bluuebunny/crossref_metadata_2025 huggingface dataset:
Network pharmacology analysis and clinical verification of Jishe Qushi capsules in rheumatoid arthritis treatment
Authors: Li Yujie , Zhang Nannan , Peng Xin , Ma Wukai , Qin Yuanxing , Yao Xueming , Huang Cong , Zhang Xudong
Published: August 2023

The study aimed to elucidate the effective chemical composition and molecular mechanism of rheumatoid arthritis (RA) treatment with Jishe Qushi capsules (JSQS) and perform clinical validation. The effective chemical components were screened by a database. We used Cytoscape software to construct the key target-RA composite target network of JSQS. Gene Ontology biofunctional analysis and Kyoto encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed for the key targets, followed by molecular docking validation of core key targets. Ninety-nine patients chosen were divided into 49 cases in the treatment group and 50 cases in the control group according to the random number table method. The control group was treated with the combination of methotrexate (MTX) plus Glucosidorum Tripterygll Totorum. The treatment group was treated with MTX plus JSQS. The treatment effects of the 2 groups were evaluated. A total of 118 key anti-RA targets were obtained for JSQS. Quercetin in Panax notoginseng, vanillic acid, scopoletin, physcion in Gardneria angustifolia, 3,5-dimethyl-4-hydroxybenzaldehyde in Zaocys dhumnades, kaempferol in Radix Paeoniae Alba, and protocatechuic aldehyde in Cibotium barometz were the main active chemical components in the composite target network. Topology analysis yields core key targets, such as TP53, INS, IL6, VEGFA, MYC, CASP3, ESR1, EGF, CCND1, PPARG, ERBB2, NFKBIA, TLR4, RELA, and CASP8, and the results of KEGG enrichment analysis showed that JSQS mainly works through pathways in cancer, phosphatidylinositol-3-kinaseRAC–serine/threonine-protein kinase signaling, and mitogen-activated protein kinase (MAPK) signaling pathway, and aryl hydrocarbon receptor nuclear translocator signaling pathway. Molecular docking results showed that the binding fraction of PPARG, VEGFA and the effective active ingredients of ridged snake dispelling capsule was >70. In the clinical trial, morning stiffness, joint pain, and VAS scores of post-treatment in the treatment group were lower than those in the control group (P < .05). Additionally, ESR, CRP, RF, anti-CCP, TNF-α, IL-6, IL-17, and Th17/Treg were lower in the treatment group than in the control group (P < .05). JSQS exert multicomponent, multipathway, and multitarget synergistic actions in RA treatment. It can significantly improve the clinical symptoms and quality of life and delay the progression of RA disease.
The effect of Baduanjin exercise on the physical and mental health of college students: A randomized controlled trial
Authors: Zhang Yaqun , Jiang Xin
Published: August 2023

Background and purpose:

Around the world, college students physical and mental health is deteriorating. Finding practical ways to enhance college students health is crucial. One of the traditional Chinese Qigong exercises is Baduanjin, which is possibly one of the most efficient workout techniques out there. However, it is unknown how Baduanjin practice may affect college students health. The purpose of this study was to evaluate the effect of Qigong Baduanjin on the physical and mental health of female college freshmen.

Materials and methods:

A total of 78 female college students were recruited and randomly divided into Baduanjin group or control group. Participants in the control group were told to keep their original habits of life and exercise. The Baduanjin exercise group received 12 weeks of Baduanjin exercise, 3 days a week and 1 hour a day. After the 12 week randomized controlled trial, the physical and mental health indexes of female students in Baduanjin group and control group were evaluated, including physical shape, physical function, physical fitness and scl-90 self-assessment scale.

Results:

Compared with the control group, at the end of the 12 week intervention, the weight, body mass index, diastolic blood pressure, systolic blood pressure, somatization score, obsessive-compulsive disorder score, interpersonal sensitivity score, depression score, anxiety score and phobic anxiety score of Baduanjin group decreased significantly. Compared with the control group, the vital capacity, vital capacity index, Stand test, Genchi test, Stand on 1 leg with closed eyes, standing bends and squats of the Baduanjin group have been significantly improved.

Conclusion:

Compared with usual activities, Qigong Baduanjin exercise has advantages in improving female college students body shape (weight and body mass index), cardiovascular and respiratory lung function, flexibility, balance ability, muscle endurance and mental health.
Pan-cancer analyses reveal GTSE1 as a biomarker for the immunosuppressive tumor microenvironment
Authors: Tan Ke , Fang Zixuan , Kong Lingzhen , Cheng Chen , Hwang Sydney , Xu Min
Published: August 2023

G2 and S phase-expressed-1 (GTSE1) has been reported to be associated with poor prognosis in many cancer types. However, the knowledge of GTSE1 across 33 cancer types remains scarce, and the mechanisms by which GTSE1 promotes cancer development remain incompletely understood. R language and TIMER2.0 were used to analyze the clinical relevance of GTSE1 across > 10,000 subjects representing 33 cancer types based on the cancer genome atlas databases. The expression of GTSE1 was upregulated in almost all cancer types and hyperactivity of GTSE1 is likely to induce DNA repair response and positively correlates with the tumor mutational burden and microsatellite instability which are both promising predictive biomarkers for immunotherapy. GTSE1 was upregulated in TP53 mutation patients. Additionally, GTSE1 also positively correlates with tumor purity and tumor infiltration of immune-suppressive myeloid-derived suppressor cells. Consistently, high expression of GTSE1 is associated with poor patient survival in many cancer types. Conclusion: Our study provides new insights into the diagnostic and prognostic role of GTSE1 in cancers and suggests therapeutic approaches for GTSE1-overexpressing cancers by targeting DNA repair response, and the tumor immune microenvironment.
Lymphatic Pathways on Indocyanine Green Lymphography in Patients with Labia Minora Hypertrophy
Authors: Yuan Ye , Li Fengyong , Zhou Yu , Li Senkai , Cao Yujiao , Liu Meichen , Li Yilin , Li Qiang
Published: August 2023

Background:

Labia minora hypertrophy (LH) is a growing aesthetic concern, yet its etiology and local lymphatic anatomy remain unclear. This study aimed to use indocyanine green (ICG) lymphography to investigate evidence of lymphedema in LH and clarify the anatomy of lymph vessels from the labia minora.

Methods:

Thirty-five patients with LH underwent preoperative ICG lymphography of their bilateral labia minora. The study reviewed demographic, ICG imaging, and measurement data to identify the characteristics of the superficial lymphatic anatomy in the labia minora.

Results:

The ICG lymphography findings revealed that 97.1% of the observed patterns were linear, and 2.9% were dermal backflow patterns. Further analysis of the linear patterns revealed the presence of 3 main superficial pathways originating from the labia minora and connecting to the labia majora and clitoral hood. These pathways were identified as the superior, median, and inferior channels. Based on the observed lymphatic mapping in the labia minora, 3 types were classified: type 1 (superior and inferior channels) accounted for 75.0% (51 sides), type 2 (median and inferior channels) accounted for 8.8% (6 sides), and type 3 (superior, median, and inferior channels) accounted for 16.2% (11 sides).

Conclusions:

The study demonstrates that ICG lymphography enables clear visualization of superficial lymph flow from the labia minora. It also suggests that lymphedema is not a common pathologic feature of LH. Understanding the lymphatic anatomy of the labia minora can provide valuable guidance for surgical interventions involving the female external genitalia.
Zanubrutinib, lenalidomide, and rituximab (ZR2 regimen) for HIV-associated diffuse large B-cell lymphoma: a real-world analysis from China
Authors: Sun Jianjun , Liu Li , Chen Jun , Wang Zhenyan , Song Wei , Qi Tangkai , Tang Yang , Xu Shuibao , Yang Junyang , Zhang Renfang
Published: August 2023

Seven patients with HIV-associated diffuse large B-cell lymphoma (HIV-DLBCL) who did not derive benefit from traditional first-line or second-line chemotherapy were all eventually treated with zanubrutinib, rituximab, and lenalidomide (the ZR2 regimen). Three patients had a complete response, three had a partial response, and one showed stable disease. The complete response rate was 42.9%, the overall response rate was 85.7%. Three patients developed either neutropenia or thrombocytopenia, and one died of lung infection 3 months after diagnosis.
Racial/ethnic disparities in estimated undiagnosed HIV infection among adolescents and adults in the United States, 2017–2021
Authors: Townes Ashley , Kota Krishna Kiran , Dailey Andre F. , Henny Kirk D.
Published: August 2023

In 2021, there were an estimated 153 500 persons aged at least 13 years with undiagnosed HIV infection. Estimated rates among Black/African American, Hispanic/Latino, and White persons were used to assess disparity trends from 2017 to 2021. Rates decreased across two absolute and relative disparity measures. Despite these declines, Black and Hispanic persons had rates 8.3 and 4.2 times the rate of White persons in 2021. Increased testing and innovative efforts are needed to address HIV-related disparities.
Home ventilation for patients with end-stage chronic obstructive pulmonary disease
Authors: Raveling Tim , Rantala Heidi A. , Duiverman Marieke L.
Published: August 2023

Purpose of the review

The number of patients with end-stage chronic obstructive pulmonary disease (COPD) treated with chronic non-invasive ventilation (NIV) has greatly increased. In this review, the authors summarize the evidence for nocturnal NIV and NIV during exercise. The authors discuss the multidisciplinary and advanced care of patients with end-stage COPD treated with NIV.

Recent findings

Nocturnal NIV improves gas exchange, health-related quality of life and survival in stable hypercapnic COPD patients. Improvements in care delivery have been achieved by relocating care from the hospital to home based; home initiation of chronic NIV is feasible, non-inferior regarding efficacy and cost-effective compared to in-hospital initiation. However, the effect of NIV on symptoms is variable, and applying optimal NIV for end-stage COPD is complex. While exercise-induced dyspnoea is a prominent complaint in end-stage COPD, nocturnal NIV will not change this. However, NIV applied solely during exercise might improve exercise tolerance and dyspnoea. While chronic NIV is often a long-standing treatment, patient expectations should be discussed early and be managed continuously during the treatment. Further, integration of advance care planning requires a multidisciplinary approach.

Although chronic NIV is an effective treatment in end-stage COPD with persistent hypercapnia, there are still important questions that need to be answered to improve care of these severely ill patients.
A minimal model of learning: quantifying the cost and benefit of learning in changing environments
Authors: Arehart Emerson , Adler Frederick R.
Published: August 2023

Many organisms have the ability to learn, but the costs and benefits of learning are difficult to quantify. We construct a minimal mathematical model of learning in which a forager attempts to maximize the amount of resources (food) it collects in a changing environment. Our model has two learning parameters:α, corresponding to the duration of the forager’s memory, andϵ, corresponding to how much the forager explores the environment to learn more about it. We analyse the effect of different regimes of environmental change on the optimal memory and exploration parametersα∗,ϵ∗. By comparing the fitness outcomes from learning foragers to the outcomes from foragers following fixed strategies, we explicitly quantify the fitness benefit (or cost) of learning as a function of environmental change. We find that in many environments, the marginal benefit of learning is surprisingly small. In every environment, it is possible to implement learning in such a way that performance is as bad or worse than following a fixed strategy. In some environments, even the best implementations of our minimal model of learning perform worse than the best fixed strategy. Finally, we find that variance in resource values negatively biases foragers’ estimates for those values, potentially explaining experimental results showing that animals prefer less variable resources.
Evolution of a cross-feeding interaction following a key innovation in a long-term evolution experiment with Escherichia coli
Authors: Turner Caroline B. , Blount Zachary D. , Mitchell Daniel H. , Lenski Richard E.
Published: August 2023

The evolution of a novel trait can profoundly change an organism’s effects on its environment, which can in turn affect the further evolution of that organism and any coexisting organisms. We examine these effects and feedbacks following the evolution of a novel function in the Long-Term Evolution Experiment (LTEE) with

Escherichia coli

. A characteristic feature of

E. coli

is its inability to grow aerobically on citrate (Cit−). Nonetheless, a Cit+ variant with this capacity evolved in one LTEE population after 31 000 generations. The Cit+ clade then coexisted stably with another clade that retained the ancestral Cit− phenotype. This coexistence was shaped by the evolution of a cross-feeding relationship based on C4-dicarboxylic acids, particularly succinate, fumarate, and malate, that the Cit+ variants release into the medium. Both the Cit− and Cit+ cells evolved to grow on these excreted resources. The evolution of aerobic growth on citrate thus led to a transition from an ecosystem based on a single limiting resource, glucose, to one with at least five resources that were either shared or partitioned between the two coexisting clades. Our findings show that evolutionary novelties can change environmental conditions in ways that facilitate diversity by altering ecosystem structure and the evolutionary trajectories of coexisting lineages.
PyHFO: Lightweight Deep Learning-powered End-to-End High-Frequency Oscillations Analysis Application
Authors: Zhang Yipeng , Liu Lawrence , Ding Yuanyi , Chen Xin , Monsoor Tonmoy , Daida Atsuro , Oana Shingo , Hussain Shaun , Sankar Raman , Aria Fallah , Engel Jerome , Staba Richard J. , Speier William , Zhang Jianguo , Nariai Hiroki , Roychowdhury Vwani
Published: August 2023

In the context of epilepsy studies, intracranially-recorded interictal high-frequency oscillations (HFOs) in EEG signals are emerging as promising spatial neurophysiological biomarkers for epileptogenic zones. While significant efforts have been made in identifying and understanding these biomarkers, deep learning is carving novel avenues for biomarker detection and analysis. Yet, transitioning such methodologies to clinical environments is difficult due to the rigorous computational needs of processing EEG data via deep learning. This paper presents our development of an advanced end to end software platform, PyHFO, aimed at bridging this gap. PyHFO provides an integrated and user-friendly platform that includes time-efficient HFO detection algorithms such as short-term energy (STE) and Montreal Neurological Institute and Hospital (MNI) detectors and deep learning models for artifact and HFO with spike classification. This application functions seamlessly on conventional computer hardware. Our platform has been validated to adeptly handle datasets from 10-minute EEG recordings captured via grid/strip electrodes in 19 patients. Through implementation optimization, PyHFO achieves speeds up to 50 times faster than the standard HFO detection method. Users can either employ our pre-trained deep learning model for their analyses or use their EEG data to train their model. As such, PyHFO holds great promise for facilitating the use of advanced EEG data analysis tools in clinical practice and large-scale research collaborations.
Young Maternal Age at first birth and Child Undernutrition in Bangladesh: Evidence from the Bangladesh Demographic Health Survey 2017-18
Authors: Hossain Md. Alamgir , Tariqujjaman Md. , Das Novel Chandra , Chandrima Rubaiya Matin , Islam S.M Hasibul , Rahman Ahmed Ehsanur , Mahmood Hassan Rushekh , Hossain Aniqa Tasnim
Published: August 2023

Background

Childhood undernutrition is a serious public health issue that includes stunting, wasting, and underweight. In Bangladesh, many adolescent girls become mothers early. Giving birth at a young age is common, adversely affecting maternal health and child undernutrition. This study investigated the association between maternal age at first birth and undernutrition of under-five children in Bangladesh.

Methods

The study is cross-sectional and data was collected from BDHS 2017–18 survey. Mothers who were pregnant at the age of ≤ 19 years were regarded as young mothers and aged >19 years were regarded as adult mothers. Children were categorized as stunting (height for age), wasting (weight for height), and underweight (weight for age) based on the z-scores -2 as per WHO median growth guidelines. Multivariate logistic regression was employed to assess the association.

Results

This study revealed that 71.5% of mothers had their first child before 19 years old. The undernutrition status of the children of younger mothers and the children of adult mothers differed significantly, stunted (p<0.001), wasted (p<0.001), and underweight (p<0.001)).

Children of mothers aged under 19 years at their 1st childbirth were 1.4 times more likely to be stunted [Adjusted odds ratio (AOR): 1.4, 95% CI: 1.02-2.46; p=0.008], 1.6 times more likely to be wasted (AOR: 1.6; 95% CI: 1.09-1.78; p=0.039), 1.5 times more likely to be underweight (AOR: 1.5, 95% CI: 1.15-2.07; p=0.004) compared to children of mothers who are adults.

Conclusion

This research will draw attention to the policymakers taking the necessary initiatives focus on the maternal age at the time of first birth, which will help reduce all forms of undernutrition in under-five children.
Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group
Authors: Otth Maria , Kasteler Rahel , Mulder Renée L. , Agrusa Jennifer , Armenian Saro H. , Barnea Dana , Bergeron Anne , Bhatt Neel S. , Bourke Stephen J. , Constine Louis S. , Goutaki Myrofora , Green Daniel M. , Hennewig Ulrike , Houdouin Veronique , Hudson Melissa M. , Kremer Leontien , Latzin Philipp , Ng Antony , Oeffinger Kevin C. , Schindera Christina , Skinner Roderick , Sommer Grit , Srinivasan Saumini , Stokes Dennis C. , Versluys Birgitta , Waespe Nicolas , Weiner Daniel J. , Dietz Andrew C. , Kuehni Claudia E.
Published: August 2023

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence, our panel currently recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.
Impact of the COVID-19 Pandemic on Same-day Discharge Adoption Following Percutaneous Coronary Intervention for Stable CAD: A National Time Series Analysis
Authors: Thangam Manoj , Grzeskowiak Michael , Masoudi Frederick A , Bunte Matthew C , Fry Edward , Pirwitz Mark , Ottenbacher Allison , Perez Ana Cristina , Miller Collin , Benedict Sarah , Amin Amit , Parikh Sahil A. , Monteleone Peter
Published: August 2023

Background

Elective percutaneous coronary intervention (PCI) historically required hospitalization post procedure. Same day discharge (SDD) has emerged as a safe and cost efficient option, although the impact of the coronavirus disease of 2019 (COVID-19) pandemic on rates of SDD and associated care episode costs remains uncertain.

Methods

A national sample of consecutive patients undergoing elective PCI at 42 hospitals (Ascension, St.Louis, MO) between May 2019 to April 2021 were identified using internal registry data and administrative claims data. Rates of SDD before and after the COVID-19 pandemic (March 2020) were compared using multivariable logistic regression adjusted for patient and procedural characteristics. Additionally, an interrupted time series model was used to determine the effect of the pandemic and policy on SDD rates before and after pandemic declaration. Lastly, we estimated total costs per PCI episode in pre and post pandemic periods.

Results

In total, 12,740 interventions were performed within 42 Ascension facilities that met study eligibility criteria (5955 PCI prior to the pandemic and 6785 after). Demographic data were similar between both populations although higher rates of dyslipidemia, prior myocardial infarction, and heart failure history were noted in the post pandemic group. Pandemic declaration was associated with a higher likelihood of SDD (OR 2.09, CI 1.93-2.25, p < 0.001). From pre-pandemic to post-pandemic, mean SDD rose from 34% to 45% (p< 0.001) with an accelerated monthly SDD adoption rate after the pandemic (0.1% per month vs 1.0% per month, p=0.02). Total costs per episode were $679.52 (95% CI $476.12 – $882.92, p < 0.001) higher in the post-pandemic period, driven by increased material costs. SDD was associated with a $2137.05 (95% CI $1925.03 – $2349.07, p < 0.001) reduction in costs relative to non-SDD episodes throughout the study period.

Conclusion

Among a large national risk-adjusted sample of consecutive patients, the COVID-19 pandemic accelerated adoption of SDD. As a care strategy, SDD was associated with reduced episode costs during elective PCI in the post-pandemic period.
Structural and biophysical analysis of aHaemophilus influenzaetripartite ATP-independent periplasmic (TRAP) transporter
Authors: Currie Michael J. , Davies James S. , Scalise Mariafrancesca , Gulati Ashutosh , Wright Joshua D. , Newton-Vesty Michael C. , Abeysekera Gayan S. , Subramanian Ramaswamy , Wahlgren Weixiao Y. , Friemann Rosmarie , Allison Jane R. , Mace Peter D. , Griffin Michael D.W. , Demeler Borries , Wakatsuki Soichi , Drew David , Indiveri Cesare , Dobson Renwick C.J. , North Rachel A.
Published: August 2023

Tripartite ATP-independent periplasmic (TRAP) transporters are secondary-active transporters that receive their substrates via a soluble binding protein to move bioorganic acids across bacterial or archaeal cell membranes. Recent cryo-EM structures of TRAP transporters provide a broad framework to understand how they work, but the mechanistic details of transport are not yet defined. Here we report the cryo-EM structure of theHaemophilus influenzae N-acetylneuraminate TRAP transporter (HiSiaQM) at 2.99 Å resolution (extending to 2.2 Å at the core), revealing new features. The improved resolution (the previousHiSiaQM structure is 4.7 Å resolution) permits accurate assignment of two Na+sites and the architecture of the substrate binding site, consistent with mutagenic and functional data. Moreover, rather than a monomer, theHiSiaQM structure is a homodimer. We observe lipids at the dimer interface, as well as a lipid trapped within the fusion that links the SiaQ and SiaM subunits. We show that the affinity (KD) for the complex between the solubleHiSiaP protein andHiSiaQM is in the micromolar range and that a related SiaP can bindHiSiaQM. This work provides key data that enhances our understanding of the ‘elevator-with-an-operator’ mechanism of TRAP transporters.
TESOGENASE, An Engineered Nuclease Editor for Enhanced Targeted Genome Integration
Authors: Nam Hangu , Xie Keqiang , Majumdar Ishita , Yang Shaobo , Starzyk Jakob , Lee Danna , Shan Richard , Li Jiahe , Wu Hao
Published: August 2023

Summary/Abstract

Non-viral DNA donor template has been widely used for targeted genomic integration by homologous recombination (HR). This process has become more efficient with RNA guided endonuclease editor system such as CRISPR/Cas9. Circular single stranded DNA (cssDNA) has been harnessed previously as agenome engineering catalyst(GATALYST) for efficient and safe targeted gene knock-in. However, the engineering efficiency is bottlenecked by the nucleoplasm trafficking and genomic tethering of cssDNA donor, especially for extra-large transgene integration. Here we developed enGager,enhancedGATALYSTassociatedgenomeeditor system by fusion of nucleus localization signal (NLS) peptide tagged Cas9 with various single stranded DNA binding protein modules through a GFP reporter Knock-in screening. The enGager system assembles an integrative genome integration machinery by forming tripartite complex for engineered nuclease editors, sgRNA and ssDNA donors, thereby facilitate the nucleus trafficking of DNA donors and increase their active local concentration at the targeted genomic site. When applied for genome integration with cssDNA donor templates to diverse genomic loci in various cell types, these enGagers outperform unfused editors. The enhancement of integration efficiency ranges from 1.5- to more than 6-fold, with the effect being more prominent for > 4Kb transgene knock-in in primary cells. We further demonstrated that enGager mediated enhancement for genome integration is ssDNA, but less dsDNA dependent. Using one of the mini-enGagers, we demonstrated large chimeric antigen receptor (CAR) transgene integration in primary T cells with exceptional efficiency and anti-tumor function. These tripartiteeditors withssDNAoptimizedgenomeengineering system (TESOGENASETM) add a set of novel endonuclease editors into the gene-editing toolbox for potential cell and gene therapeutic development based on ssDNA mediated non-viral genome engineering.

Highlight

A reporter Knock-in screening establishes enGager system to identify TESOGENASE editor to improving ssDNA mediated genome integration

Mini-TESOGENASEs developed by fusing Cas9 nuclease with novel ssDNA binding motifs

mRNA mini-TESOGENASEs enhance targeted genome integration via various non-viral delivery approaches

Efficient functional CAR-T cell engineering by mini-TESOGENASE
Model discovery approach enables non-invasive measurement of intra-tumoral fluid transport in dynamic MRI
Authors: Woodall Ryan T. , Esparza Cora C. , Gutova Margarita , Wang Maosen , Cunningham Jessica J. , Brummer Alexander B. , Stine Caleb A. , Brown Christine C. , Munson Jennifer M. , Rockne Russell C.
Published: August 2023

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a routine method to non-invasively quantify perfusion dynamics in tissues. The standard practice for analyzing DCE-MRI data is to fit an ordinary differential equation to each voxel. Recent advances in data science provide an opportunity to move beyond existing methods to obtain more accurate measurements of fluid properties. Here, we developed a localized convolutional function regression that enables simultaneous measurement of interstitial fluid velocity, diffusion, and perfusion in 3D. We validated the method computationally and experimentally, demonstrating accurate measurement of fluid dynamicsin situandin vivo. Applying the method to human MRIs, we observed tissue-specific differences in fluid dynamics, with an increased fluid velocity in breast cancer as compared to brain cancer. Overall, our method represents an improved strategy for studying interstitial flows and interstitial transport in tumors and patients. We expect that it will contribute to the better understanding of cancer progression and therapeutic response.

One-Sentence Summary

A physics-informed computational method enables accurate and efficient measurement of fluid dynamics in individual patient tumors and demonstrates differences between tissues.
Exploring the Residue-Level Interactions between the R2ab Protein and Polystyrene Nanoparticles
Authors: Somarathne Radha P. , Misra Sandeep K. , Kariyawasam Chathuri S. , Kessl Jacques J. , Sharp Joshua S. , Fitzkee Nicholas C.
Published: August 2023

In biological systems, proteins can bind to nanoparticles to form a “corona” of adsorbed molecules. The nanoparticle corona is of high interest because it impacts the organism’s response to the nanomaterial. Understanding the corona requires knowledge of protein structure, orientation, and dynamics at the surface. Ultimately, a residue-level mapping of protein behavior on nanoparticle surfaces is needed, but this mapping is difficult to obtain with traditional approaches. Here, we have investigated the interaction between R2ab and polystyrene nanoparticles (PSNPs) at the level of individual residues. R2ab is a bacterial surface protein fromStaphylococcus epidermidisand is known to interact strongly with polystyrene, leading to biofilm formation. We have used mass spectrometry after lysine methylation and hydrogen-deuterium exchange (HDX) NMR spectroscopy to understand how the R2ab protein interacts with PSNPs of different sizes. Through lysine methylation, we observe subtle but statistically significant changes in methylation patterns in the presence of PSNPs, indicating altered protein surface accessibility. HDX measurements reveal that certain regions of the R2ab protein undergo faster exchange rates in the presence of PSNPs, suggesting conformational changes upon binding. Both results support a recently proposed “adsorbotope” model, wherein adsorbed proteins consist of unfolded anchor points interspersed with regions of partial structure. Our data also highlight the challenges of characterizing complex protein-nanoparticle interactions using these techniques, such as fast exchange rates. While providing insights into how proteins respond to nanoparticle surfaces, this research emphasizes the need for advanced methods to comprehend these intricate interactions fully at the residue level.

TOC Image

Lysine methylation and hydrogen-deuterium exchange can reveal useful structural details about protein adsorption to nanoparticle surfaces.
Differentiation of Wharton’s Jelly-derived mesenchymal stem cells into insulin-producing beta cells with the enhanced functional level on electrospun PRP-PVP-PCL/PCL nanofibers scaffold
Authors: Hashemi Seyed Mohammad Javad , Enderami Seyed Ehsan , Barzegar Ali , Mansour ReyhanehNassiri
Published: August 2023

Diabetes is a global problem that threatens human health. Cell therapy methods using stem cells and tissue engineering of pancreatic islets as new therapeutic approaches have increased the chances of successful diabetes treatment. In this study, to differentiate Wharton’s Jelly-derived mesenchymal stem cells (WJ-MSCs) into insulin-producing cells (IPCs) with improved maturity and function, platelet-rich plasma (PRP)-Polyvinylpyrrolidone (PVP)-Polycaprolactone (PCL)/PCL nanofiber scaffold was designed and used. WJ-MSCs-derived IPCs on PRP-PVP-PCL/PCL scaffold took round cluster morphology, which is the typical morphology of pancreatic islets. Real-time PCR, immunocytochemistry, and flow cytometry data showed a significant increase in pancreatic marker genes and insulin in WJ-MSCs-derived IPCs on the PRP-PVP-PCL/PCL scaffold compared to the two-dimensional (2D) experimental group. Also, using the ELISA assay, a significant increase in the secretion of insulin and C-peptide was measured in the WJ-MSCs-derived IPCs of the three-dimensional (3D) experimental group compared to the 2D experimental group, which indicated a significant improvement in the functional level of the WJ-MSCs-derived IPCs in the 3D group. The results showed that the PRP-PVP-PCL/PCL scaffold can provide an ideal microenvironment for the engineering of pancreatic islets and the generation of IPCs.
Nanobodies counteract the toxicity of an amyloidogenic light chain by stabilizing a partially open dimeric conformation
Authors: Luca Broggini , Maria Barzago Monica , Valentina Speranzini , Tim Schulte , Federica Sonzini , Matteo Giono , Margherita Romeo , Paolo Milani , Serena Caminito , Giulia Mazzini , Paola Rognoni , Giampaolo Merlini , Carlo Pappone , Luigi Anastasia , Mario Nuvolone , Giovanni Palladini , Luisa Diomede , Stefano Ricagno
Published: August 2023

Light chain amyloidosis (AL) is a systemic disease where fibrillar deposition of misfolded immunoglobulin light chains (LCs) severely affects organ function and results in poor prognosis for patients, especially when heart involvement is severe. Particularly relevant in this context is the cardiotoxicity exerted by still uncharacterized soluble LC species. Here, with the final goal of identifying alternative therapeutic strategies to tackle AL amyloidosis, we produced five llama-derived nanobodies (Nbs) specific against H3, a well-characterized amyloidogenic and cardiotoxic LC from an AL patient with severe cardiac involvement. We found that Nbs are specific and potent agents capable of abolishing H3 soluble toxicity inC. elegans in vivomodel. Structural characterization of H3-Nb complexes revealed that the protective effect of Nbs is related to their ability to bind to the H3 VLdomain and stabilise an unexpected partially open LC dimer in which the two VLdomains no longer interact with each other. Thus, while identifying potent inhibitors of LC soluble toxicity, we also describe the first non-native structure of an amyloidogenic LC that may represent a crucial step in toxicity and aggregation mechanisms.
PKC modulator bryostatin-1 therapeutically targets CNS innate immunity to attenuate neuroinflammation and promote remyelination
Authors: Gharibani Payam , Abramson Efrat , Shanmukha Shruthi , Smith Matthew D. , Godfrey Wesley H. , Lee Judy J. , Hu Jingwen , Baydyuk Maryna , Dorion Marie-France , Deng Xiaojing , Guo Yu , Hwang Soonmyung , Huang Jeffrey K. , Calabresi Peter A. , Kornberg Michael D. , Kim Paul M.
Published: August 2023

In multiple sclerosis (MS), microglia and macrophages within the central nervous system (CNS) play an important role in determining the balance between myelin repair and demyelination/neurodegeneration. Phagocytic and regenerative functions of these CNS innate immune cells support remyelination, whereas chronic and maladaptive inflammatory activation promotes lesion expansion and disability, particularly in the progressive forms of MS. No currently approved drugs convincingly target microglia and macrophages within the CNS, contributing to the critical lack of therapies promoting remyelination and slowing progression in MS. Here, we found that the protein kinase C (PKC)-modulating drug bryostatin-1 (bryo-1), a CNS-penetrant compound with an established human safety profile, produces a shift in microglia and CNS macrophage transcriptional programs from pro-inflammatory to regenerative phenotypes, both in vitro and in vivo. Treatment of microglia with bryo-1 prevented the activation of neurotoxic astrocytes while stimulating scavenger pathways, phagocytosis, and secretion of factors that promote oligodendrocyte differentiation. In line with these findings, systemic treatment with bryo-1 augmented remyelination following a focal demyelinating injury in vivo. Our results demonstrate the potential of bryo-1 and functionally related PKC modulators as myelin regenerative and neuroprotective agents in MS and other neurologic diseases through therapeutic targeting of microglia and CNS-associated macrophages.

One Sentence Summary

PKC modulation in CNS innate immune cells favors the activation of a beneficial phenotype that promotes myelin regeneration and neuroprotection.
Behavioural, physiological, and genetic drivers of coping
Authors: Bhattacharjee Debottam , Guðjónsdóttir Aníta Rut , Chova Paula Escriche , Middelburg Esmee , Jäckels Jana , de Groot Natasja G. , Wallner Bernard , Massen Jorg J.M. , Pflüger Lena S.
Published: August 2023

Animals regularly experience stressful situations, ranging from predation to social stress, yet successfully deal with them on most occasions. This adaptive mechanism, coping, reduces the adverse effects of stressors through behavioural and physiological efforts, failing to which may result in reduced fitness. However, considerable variation in coping is observed. Unlike in humans, coping is often considered a personality trait in non-human animals due to construct similarity, resulting in conceptual ambiguity. Besides, limited multidisciplinary research has rendered comprehending the drivers of coping in animals challenging. We assessed repetitive behavioural coping or coping styles (n=30), emotional arousal (n=12), and consistent inter-individual differences, i.e., personalities (n=32) of long-tailed macaques (Macaca fascicularis) using observations, ecologically relevant experiments, and infrared thermography. We finally investigated the association of coping with a Valine/Methionine polymorphism encoded by the Catechol-O-methyltransferase (COMT) gene (n=26), which is widely known for its involvement in human stress regulation. Our findings suggest that personality and the presence of the human equivalentCOMTVal158Met polymorphism in long-tailed macaques are associated with ‘emotion-focused’ and ‘problem-focused’ coping styles. These coping styles were consistent with emotional arousal as measured with infrared thermography. We discuss these proximate drivers of coping for a better understanding of its evolution in primates.
Large-scale analyses reveal the contribution of adaptive evolution in pathogenic and non-pathogenic fungal species
Authors: Pereira Danilo , Bolton Melvin D , Friesen Timothy L , Stephan Wolfgang , Dutheil Julien Y , Stukenbrock Eva H
Published: August 2023

Genome studies of fungal pathogens have presented evidence for exceptionally high rates of evolution. It has been proposed that rapid adaptation is a hallmark of pathogen evolution that facilitates the invasion of new host niches and the overcoming of intervention strategies such as fungicide applications and drug treatments. To which extent high levels of genetic variation within and between species correlate with adaptive protein evolution in fungi more generally has so far not been explored. In this study, we addressed the contribution of adaptive evolution relative to genetic drift in 20 fungal species, hereby exploring genetic variation in 2,478 fungal genomes. We reannotated positions of protein-coding genes to obtain a high-quality dataset of 234,427 full-length core gene and 25,612 accessory gene alignments. We applied an extension of the McDonald-Kreitman test that models the distributions of fitness effects to infer the rate of adaptive (ωA) and non-adaptive (ωNA) non-synonymous substitutions in protein-coding genes. To explore the relevance of recombination on local adaptation rates, we inferred the population genomic recombination rate for all 20 species. Our analyses reveal extensive variation in rates of adaptation and show that high rates of adaptation are not a hallmark of a pathogenic lifestyle. Up to 83% of non-synonymous substitutions are adaptive in the speciesParastagonospora nodorum. However, non-synonymous substitutions in other species, including the prominent rice-infecting pathogenMagnaporthe oryzae, are predominantly non-adaptive (neutral or slightly deleterious). Correlating adaptation measures with effective population size and recombination rate, we show that effective population size is a primary determinant of adaptive evolution in fungi. At the genome scale, recombination rate variation explains variation in both ωAand ωNA. Finally, we demonstrate the robustness of our estimates using simulations. We underline the value of population genetic principles in studies of fungal evolution, and we highlight the importance of demographic processes in adaptive evolution of pathogenic and non-pathogenic species.
A viral vector model for circuit-specific synucleinopathy
Authors: Lantheaume Alexia , Schöneberg Nina , Rodriguez-Rozada Silvia , Doll Dennis , Schellenberger Michael , Kobel Konstantin , Katzenberger Kilian , Signoret-Genest Jérémy , Tissone Angela Isabel , Ip Chi Wang , Esposito Maria Soledad , Tovote Philip
Published: August 2023

In Parkinson’s disease (PD), pathomechanisms such as aberrant network dysfunctions can be elucidated by conducting multiscale explorations in animal models. However, the lack of specificity in the existing models limits a restricted targeting of individual network elements and characterization of PD as a “circuitopathy”. We therefore developed a cell-type specific viral vector (AAV2/9-CreON-A53T-αSyn) mouse model that allows to induce synucleinopathy within individual circuit elementsin vivo. When specifically targeted to dopaminergic (DA) neurons of the substantia nigra pars compacta (SNc), our approach recapitulates the main hallmarks of the disease, namely Lewy-body-like aggregation, progressive cellular and nigrostriatal projections loss, together with locomotor impairment. Our strategy is supported by new state-of-the-art analytical approaches for cell quantification and behavior characterization. Altogether, we provide a novel model of synucleinopathy, which offers new opportunities to study the contribution of individual network elements to disease pathomechanisms.
The marmoset default-mode network identified by deactivations in task-based fMRI studies
Authors: Dureux Audrey , Zanini Alessandro , Schaeffer David J. , Johnston Kevin , Gilbert Kyle M. , Everling Stefan
Published: August 2023

Understanding the default-mode network (DMN) in the common marmoset (Callithrix jacchus) has been challenging due to inconsistencies with human and marmoset DMNs. By analyzing task-negative activation in fMRI studies, we identified medial prefrontal cortical areas, rostral auditory areas, entorhinal cortex, posterior cingulate cortex area 31, hippocampus, hypothalamus, and basomedial amygdala as marmoset DMN components. Notable, medial and posterior parietal areas that were previously hypothesized to be part of the DMN were activated during visual task blocks. Seed analysis using resting-state fMRI showed strong connectivity between task-negative areas, and tracer data supported a structural network aligning with this functional DMN. These findings challenge previous definition of the marmoset DMN and reconcile many inconsistencies with the DMNs observed in humans, macaque monkeys, and even rodents. Overall, these results highlight the marmoset as a powerful model for DMN research, with potential implications for studying neuropsychiatric disorders where DMN activity and connectivity are altered.
Methods for evaluating unsupervised vector representations of genomic regions
Authors: Zheng Guangtao , Rymuza Julia , Gharavi Erfaneh , LeRoy Nathan J. , Zhang Aidong , Sheffield Nathan C.
Published: August 2023

Representation learning models have become a mainstay of modern genomics. These models are trained to yield vector representations, or embeddings, of various biological entities, such as cells, genes, individuals, or genomic regions. Recent applications of unsupervised embedding approaches have been shown to learn relationships among genomic regions that define functional elements in a genome. Unsupervised representation learning of genomic regions is free of the supervision from curated metadata and can condense rich biological knowledge from publicly available data to region embeddings. However, there exists no method for evaluating the quality of these embeddings in the absence of metadata, making it difficult to assess the reliability of analyses based on the embeddings, and to tune model training to yield optimal results. To bridge this gap, we propose four evaluation metrics: the cluster tendency score (CTS), the reconstruction score (RCS), the genome distance scaling score (GDSS), and the neighborhood preserving score (NPS). The CTS and RCS statistically quantify how well region embeddings can be clustered and how well the embeddings preserve information in training data. The GDSS and NPS exploit the biological tendency of regions close in genomic space to have similar biological functions; they measure how much such information is captured by individual region embeddings in a set. We demonstrate the utility of these statistical and biological scores for evaluating unsupervised genomic region embeddings and provide guidelines for learning reliable embeddings.

Availability

Code is available athttps://github.com/databio/geniml
Epigenome-wide profiling in the dorsal raphe nucleus highlights cell-type-specific changes inTNXBin Alzheimer’s disease
Authors: Riemens RJM , Pishva E , Iatrou A , Roubroeks J , Nolz J , Lardenoije R , Ali M , Del Sol A , Delgado-Morales R , Esteller M , Kenis G , Rutten BPF , Lesch KP , Ginsberg SD , Coleman P , Mill J , Mastroeni D , Ramirez A , Haaf T , Lunnon K , van den Hove DLA
Published: August 2023

Recent studies have demonstrated that the dorsal raphe nucleus (DRN) is among the first brain regions affected in Alzheimer’s disease. Hence, in this study we conducted the first comprehensive epigenetic analysis of the DRN in AD, targeting both bulk tissue and single isolated cells. The Illumina Infinium MethylationEPIC BeadChip array was used to analyze the bulk tissue, assessing differentially modified positions (DMoPs) and regions (DMoRs) associated with Braak stage. The strongest Braak stage-associated DMoR inTNXBwas targeted in a second patient cohort utilizing single laser-capture microdissected serotonin-positive (5-HT+) and -negative (5-HT-) cells isolated from the DRN. Our study revealed previously identified epigenetic loci, includingTNXBandPGLYRP1, and novel loci, includingRBMXL2,CAST,GNAT1,MALAT1, andDNAJB13. Strikingly, we found that the methylation profile ofTNXBdepends both on disease phenotype and cell type analyzed, emphasizing the significance of single cell(-type) neuroepigenetic studies in AD.