications, such as histone methylation, are found to play a key role in tumorigenesis of different cancers. However, the concentration of circulating nucleosomes in blood, as a biomarker of the contributive value of ctDNA molecular profiling in patient management at diagnosis or during patient follow-up has not previously been investigated.

Results

Significantly elevated concentrations of H3K27Me3-nucleosomes were found in plasmas at diagnosis and during the follow-up of NSCLC patients compared to healthy donors (median: 24ng/ml; 16.9ng/ml vs 8ng/ml, p-value<0.0001, respectively). Interestingly, by combining H3K27Me3 level and ctDNA molecular profile, we found that 25.5% of the patients had high levels of H3K27Me3 (above cut-off level at 22.5 ng/ml) and no somatic alteration detected at diagnosis. This strongly supports the presence of non-mutated ctDNA in the corresponding plasma. During patient follow-up, H3K27Me3 level was lower in ctDNA-negative group compared to ctDNA-positive group (medianctDNA-= 13.4 ng/mL vs medianctDNA+ = 26.1 ng/mL, respectively, p_value<0.0001). In 41.8% of the samples, no somatic mutation and low level of H3K27Me3-nucleosomes were observed suggesting molecular indicator of treatment response. In contrast, high H3K27Me3-nucleosome level was found in 15.1% of the sample despite no somatic mutations being detected allowing the identification of disease progression from 43.1% to 58.2% over molecular profiling alone.

Conclusion

Measuring H3K27Me3-nucleosome levels in combination with ctDNA molecular profiling may not only improve confidence in the negative molecular result in cfDNA in lung cancer at diagnosis, it may also be a promising biomarker for Molecular Residual Disease (MRD) monitoring during and/or after treatment.
The Medical Knowledge Oligarchies
Authors: Matos João , Nakayama Luis , Charpignon Marie-Laure , Gallifant Jack , Kashkooli Mohammad , Carli Francesco , Celi Leo Anthony
Published: June 2023

Introduction

Healthcare policies and clinical decisions heavily rely on research publications from high-impact medical journals. A lack of author diversity in medical publications poses a risk to underrepresented groups. To promote equity in healthcare medical decisions, fostering collaborations within research groups is crucial. This study integrates scientometrics with network analysis to uncover intricate co-authorship networks and examine diversity and inclusion in scientific collaboration.

Methods

The authors’ metadata from five high-impact medical journals were collected, and a weighted graph of co-authorships was constructed. The study addresses four research questions: identifying influential authors, exploring research output communities, analyzing collaboration patterns, and examining the evolution of collaboration over time.

Results

Central nodes are significantly more likely to be male or from high-income countries. Further, when evaluated over time, the graph reveals concerning trends in diversity where collaboration with authors from lower income countries is not growing. All code is publicly available on GitHub.

Discussion

The findings underscore the need to promote diversity within research niches and question the role of gatekeepers in facilitating inclusivity. Future studies should expand the scope of network analysis and explore additional factors such as funding sources and guidelines.

Conclusion

Overall, this study contributes a framework for auditing diversity and inclusion in scientific collaboration, aiming to promote transparency and a more equitable medical knowledge production system.
Cardioprotective effect of the low energy extracorporeal shock wave on the doxorubicin-induced cardiomyopathy in breast cancer patients
Authors: Song Shinjeong , Woo Joohyun , Kim HyunGoo , Lee Jun Woo , Lim Woosung , Moon Byung-In , Kwon Kihwan
Published: June 2023

Background

Doxorubicin is a highly effective anti-cancer drug but causes left ventricular (LV) dysfunction, and also induces late-onset cardiomyopathy. Extensive research has been done and is being done to discover preventive treatments. However, an effective and clinically applicable preventive treatment is yet to be discovered. Cardiac Extracorporeal shock waves therapy (C-ESWT) has been suggested to treat inflammatory and ischemic diseases and protect cardiomyocytes from doxorubicin-induced cardiomyopathy. The aim of this study is to assess the safety and efficacy of C-ESWT in treating patients with doxorubicin.

Methods

A single-center, randomized, prospective controlled study to evaluate the prevention and safety of doxorubicin-induced cardiomyopathy using C-ESWT was performed. We enrolled 64 breast cancer patients. C-ESWT group 33 patients were treated with our cardiac shock wave therapy (200 shots/spot at 0.09mJ/mm2 for 20 spots, 3 times a week every two-chemotherapy cycles). Efficacy endpoints were LVGLS by 2D speckle tracking echocardiography using Tomtec software and CTRCD. Echocardiography should be performed on the baseline line and every 4 cycles of chemotherapy, followed by a follow-up 3,6 months after chemotherapy to compare the incidence of cardiomyopathy of subclinical LV dysfunction due to chemotherapy between the two groups. CTRCD was defined as a reduction in LV ejection fraction (EF) from a baseline greater than 10% to less than 55% and subclinical CTRCD was defined as a GLS reduction of ≥ 15% compared to the baseline value.

Results

Participants averaged 50±9 years in age, 100% female. In the results of follow-up 6 months after the end of chemotherapy, there was a significant difference in delta LVGLS between the ESW group and the control group (EF; -0.2±7.7% vs. -3.7±14.2 p-value; 0.076, GLS; -1.2±9.3% vs. -11.2±9.5% p-value; <0.001). In the control group, 2 patients developed CTRCD. A total of 27% (14 patients) of patients developed subclinical LV dysfunction (Control group; 11 vs. ESW group; 3). ESW therapy was performed safely without any serious adverse events.

Conclusion

In this prospective study, C-ESWT established efficacy in preventing CRTCD as well as chemotherapy-induced cardiomyopathy using doxorubicin chemotherapy and the safety of C-ESWT use in breast cancer patients.
The associations of long-term physical activity in adulthood with later biological ageing and all-cause mortality – a prospective twin study
Authors: Kankaanpää Anna , Tolvanen Asko , Joensuu Laura , Waller Katja , Heikkinen Aino , Kaprio Jaakko , Ollikainen Miina , Sillanpää Elina
Published: June 2023

Objectives

The association between leisure-time physical activity (LTPA) and a lower risk of mortality is susceptible to bias from multiple sources. We investigated the potential of biological ageing to mediate the association between long-term LTPA and mortality and whether the methods used to account for reverse causality affect the interpretation of this association.

Methods

Study participants were twins from the older Finnish Twin Cohort (n=22,750; 18–50 years at baseline). LTPA was assessed using questionnaires in 1975, 1981 and 1990. The mortality follow-up lasted until 2020 and biological ageing was assessed using epigenetic clocks in a subsample (n=1,153) with blood samples taken during the follow-up. Using latent profile analysis, we identified classes with distinct longitudinal LTPA patterns and studied differences in biological ageing between these classes. We employed survival models to examine differences in total, short-term and long-term all-cause mortality, and multilevel models for twin data to control for familial factors.

Results

We identified four classes of long-term LTPA: sedentary, moderately active, active and highly active. Although biological ageing was accelerated in sedentary and highly active classes, after adjusting for other lifestyle-related factors, the associations mainly attenuated. Physically active classes had a maximum 7% lower risk of total mortality over the sedentary class, but this association was consistent only in the short term and could largely be accounted for by familial factors. LTPA exhibited less favourable associations when prevalent diseases were exclusion criteria rather than covariate.

Conclusion

Being active may reflect a healthy phenotype instead of causally reducing mortality.
Development of MAPT S305 mutation models exhibiting elevated 4R tau expression, resulting in altered neuronal and astrocytic function
Authors: Bowles KR , Pugh DA , Pedicone C , Oja L , Weitzman SA , Liu Y , Chen JL , Disney MD , Goate AM
Published: June 2023

Due to the importance of 4R tau in the pathogenicity of primary tauopathies, it has been challenging to model these diseases in iPSC-derived neurons, which express very low levels of 4R tau. To address this problem we have developed a panel of isogenic iPSC lines carrying theMAPTsplice-site mutations S305S, S305I or S305N, derived from four different donors. All three mutations significantly increased the proportion of 4R tau expression in iPSC-neurons and astrocytes, with up to 80% 4R transcripts in S305N neurons from as early as 4 weeks of differentiation. Transcriptomic and functional analyses of S305 mutant neurons revealed shared disruption in glutamate signaling and synaptic maturity, but divergent effects on mitochondrial bioenergetics. In iPSC-astrocytes, S305 mutations induced lysosomal disruption and inflammation and exacerbated internalization of exogenous tau that may be a precursor to the glial pathologies observed in many tauopathies. In conclusion, we present a novel panel of human iPSC lines that express unprecedented levels of 4R tau in neurons and astrocytes. These lines recapitulate previously characterized tauopathy-relevant phenotypes, but also highlight functional differences between the wild type 4R and mutant 4R proteins. We also highlight the functional importance ofMAPTexpression in astrocytes. These lines will be highly beneficial to tauopathy researchers enabling a more complete understanding of the pathogenic mechanisms underlying 4R tauopathies across different cell types.
Mechanical Force Works as a Biological Cue in Postnatal Murine Tendon Development
Authors: Usami Yuna , Jiang Xi , Dyment Nathaniel A , Kokubun Takanori
Published: June 2023

The musculoskeletal system provides structural stability and coordination to enable movement. Tendons have the essential role of efficiently transmitting force generated from muscle contraction to bone to enable ambulation. In doing so, they resist high external forces. In fact, muscle contraction during embryonic development is required to maintain tendon growth and differentiation. Nonetheless, defining the types and magnitudes of loads that act on tendons during embryonic and early postnatal periods is quite difficult. In this study, we aimed to define the physiologic limb movement and forces experienced during these stages in the murine model. We found that late-stage embryos had limited amniotic space, which attenuated limb movement. In the neonatal phase, physical ability, as measured by rollover function and locomotion, increased. These changes, which likely corresponded to increased forces applied to the tendons, corresponded with the expression of tenogenic markers during the embryo to postnatal phase. In particular, we found that the upregulation ofScxandTnmdcorrelated with increased movement during the two weeks after birth. Our results help define the spatiotemporal role of mechanical force, including internal and external factors, in tendon growth and development.

Highlights

Assessed limb movement in amnion.

Space limitation attenuated limb movement in the late-stage embryos.

Defined the mechanical force from the limb’s physiological environment.

Scx and Tnmd were upregulated synchronically with rollover function and locomotion.

Mechanical forces may work as the cue of tendon development
Jaw size variation is associated with a novel craniofacial function for galanin receptor 2 in an adaptive radiation of pupfishes
Authors: Palominos M. Fernanda , Muhl Vanessa , Richards Emilie J. , Miller Craig T. , Martin Christopher H.
Published: June 2023

Understanding the genetic basis of novel adaptations in new species is a fundamental question in biology that also provides an opportunity to uncover new genes and regulatory networks with potential clinical relevance. Here we demonstrate a new role forgalr2in vertebrate craniofacial development using an adaptive radiation of trophic specialist pupfishes endemic to San Salvador Island in the Bahamas. We confirmed the loss of a putativeSrytranscription factor binding site in the upstream region ofgalr2in scale-eating pupfish and found significant spatial differences ingalr2expression among pupfish species in Meckel’s cartilage and premaxilla using in situ hybridization chain reaction (HCR). We then experimentally demonstrated a novel function for Galr2 in craniofacial development and jaw elongation by exposing embryos to drugs that inhibit Galr2 activity. Galr2-inhibition reduced Meckel’s cartilage length and increased chondrocyte density in both trophic specialists but not in the generalist genetic background. We propose a mechanism for jaw elongation in scale-eaters based on the reduced expression ofgalr2due to the loss of a putativeSrybinding site. Fewer Galr2 receptors in the scale-eater Meckel’s cartilage may result in their enlarged jaw lengths as adults by limiting opportunities for a postulated Galr2 agonist to bind to these receptors during development. Our findings illustrate the growing utility of linking candidate adaptive SNPs in non-model systems with highly divergent phenotypes to novel vertebrate gene functions.