bluuebunny/crossref_metadata_2025 huggingface dataset:
Anisotropic microtopography surface of chitosan scaffold regulating skin precursor-derived Schwann cells towards repair phenotype promotes neural regeneration
Authors: Cong Meng , Wu Xia , Zhu Lingjie , Gu Guohao , Ding Fei , Li Guicai , Shi Haiyan
Published: January 2024

For repairing peripheral nerve and spinal cord defects, biomaterial scaffold-based cell-therapy was emerged as an effective strategy, requiring the positive response of seed cells to biomaterial substrate and environment signals. Previous work highlighted that the imposed surface properties of scaffold could provide important guidance cues to adhered cells for polarization. However, the insufficiency of native Schwann cells and unclear cellular response mechanisms remained to be addressed. Given that, this study aimed to illuminate the micropatterned chitosan-film action on the rat skin precursor-derived Schwann cells (SKP-SCs). Chitosan-film with different ridge/groove size was fabricated and applied for the SKP-SCs induction. Results indicated that SKP-SCs cultured on 30 μm size microgroove surface showed better oriented alignment phenotype. Induced SKP-SCs presented similar genic phenotype as repair Schwann cells, increasing expression of c-Jun, neural cell adhesion molecule, and neurotrophic receptor p75. Moreover, SKP-SC-secretome was subjected to cytokine array GS67 assay, data indicated the regulation of paracrine phenotype, a panel of cytokines was verified up-regulated at secreted level and gene expression level in induced SKP-SCs. These up-regulated cytokines exhibit a series of promotive neural regeneration functions, including cell survival, cell migration, cell proliferation, angiogenesis, axon growth, and cellular organization etc. through bioinformatics analysis. Furthermore, the effectively polarized SKP-SCs-sourced secretome, promoted the proliferation and migration capacity of the primarily cultured native rat Schwann cells, and augmented neurites growth of the cultured motoneurons, as well as boosted axonal regrowth of the axotomy-injured motoneurons. Taken together, SKP-SCs obtained pro-neuroregeneration phenotype in adaptive response to the anisotropic topography surface of chitosan-film, displayed the oriented parallel growth, the transition towards repair Schwann cell genic phenotype, and the enhanced paracrine effect on neural regeneration. This study provided novel insights into the potency of anisotropic microtopography surface to Schwann-like cells phenotype regulation, that facilitating to provide promising engineered cell-scaffold in neural injury therapies.
Joint involvement in sarcoidosis: systematic review and meta-analysis of prevalence, clinical pattern and outcome
Authors: Yeung Terence , Grebowicz Adrian , Nevskaya Tatiana , Zahid Sulman , Pope Janet E
Published: January 2024

Objectives

To characterize joint involvement (JI) in sarcoidosis, a systematic search of MEDLINE, EMBASE and Cochrane Library was conducted from inception to July 2022 for publications reporting its prevalence, pattern, treatment and outcome.

Methods

The pooled prevalence estimates (PPE) with 95% CI were calculated using binomial distribution and random effects. Meta-regression method was used to examine factors affecting heterogeneity between studies.

Results

Forty-nine articles were identified comprising a total of 8574 sarcoidosis patients, where 12% presented with JI (95% CI 10, 14; I2 = 0%). The PPE for sarcoid arthritis (SA) was 19% (95% CI 14, 24; I2 = 95%), and 32% (95% CI 13, 51; I2 = 99%) for arthralgia. Heterogeneity was due to higher JI prevalence reported in Western Asia and the Middle East, in rheumatology clinics and via surveys. Sample size of SA varied from 12 to 117 cases. Ankles were most frequently affected (PPE 80%) followed by knees and wrists. Monoarthritis was uncommon (PPE 1%; 95% CI 0, 2; I2 = 55%). Acute SA prevailed (PPE 79%; 95% CI 72, 88; I2 = 69%) with an equal proportion of oligo and polyarthritis and was frequently accompanied by erythema nodosum (PPE 62%; 95% CI 52, 71; I2 = 16%). Chronic SA was predominantly polyarticular with a higher frequency of the upper extremity joints affected. Most common non-articular manifestations with SA included fever (52%), erythema nodosum (41%), hilar adenopathy (86%) and interstitial lung disease (23%) of which one-third required corticosteroids and/or immunosuppressants.

Conclusion

SA occurred early in the disease with a PPE of 19% and most frequent pattern of acute oligo- or polyarthritis predominantly affecting the lower extremity large joints.
Tracing carbon and nitrogen reserve remobilization during spring leaf flush and growth following defoliation
Authors: Hart Ashley T , Landhäusser Simon M , Wiley Erin
Published: January 2024

Woody plants rely on the remobilization of carbon (C) and nitrogen (N) reserves to support growth and survival when resource demand exceeds supply at seasonally predictable times like spring leaf flush and following unpredictable disturbances like defoliation. However, we have a poor understanding of how reserves are regulated and whether distance between source and sink tissues affects remobilization. This leads to uncertainty about which reserves—and how much—are available to support plant functions like leaf growth. To better understand the source of remobilized reserves and constraints on their allocation, we created aspen saplings with organ-specific labeled reserves by using stable isotopes (13C,15N) and grafting unlabeled or labeled stems to labeled or unlabeled root stocks. We first determined which organs had imported root or stem-derived C and N reserves after spring leaf flush. We then further tested spatial and temporal variation in reserve remobilization and import by comparing (i) upper and lower canopy leaves, (ii) early and late leaves, and (iii) early flush and re-flush leaves after defoliation. During spring flush, remobilized root C and N reserves were preferentially allocated to sinks closer to the reserve source (i.e., lower vs upper canopy leaves). However, the reduced import of 13C in late versus early leaves indicates reliance on C reserves declined over time. Following defoliation, re-flush leaves imported the same proportion of root N as spring flush leaves, but they imported a lower proportion of root C. This lower import of reserve C suggests that, after defoliation, leaf re-flush rely more heavily on current photosynthate, which may explain the reduced leaf mass recovery of re-flush canopies (31% of initial leaf mass). The reduced reliance on reserves occurred even though roots retained significant starch concentrations (~5% dry wt), suggesting that aspen prioritizes the maintenance of root reserves at the expense of fast canopy recovery.
Maize Kernel-Associated Metagenomes Reveal Potential Microbe–Microbe Interactions that Underlie Fusarium Ear Rot Disease
Authors: Adams Alison , Landry Dana , Sykes Virginia , Rickman Tara , Cham Alhagie K. , Timling Annemarie , Kelly Heather , McBeath Jenifer H. , Olukolu Bode A.
Published: January 2024

As an alternative to host resistance, transgenic expression of entomocidal and antimicrobial proteins from Bacillus thuringiensis ( Bt) in maize can mitigate Fusarium ear rot (FER). This study evaluated FER in Bt and conventional maize and the role of microbes in the kernel-associated metagenome using quantitative reduced representation sequencing. Our results revealed significant differences in FER severity across environments and varieties and between inoculation treatments. The lower FER scores of conventional maize Spectrum 6416 relative to other varieties highlighted resistant alleles in maize germplasm, whereas strong correlations indicated FER-induced yield loss. Mitigation of FER by transgenes was validated by about threefold enrichment of Fusarium verticillioides ( Fv) postinoculation compared with nonsignificant Fv enrichment in conventional maize. Although the major causal pathogen of FER, Fv, was the most abundant species in the metagenomes ( r = 0.41 to 0.49), a similar degree of correlation was observed between FER and several Fusarium spp. ( r = 0.2 to 0.56). The potential FER-suppressing properties of Talaromyces stipitatus and Ustilago maydis were indicated by negative correlations with FER ( r = –0.22 to –0.42), Fv, and some Fusarium spp. The more FER-resistant varieties consistently enriched for potential FER-suppressing Burkholderia cenocepacia (negatively correlated with Fv). This suggests host genetic background-dependent recruitment of beneficial microbes that suppress pathogens and that microbe–microbe interactions play a role in FER severity. Quantitative and species/strain-level metagenomic profiles hold promise for identifying robust disease-suppressing microbes and microbes that act in synergy with pathogens and for developing holobiont-aware breeding strategies that account for host–microbiome coevolution and host genotype, microbiome/metagenome, and environment interactions.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Comparative Multi-Omics Analysis of Broomcorn Millet in Response to Anthracocystis destruens Infection
Authors: Wu Enguo , Li Xuepei , Ma Qian , Wang Honglu , Han Xiaowei , Feng Baili
Published: January 2024

Anthracocystis destruens is the causal agent of broomcorn millet ( Panicum miliaceum) smut disease, which results in serious yield losses in broomcorn millet production. However, the molecular basis underlying broomcorn millet defense against A. destruens is less understood. In this study, we investigated how broomcorn millet responds to infection by A. destruens by employing a comprehensive multi-omics approach. We examined the responses of broomcorn millet across transcriptome, metabolome, and microbiome levels. Infected leaves exhibited an upregulation of genes related to photosynthesis, accompanied by a higher accumulation of photosynthesis-related compounds and alterations in hormonal levels. However, broomcorn millet genes involved in immune response were downregulated post A. destruens infection, suggesting that A. destruens may suppress broomcorn millet immunity. In addition, we show that the immune suppression and altered host metabolism induced by A. destruens have no significant effect on the microbial community structure of broomcorn millet leaf, thus providing a new perspective for understanding the tripartite interaction between plant, pathogen, and microbiota.
Application of a U-Net Neural Network to the Puccinia sorghi–Maize Pathosystem
Authors: Holan Katerina L. , White Charles H. , Whitham Steven A.
Published: January 2024

Computer vision approaches to analyze plant disease data can be both faster and more reliable than traditional, manual methods. However, the requirement of manually annotating training data for the majority of machine learning applications can present a challenge for pipeline development. Here, we describe a machine learning approach to quantify Puccinia sorghi incidence on maize leaves utilizing U-Net convolutional neural network models. We analyzed several U-Net models with increasing amounts of training image data, either randomly chosen from a large data pool or randomly chosen from a subset of disease time course data. As the training dataset size increases, the models perform better, but the rate of performance decreases. Additionally, the use of a diverse training dataset can improve model performance and reduce the amount of annotated training data required for satisfactory performance. Models with as few as 48 whole-leaf training images are able to replicate the ground truth results within our testing dataset. The final model utilizing our entire training dataset performs similarly to our ground truth data, with an intersection over union value of 0.5002 and an F1 score of 0.6669. This work illustrates the capacity of U-Nets to accurately answer real-world plant pathology questions related to quantification and estimation of plant disease symptoms.

[Formula: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Indole Alkaloid Production by the Halo Blight Bacterium Treated with the Phytoalexin Genistein
Authors: Cooper Bret , Yang Ronghui , Campbell Kimberly B.
Published: January 2024

When Pseudomonas savastanoi pv. phaseolicola, the bacterium that causes halo blight, induces hypersensitive immunity in common bean leaves, salicylic acid and phytoalexins accumulate at the site of infection. Both salicylic acid and the phytoalexin resveratrol exert antibiotic activities and toxicities in vitro, adversely disrupting the P. savastanoi pv. phaseolicola proteome and metabolism and stalling replication and motility. These efficacious properties likely contribute to the cessation of bacterial spread in beans. Genistein is an isoflavonoid phytoalexin that also accumulates during bean immunity, so we tested its antibiotic potential in vitro. Quantitative proteomics revealed that genistein did not induce proteomic changes in P. savastanoi pv. phaseolicola in the same way that salicylic acid or resveratrol did. Rather, a dioxygenase that could function to metabolize genistein was among the most highly induced enzymes. Indeed, high-throughput metabolomics provided direct evidence for genistein catabolism. Metabolomics also revealed that genistein induced the bacterium to produce indole compounds, several of which had structural similarity to auxin. Additional mass spectrometry analyses proved that the bacterium produced an isomer of the auxin indole-3-acetic acid but not indole-3-acetic acid proper. These results reveal that P. savastanoi pv. phaseolicola can tolerate bean genistein and that the bacterium likely responds to bean-produced genistein during infection, using it as a signal to increase pathogenicity, possibly by altering host cell physiology or metabolism through the production of potential auxin mimics.
Quantitative Trait Loci Analysis and Marker Development for Fruit Rot Resistance in Cranberry Shows Potential Genetic Association with Epicuticular Wax
Authors: Kawash Joseph , Erndwein Lindsay , Johnson-Cicalese Jennifer , Knowles Sara , Vorsa Nicholi , Polashock James
Published: January 2024

Fruit rot is a fungal disease complex that threatens cranberry yields in North American growing operations. Management of fruit rot is especially difficult because of the diversity of the infecting fungal species, and although infections take place early in the season, the pathogens usually remain latent in the ovary until the fruit ripen. Control methods heavily rely on fungicide applications, a practice that may be limited in viability long term. Breeding for fruit rot resistance (FRR) is essential for sustainable production. It is likely that field resistance is multifaceted and involves a myriad of traits that fortify cranberry plants against the biotic and abiotic stresses contributing to fruit rot. In this study, we identified quantitative trait loci (QTL) for FRR in a segregating population. Interestingly, a QTL associated with resistance was found to overlap with one associated with fruit epicuticular wax (ECW). A single-nucleotide polymorphism genotyping assay successfully identified accessions that exhibit the desired phenotypes (i.e., less rot and more ECW), thus making it a useful tool for marker-assisted selection. Candidate genes that may contribute to FRR and ECW were also identified. This work will expedite breeding for improved cranberry fruit quality.
Integrated Care for Persons With Persistent Gynecologic Conditions
Authors: Witzeman Kathryn A. , Lieberman Alison , Beckman Elizabeth Joy , Ross Kaitlin V. , Coons Helen L.
Published: January 2024

Persons with persistent gynecologic conditions frequently cope with complex biopsychosocial challenges and benefit from integrated behavioral health evaluation and treatment within gynecologic practices. Integrated care refers to the provision of behavioral health services within a health care setting which contributes to improved patient, provider, and practice outcomes, however, has not been commonly provided in traditional gynecologic practices. Several models of integrated behavioral health are reviewed. Each model holds specific applications in primary and specialty gynecology settings and may enhance the gynecologic patient experience. This article reviews current research supporting integrated care and describes implementation, funding, and evaluation to improve patient outcomes.
The Pressing Need to Integrate Mental Health into Obstetric Care
Authors: Zimmermann Martha , Moore Simas Tiffany A. , Howard Margaret , Byatt Nancy
Published: January 2024

Mental health and substance use conditions are prevalent among perinatal individuals. These conditions have a negative impact on the health of perinatal individuals, their infants, and families, yet are underdiagnosed and undertreated. Populations that have been marginalized disproportionately face barriers to accessing care. Integrating mental health into obstetric care could address the perinatal mental health crisis. We review perinatal mental health conditions and substance use, outline the impact associated with these conditions, and describe the promise and potential of integrating mental health into obstetric settings to improve outcomes for patients receiving obstetric and gynecologic care.
Screening, Assessment, and Treatment of Perinatal Mental Health in Obstetrical Settings
Authors: Gimbel Lauren A. , Zimmermann Martha , Byatt Nancy , Moore Simas Tiffany A. , Hoffman M. Camille
Published: January 2024

Perinatal mood and anxiety disorders (PMADs) are common, yet obstetricians receive little training prior to independent practice on screening, assessing, diagnosing, and treating patients with depression and anxiety. Untreated PMADs lead to adverse pregnancy and fetal outcomes. Obstetricians are in a unique position to address PMADs. The following serves as a resource for addressing PMADs in obstetric practice.
Behavioral Health Integration on Inpatient Obstetric Units: Program Development, Strategies for Implementation, and Lessons Learned
Authors: Kwitowski Melissa A. , Lebin Lindsay G. , Kelleher Jessalyn , Zsemlye Meggan , Nagle-Yang Sarah
Published: January 2024

Perinatal mood and anxiety disorders and substance use disorders are the primary causes of maternal mortality in the postpartum period and represent major public health concerns. Despite this, these conditions remain undertreated. Behavioral health integration in outpatient obstetric settings is necessary but insufficient to meet the needs of all patients. Inpatient behavioral health integration represents a promising avenue for addressing gaps in care. Results from recent program development indicate that needs assessment, stakeholder backing, collaboration with existing programs, and adaptability are key factors in successful implementation.
Genitourinary Syndrome of Menopause: Pathophysiology, Clinical Presentation, and Differential Diagnosis
Authors: CLARK AMANDA L. , GOETSCH MARTHA F.
Published: January 2024

Scientific information is incomplete regarding the genitourinary syndrome of menopause. Both the lower genital and urinary tracts are rich in receptors for reproductive hormones and are highly susceptible to waning ovarian hormones at menopause. Symptoms of dryness and pain emerge in late perimenopause, but they can also result earlier from cancer therapies or bilateral oophorectomy. Lower urinary tract symptoms rise in prevalence at midlife and increase further with advancing age. Because ovarian senescence is typically followed by years of aging, some postmenopausal complaints may be attributable to increasing longevity.
Sexual Dysfunction and Dyspareunia in the Setting of the Genitourinary Syndrome of Menopause
Authors: Gaddam Neha G. , Kingsberg Sheryl A. , Iglesia Cheryl B.
Published: January 2024

Sexual dysfunction is a common consequence of the genitourinary syndrome of menopause (GSM). In this book chapter, we discuss the pathophysiology, prevalence, evaluation, and evidence-based management of sexual dysfunction in patients affected by GSM. Additionally, we present an algorithm to guide clinicians in the management and treatment of sexual dysfunction in this setting based on available evidence and best practices.
Longitudinal Association of Mid-Life Ten Year Cardiovascular Disease Risk Score with Brain Biomarkers of Alzheimer’s Disease, Neurodegeneration and White Matter Hyper Intensities in Cognitively Unimpaired Older Adults: Heart SCORE Brain Study
Authors: Saeed Anum , Chang Yue Fang , Swanson Justin , Vu Michael , Mapstone Mark , Villemagne Victor L , Snitz Beth E. , Royse Sarah K , Lopresti Brian , Aizenstein Howard J. , Wu Minjie , Kip Kevin , Reis Steven E. , Lopez Oscar , Cohen Ann
Published: January 2024

Introduction

Atherosclerotic cardiovascular disease (ASCVD) risk factors in mid-life have been associated with cognitive decline and late-life dementia. However, the role of these risk factors in preclinical Alzheimer’s disease (AD) pathophysiology remains elusive. We investigated whether mid-life 10-year pooled cohort equations (PCE) based ASCVD risk is associated with late-life amyloid, tau, neurodegeneration [AT(N)] measures and white matter hyperintensities (WMHI).

Methods

Participants enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study between 2003-2005 (mid-life) and underwent brain MRI and PET scans in 2018-2022 (age >65 years, late-life) to detect and quantify amyloid (A, PiB-PET) and tau (T, Flortaucipir (FTP) PET) deposition, cortical thickness (N) and white matter hyperintensities (WMHIs). Mid-life PCE ASCVD risk was categorized as; borderline (5%-7.4%), intermediate (7.5%-<15%), or high (≥15%). Association of midlife ASCVD risk HR (5% CI) was assessed using logistic and linear regressions with A, T, or N and chi square beta coefficients for WMHI in latelife.

Results

Over a ∼16y follow up, in 135 participants (mean age 73y), A and T showed no significant association with mid-life ASCVD risk. Neurodegeneration had a graded association with mid-life ASCVD risk categories (ORASCVDhighvslowrisk%6.98 [2.44-19.95]; p<0.05) driven by self-identified Black race and age. In a subset n=60, ASCVD risk score was also associated with WMHIs ((β=0.42 ± 0.22; p=0.05)in a model adjusted for inflammation and education.

Conclusions

In this asymptomatic, diverse cohort, 10y ASCVD risk was predictive of late-life neurodegeneration and white matter hyperintensities but not amyloid or tau. These data suggest that ASCVD risk factors in midlife may lead to a state of vulnerability (through increased neurodegeneration and white matter hyperintensities) which may progress to cognitive decline and dementia. Further mechanistic studies are warranted to test this hypothesis.

Abstract Figure
A self-report tool for identification of individuals with coronary atherosclerosis – The Swedish CArdioPulmonary BioImage Study
Authors: Bergström Göran , Hagberg Eva , Björnson Elias , Adiels Martin , Bonander Carl , Strömberg Ulf , Andersson Jonas , Brunström Mattias , Carlhäll Carl-Johan , Engström Gunnar , Erlinge David , Goncalves Isabel , Gummesson Anders , Hagström Emil , Hjelmgren Ola , James Stefan , Janzon Magnus , Jonasson Lena , Lind Lars , Magnusson Martin , Oskarsson Viktor , Sundström Johan , Svensson Per , Söderberg Stefan , Themudo Raquel , Östgren Carl Johan , Jernberg Tomas
Published: January 2024

Background

Coronary atherosclerosis detected by imaging is a marker of elevated cardiovascular risk. However, imaging involves large resources and exposure to radiation. The aim was, therefore, to test whether non-imaging data, specifically data that can be self-reported, could be used to identify individuals with moderate to severe coronary atherosclerosis.

Methods

We used data from the population based Swedish CArdioPulmonary BioImage Study (SCAPIS) in individuals with coronary computed tomography angiography (CCTA, n=25,182) and coronary artery calcification score (CACS, n=28,701), aged 50-64 years without previous ischemic heart disease. We developed a risk prediction tool utilizing variables that could be assessed from home (a so-called self-report tool). For comparison, we also developed a tool utilizing variables from laboratory tests, physical examinations and self-report (a so-called clinical tool) and evaluated both models using receiver operating characteristic curve analysis, external validation, and bench-marked against factors in the Pooled Cohort Equation (PCE).

Results

The self-report tool (n=14 variables) and the clinical tool (n=23 variables) showed high-to-excellent discriminative ability to identify SIS ≥4 (AUC 0.79 and 0.80, respectively) and significantly better than PCE (AUC 0.76, p<0.001). The tools showed a larger net benefit in clinical decision making at relevant threshold probabilities. The self-report tool identified 65% of all individuals with SIS ≥4 in the top 30% of the highest-risk individuals. Tools developed for CACS ≥100 performed similarly.

Conclusions

We have developed a self-report tool which effectively identifies individuals with moderate to severe coronary atherosclerosis. The self-report tool may serve as pre-screening tool towards a cost-effective CT-based screening program for high-risk individuals.

Clinical Perspective

What Is New?

We have developed a self-report tool which with a good-to-excellent discriminative ability identifies individuals with moderate to severe coronary atherosclerosis.

The self-report tool can be executed from home and has a similar performance to a clinical tool requiring a clinical visit involving blood tests and physical examination.

What Are the Clinical Implications?

The self-report tool could serve as an initial step towards a cost-effective screening program to identify high-risk individuals or used to identify individuals who would benefit from further risk refinement by cardiac imaging.
Crosstalk between the RNA-binding proteins Regnase-1 and -3 shapes mast cell survival and cytokine expression
Authors: Bataclan Marian , Leoni Cristina , Moro Simone G. , Pecoraro Matteo , Wong Elaine H. , Heissmeyer Vigo , Monticelli Silvia
Published: January 2024

Post-transcriptional regulation of immune-related transcripts by RNA-binding proteins (RBPs) impacts immune cell responses, including mast cell functionality. Despite their importance in immune regulation, the functional role of most RBPs remains to be understood. By manipulating the expression of specific RBPs in mast cells, coupled with mass spectrometry and transcriptomic analyses, we found that the Regnase family of proteins acts as a potent regulator of mast cell physiology. Specifically, Regnase-1 is required to maintain basic cell proliferation and survival, while both Regnase-1 and −3 cooperatively regulate the expression of inflammatory transcripts upon mast cell activation, withTnfbeing a primary target of both proteins. In mast cells, Regnase-3 directly interacts with Regnase-1 and is necessary to restrain Regnase-1 expression through the destabilization of its transcript. Overall, our study identifies protein interactors of endogenously expressed Regnase factors, characterizes the regulatory interplay between Regnase family members in mast cells, and establishes their role in the control of mast cell homeostasis and inflammatory responses.
Mitochondrial Transplantation promotes protective effector and memory CD4+T cell response duringMycobacterium tuberculosisinfection and diminishes exhaustion and senescence in elderly CD4+T cells
Authors: Headley Colwyn A. , Gautam Shalini , Olmo-Fontanez Angelica , Garcia-Vilanova Andreu , Dwivedi Varun , Schami Alyssa , Weintraub Susan , Tsao Philip S. , Torrelles Jordi B. , Turner Joanne
Published: January 2024

Tuberculosis (TB), caused by the bacteriumMycobacterium tuberculosis(M.tb), remains a significant health concern worldwide, especially in populations with weakened or compromised immune systems, such as the elderly. Proper adaptive immune function, particularly a CD4+T cell response, is central to host immunity againstM.tb. Chronic infections, such asM.tb, as well as aging promote T cell exhaustion and senescence, which can impair immune control and promote progression to TB disease. Mitochondrial dysfunction contributes to T cell dysfunction, both in aging and chronic infections and diseases. Mitochondrial perturbations can disrupt cellular metabolism, enhance oxidative stress, and impair T-cell signaling and effector functions. This study examined the impact of mitochondrial transplantation (mito-transfer) on CD4+T cell differentiation and function using aged mouse models and human CD4+T cells from elderly individuals. Our study revealed that mito-transfer in naïve CD4+T cells promoted the generation of protective effector and memory CD4+T cells duringM.tbinfection in mice. Further, mito-transfer enhanced the function of elderly human T cells by increasing their mitochondrial mass and modulating cytokine production, which in turn reduced exhaustion and senescence cell markers. Our results suggest that mito-transfer could be a novel strategy to reestablish aged CD4+T cell function, potentially improving immune responses in the elderly and chronic TB patients, with a broader implication for other diseases where mitochondrial dysfunction is linked to T cell exhaustion and senescence.
Computation-aided Design of Rod-Shaped Janus Base Nanopieces for Improved Tissue Penetration and Therapeutics Delivery
Authors: Lee Jinhyung , Zhang Wuxia , Nguyen Danh , Zhou Libo , Amengual Justin , Zhai Jin , Cote Trystin , Landolina Maxwell , Ahmadi Elham , Sands Ian , Mishra Neha , Yu Hongchuan , Nieh Mu-Ping , Wang Kepeng , Li Ying , Chen Yupeng
Published: January 2024

Despite the development of various drug delivery technologies, there remains a significant need for vehicles that can improve targeting and biodistribution in “hard-to-penetrate” tissues. Some solid tumors, for example, are particularly challenging to penetrate due to their dense extracellular matrix (ECM). In this study, we have formulated a new family of rod-shaped delivery vehicles named Janus base nanopieces (Rod JBNps), which are more slender than conventional spherical nanoparticles, such as lipid nanoparticles (LNPs). These JBNp nanorods are formed by bundles of DNA-inspired Janus base nanotubes (JBNts) with intercalated delivery cargoes. To develop this novel family of delivery vehicles, we employed a computation-aided design (CAD) methodology that includes molecular dynamics and response surface methodology. This approach precisely and efficiently guides experimental designs. Using an ovarian cancer model, we demonstrated that JBNps markedly improve penetration into the dense ECM of solid tumors, leading to better treatment outcomes compared to FDA-approved spherical LNP delivery. This study not only successfully developed a rod-shaped delivery vehicle for improved tissue penetration but also established a CAD methodology to effectively guide material design.
Regulatory T cells control type 1-driven immunopathology restraining GM-CSF-producing helper T cells
Authors: Costa-Pereira Sara , Lanzinger Margit , Andreadou Myrto , Nunez Nicolas , Villar-Vesga Juan , Prisco Francesco , Häne Philipp , Roussel Elsa , Krishnarajah Sinduya , Lindemann Rachel Chanel , Westermann Frederike , Oberbichler Laura , Sethi Aakriti , Da Silva André Fonseca , Lutz Mirjam , Tugues Sonia , Mundt Sarah , Kipar Anja , Greter Melanie , De Feo Donatella , Becher Burkhard
Published: January 2024

Regulatory T (Treg) cells are critical for maintaining peripheral tolerance and preventing autoimmunity. Tregcell depletion or dysfunction rapidly results in fatal multiorgan inflammation linked to unrestrained effector T cell expansion, but the cytokine network underlying immunopathology, and its direct cellular mediators, remain elusive. Here, we combined gene targeting, fate-mapping tools, and high-dimensional cytometry to identify the T helper (TH) cell-derived cytokines and responding cells that execute inflammatory tissue damage upon global loss of peripheral tolerance in mice. We found that THcell-derived GM-CSF, but not IL-17A, directed the ensuing immunopathology and thereby mortality through recruitment of tissue-invading phagocytes and granulocytes, and enhancement of their reactive oxygen species production and phagocytic proficiency. Our study highlights the critical role of Tregcells in controlling GM-CSF- producing THcells and type 1-responses to restrain phagocyte-mediated tissue destruction and provides a framework for the use of anti-GM-CSF therapies in patients with chronic inflammatory disorders.
Systemic Genome Correlation Loss as a Central Characteristic of Spaceflight
Authors: Sakharkar Anurag , Lukong Erique , Sanders Lauren M. , Costes Sylvain V. , Taghibiglou Changiz , Yang Jian
Published: January 2024

Space exploration has captured the imagination of humanity for generations. From the first steps on the moon to the recent Mars rover and Artemis lunar exploration missions, space travel has always been an ambitious goal for humanity. However, as we venture further into space and prepare for long-term missions to other planets, the physiological and health risks associated with prolonged space travel are becoming more prominent. Most current research on astronaut health focuses on identifying individual genes or pathways for specific symptoms astronauts face. The human system is complex and delicate, and the effects of microgravity, radiation, and isolation on astronaut health during long-duration spaceflight are still not fully understood. This study used a novel ranking and analysis methodology to combine space omics data from multiple datasets in the NASA OSDR repository. The data was used to generate a multi-omic, integrative bioinformatics analysis pipeline, which identified and characterized a genome-wide spaceflight gene expression correlation loss as a central biosignature for astronaut health on the International Space Station (ISS). Our findings indicate that genome-wide correlation loss corresponds to a breakdown in gene synchronization and cooperation, showcasing the systemic symptoms spaceflight induces and their genomic roots.
Phylogenomic Analysis of Target Enrichment and Transcriptome Data Uncovers Rapid Radiation and Extensive Hybridization in Slipper Orchid GenusCypripediumL
Authors: Lagou Loudmila Jelinscaia , Kadereit Gudrun , Morales-Briones Diego F.
Published: January 2024

Background and Aims

Cypripediumis the most widespread and morphologically diverse genus of slipper orchids. Despite several published phylogenies, the topology and monophyly of its infrageneric taxa remained uncertain. Here, we aimed to reconstruct a robust section-level phylogeny ofCypripediumand explore its evolutionary history using target capture data for the first time.

Methods

We used the orchid-specific bait set Orchidaceae963 in combination with transcriptomic data to reconstruct the phylogeny ofCypripediumbased on 913 nuclear loci, covering all 13 sections. Subsequently, we investigated discordance among nuclear and chloroplast trees, estimated divergence times and ancestral ranges, searched for anomaly zones, polytomies, and diversification rate shifts, and identified potential gene (genome) duplication and hybridization events.

Key Results

All sections were recovered as monophyletic, contrary to the two subsections within sect.Cypripedium. The two subclades within this section did not correspond to its subsections but matched the geographic distribution of their species. Additionally, we discovered high levels of discordance in the short backbone branches of the genus and within sect.Cypripedium, which can be attributed to hybridization events detected based on phylogenetic network analyses, and incomplete lineage sorting caused by rapid radiation. Our biogeographic analysis suggested a Neotropical origin of the genus during the Oligocene (∼30 Ma), with a lineage of potentially hybrid origin spreading to the Old World in the Early Miocene (∼22 Ma). The rapid radiation at the backbone likely occurred in Southeast Asia around the Middle Miocene Climatic Transition (∼15–13 Ma), followed by several independent dispersals back to the New World. Moreover, the Pliocene-Quaternary glacial cycles may have contributed to further speciation and reticulate evolution withinCypripedium.

Conclusions

Our study provided novel insights into the evolutionary history ofCypripediumbased on high-throughput molecular data, shedding light on the dynamics of its distribution and diversity patterns from its origin to the present.
A microRNA that controls the emergence of embryonic movement
Authors: Menzies Jonathan A. C. , Chagas Andre M. , Baden Tom , Alonso Claudio R.
Published: January 2024

Movement is a key feature of animal systems, yet its embryonic origins are not fully understood. Here we investigate the genetic basis underlying the embryonic onset of movement inDrosophilafocusing on the role played by small non-coding RNAs (microRNAs, miRNAs). To this end, we first develop a quantitative behavioural pipeline capable of tracking embryonic movement in large populations of fly embryos, and using this system, discover that theDrosophilamiRNAmiR-2b-1plays a role in the emergence of movement. Through the combination of spectral analysis of embryonic motor patterns, cell sorting and RNAin situs, genetic reconstitution tests, and neural optical imaging we define thatmiR-2b-1influences the emergence of embryonic movement by exerting actions in the developing nervous system. Furthermore, through the combination of bioinformatics coupled to genetic manipulation of miRNA expression and phenocopy tests we identify a previously uncharacterised (but evolutionarily conserved) chloride channel encoding gene – which we termMovement Modulator(Motor)– as a genetic target that mechanistically linksmiR-2b-1to the onset of movement. Cell-specific genetic reconstitution ofmiR-2b-1expression in a null miRNA mutant background, followed by behavioural assays and target gene analyses, suggest thatmiR-2b-1affects the emergence of movement through effects in sensory elements of the embryonic circuitry, rather than in the motor domain. Our work thus reports the first miRNA system capable of regulating embryonic movement, suggesting that other miRNAs are likely to play a role in this key developmental process inDrosophilaas well as in other species.
Legacy copper/nickel mine tailings potentially harbor novel iron/sulfur cycling microorganisms within highly variable communities
Authors: Chen Molly , Grégoire Daniel S. , Bain Jeffrey G. , Blowes David W. , Hug Laura A.
Published: January 2024

The oxidation of sulfide-bearing mine tailings catalysed by acidophilic iron and sulfur-oxidizing bacteria releases toxic metals and other contaminants into soil and groundwater as acid mine drainage. Understanding the environmental variables that control the community structure and metabolic activity of endogenous microbes living in tailings (especially the abiotic stressors of low pH and high dissolved metal content) is crucial to developing sustainable bioremediation strategies. We determined the microbial community composition along two continuous vertical gradients of Cu/Ni mine tailings at each of two tailings impoundments near Sudbury, Ontario. 16S rRNA amplicon data showed high variability in community diversity and composition between locations, as well as at different depths within each location. A temporal comparison for one tailings location showed low fluctuation in microbial communities across 2 years. Differences in community composition correlated most strongly with pore-water pH, Eh, alkalinity, salinity, and the concentration of several dissolved metals (including iron, but not copper or nickel). The relative abundances of individual genera differed in their degrees of correlation with geochemical factors. Several abundant lineages present at these locations have not previously been associated with mine tailings environments, including novel species predicted to be involved in iron and sulfur cycling.
IgG hexamers initiate acute lung injury
Authors: Cleary Simon J. , Seo Yurim , Tian Jennifer J. , Kwaan Nicholas , Bulkley David P. , Bentlage Arthur E. H. , Vidarsson Gestur , Boilard Éric , Spirig Rolf , Zimring James C. , Looney Mark R.
Published: January 2024

Antibodies can initiate lung injury in a variety of disease states such as autoimmunity, transfusion reactions, or after organ transplantation, but the key factors determining in vivo pathogenicity of injury-inducing antibodies are unclear. A previously overlooked step in complement activation by IgG antibodies has been elucidated involving interactions between IgG Fc domains that enable assembly of IgG hexamers, which can optimally activate the complement cascade. Here, we tested the in vivo relevance of IgG hexamers in a complement-dependent alloantibody model of acute lung injury. We used three approaches to block alloantibody hexamerization (antibody carbamylation, the K439E Fc mutation, or treatment with domain B from Staphylococcal protein A), all of which reduced acute lung injury. Conversely, Fc mutations promoting spontaneous hexamerization made a harmful alloantibody into a more potent inducer of acute lung injury and rendered an innocuous alloantibody pathogenic. Treatment with a recombinant Fc hexamer ‘decoy’ therapeutic protected mice from lung injury, including in a model with transgenic human FCGR2A expression that exacerbated pathology. These results indicate a direct in vivo role of IgG hexamerization in initiating acute lung injury and the potential for therapeutics that inhibit or mimic hexamerization to treat antibody-mediated diseases.

Brief summary

IgG antibodies can form hexamers. This study shows that hexamer assembly is an important event determining the ability of IgG to trigger acute lung injury.

Graphical abstract
Cell morphology as a quantifier for functional states of resident tissue macrophages
Authors: Schnitzerlein Miriam , Wegner Anja , Brahim Oumaima Ben , Uderhardt Stefan , Zaburdaev Vasily
Published: January 2024

Resident tissue macrophages (RTMs) are essential for maintaining homeostasis in a physiological tissue state. They monitor interstitial fluids, contain acute damage while actively preventing inflammation, and remove dead cells and debris. All these cellular functions are accompanied by characteristic changes in cell morphology, the expression of which can provide information about the functional status of the cells. What is currently known about morphological patterns and dynamic behavior of macrophages is derived primarily from experimentalex vivocell cultures. However, how macrophages operate in living organisms is in many ways fundamentally different from how they do in a cell culture system. In this work, we employed an intravital imaging platform to generate dynamic data from peritoneal RTMsin vivoin mice under various conditions induced either chemically or physically. Using this data, we built an image processing pipeline and defined a set of human-interpretable cell size and shape features which allowed us to quantify RTM morphodynamics over time. We used those features to quantitatively differentiate cells in various functional states - when macrophages are activated, for instance, or when they “shut down” due to detrimental changes in the environment. The qualitative morphology changes associated with these functional states could be inferred directly from the quantitative measurements. Finally we used the set of cell morphology features monitoring the health of RTMs to improve a setup for explanted tissues. Thus, the proposed method is a versatile tool to provide insights into the dynamic behavior ofbona fidemacrophagesin vivoand helps distinguish between physiological and pathological cell states.

Author summary

Mammalian tissues are constantly subjected to various stresses - due to pathogens, cell death and molecular waste products - which have to be resolved properly to prevent unwanted inflammatory processes and thus maintain tissue homeostasis. To find such incidents, resident tissue macrophages (RTMs)in vivodisplay constant sampling behavior which is accompanied by dynamic changes to their morphology. These changes of cellular features are not yet fully understood and were even not yet quantified for RTMs in living organisms. To fill this knowledge gap, we have used an intravital imaging platform to generate time-lapse images of RTMs over time in the peritoneal serosa of a living mouse. Subsequently we have built a custom image processing pipeline to assess the morphology and dynamics of the cells. We could use these measurements to recover the qualitative cell morphology changes over time and even differentiate cells in distinct physiological and pathological states. Thus this analysis lays the basis to the further development of a mathematical model or RTM sampling dynamics or may even be the first step to diagnose macrophages in disease contexts.
10x Genomics Gene Expression Flex is a powerful tool for single-cell transcriptomics of xenograft models
Authors: Llora-Batlle Oriol , Farcas Anca , Fransen Doreth , Floc’h Nicolas , Talbot Sara , Schwiening Alix , Bojko Laura , Calver John , Josipovic Natasa , Lashuk Kanstantsin , Schueler Julia , Prodan Andrei , Mooijman Dylan , McDermott Ultan
Published: January 2024

The 10x Genomics Gene Expression Flex protocol allows profiling of fixed or frozen material, greatly simplifying the logistics of sample collection, storage and transfer prior to single -cell sequencing. The method makes single-cell transcriptomics possible for existing fresh-frozen or FFPE tissue samples, but also facilitates the logistics of the sampling process, allowing instant preservation of samples. The technology relies on species-specific probes available for human and mouse. Nevertheless, processing of patient-derived (PDX) or cell line (CDX) xenografts, which contain mixed human and mouse cells, is currently not supported by this protocol due to the high degree of homology between the probe sets. Here we show that it is feasible to simultaneously profile populations containing both human and mouse cells by mixing the transcriptome probe sets of both species.Cellrangeroutputs a count table for each of the species allowing evaluation of the performance of the different probe sets. Cross-reactive probes are greatly outperformed by the specific probe hybridizations leading to a clear difference in the recovery of UMIs and unique genes per cell. Furthermore, we developed a pipeline that removes cross-reactive signal from the data and provides species-specific count tables for further downstream analysis. Hence, the 10x Genomics Gene Expression Flex protocol can be used to process xenograft samples without the need for separation of human and mouse cells by flow sorting and allows analysis of the human and mouse single-cell transcriptome from each sample. We anticipate it will be increasingly used for single-cell sequencing of cancer cell line and patient-derived xenografts, facilitating the preservation of the samples and allowing the interrogation of both the (human) xenograft and the (mouse) tumor microenvironment at single-cell resolution.