Varicella Pneumonia in an Immunocompetent Young Adult in the Vaccine Era

A 26-year-old female presented to the Emergency Department (ED) on March 16, 2019, with a 1-day history of fever and generalized, pruritic, maculopapular, and vesicular rash that began to appear on the face. Her 4-year-old son had been treated for chickenpox 2 weeks earlier. The patient received one dose of varicella vaccine in childhood and had no history of varicella. She had no significant medical history. At presentation, her body temperature was 37.4°C, and other vital signs were stable. Laboratory tests revealed a white blood cell count of 3,220 cells/mm³ with 3% atypical lymphocytes, a platelet count of 143,000/mm³, and an alanine aminotransferase level of 46 U/L, and a C-reactive protein of 20.57 mg/L. Chest radiography showed no definite abnormalities in both lung fields. Because the patient refused to be hospitalized for intravenous acyclovir therapy, we prescribed oral valacyclovir 1 g twice daily. She was discharged home with a plan for close follow-up in an outpatient clinic. On day 4 after discharge, the patient was afebrile, and some of the vesicular lesions had crusted (Fig. 1A); however, she complained of a mild cough and dyspnea. Repeated chest radiography (Fig. 1B) and computed tomography (CT) (Fig. 1C and D) demonstrated typical radiologic findings of varicella pneumonia in the early stages. Varicella-zoster virus (VZV) polymerase chain reaction in plasma performed at the ED was confirmed to be positive. After a 7-day course of oral valacyclovir therapy, cough and dyspnea were gradually improved and all skin lesions had fully crusted. One month later, the patient''s symptoms were completely resolved, and repeated chest radiography and CT showed improvement of multiple inflammatory nodules in both lungs.Open in a separate windowFig. 1Clinical and radiologic findings at the outpatient clinic on the 4th day of oral antiviral therapy. (A) A clinical photograph of the face revealed characteristic rash consisting of erythematous macules, ruptured vesicles, and crusted papules. (B) Chest radiography showed suspicious patchy opacities in both lower lung fields. (C, D) Chest computed tomography demonstrated multiple 5–10 mm in diameter nodules with surrounding ground-glass opacities (arrows) in both lungs.The images are published under the agreement of the patient.In Korea, a live attenuated varicella vaccine was first introduced in 1988 and universal one-dose varicella vaccination was recommended for children by the National Immunization Program since 2005. Despite the routine vaccine coverage, the nationwide varicella incidence in Korea has not declined substantially.1 Varicella can cause severe complications more often in adults, pregnant women, and immunocompromised hosts than in healthy children.2 Varicella pneumonia, one of the serious, life-threatening complications, occurs in 1 in 400 cases of infection among adults, compared with 0.3 in 10,000 cases of infection among children.3,4 Respiratory symptoms including cough, dyspnea, tachypnea, pleuritic chest pain, and hemoptysis usually develop within 1 to 6 days after the rash has appeared.5,6 Chest radiographs usually reveal multiple, bilateral, 1–10 mm in diameter ill-defined nodules with or without a surrounding halo of ground-glass attenuation.7,8 An overall mortality rate of varicella pneumonia in adults is between 10% and 30%.9 However, the clinical manifestations of varicella in vaccinated individuals are often mild.10,11 It is presumed that this patient also had a mild clinical course due to past vaccination history. Therefore, to predict disease severity, it is important to check the vaccination status in immunocompetent adult patients suspected of varicella, especially if they were born between 1988 and 2005 in Korea. Also, patients who complain of new respiratory symptoms after the onset of rash should consider follow-up chest radiography with or without CT scans to confirm varicella pneumonia, even if the initial chest radiography was normal. Further large-scale studies are needed on the epidemiology, clinical features, and radiologic findings of varicella pneumonia in vaccinated adults.     

The Origin of Ovarian Cancer Species and Precancerous Landscape

Unlike other human cancers, in which all primary tumors arise de novo, ovarian epithelial cancers are primarily imported from either endometrial or fallopian tube epithelium. The prevailing paradigm in the genesis of high-grade serous carcinoma (HGSC), the most common ovarian cancer, posits to its development in fallopian tubes through stepwise tumor progression. Recent progress has been made not only in gathering terabytes of omics data but also in detailing the histologic–molecular correlations required for looking into, and making sense of, the tissue origin of HGSC. This emerging paradigm is changing many facets of ovarian cancer research and routine gynecology practice. The precancerous landscape in fallopian tubes contains multiple concurrent precursor lesions, including serous tubal intraepithelial carcinoma (STIC), with genetic heterogeneity providing a platform for HGSC evolution. Mathematical models imply that a prolonged time (decades) elapses from the development of a TP53 mutation, the earliest known molecular alteration, to an STIC, followed by a shorter span (6 years) for progression to an HGSC. Genetic predisposition accelerates the trajectory. This timeline may allow for the early diagnosis of HGSC and STIC, followed by intent-to-cure surgery. This review discusses the recent advances in this tubal paradigm and its biological and clinical implications, alongside the promise and challenge of studying STIC and other precancerous lesions of HGSC.

Elucidating the pathogenesis in early cancer development is fundamental in identifying biomarkers for early detection and for the exploration of cost-effective strategies of cancer prevention. This task represents an unmet need in cancers that are not amenable to routine cancer screening or primary prevention. Ovarian cancer is one such example—the malignancy is located deep in the pelvis, is not readily detected clinically, and is highly fatal. Currently, there are few effective approaches to intercepting its progression from a noninvasive precursor stage to an advanced, incurable stage.The study of the early progression of ovarian cancer is confounded by the fact that ovarian cancer is a constellation of various neoplasms rather than being a single disease, notwithstanding the fact that almost all ovarian epithelial cancers are developmentally related to the Müllerian duct, an anlage of female reproductive tract components including fallopian tubes, uterus, the uterine cervix, and the superior portion of the vagina. Ovarian carcinomas are conventionally classified according to histologic subtype, and each subtype is characterized by distinct clinicopathologic and molecular features as well as tissue of origin (Figure 1). For simplicity, ovarian carcinomas can be broadly classified as type 1 or 2.^1,2 Type 1 carcinomas include clear cell, endometrioid, mucinous, and low-grade serous carcinomas, whereas type 2 carcinomas mainly comprise high-grade serous carcinomas (HGSCs). Type 2 ovarian cancers are distinguishable from type 1 neoplasms by several features: i) more frequent high-stage disease at diagnosis, ii) universal TP53 mutations, iii) either a defective homologous recombination DNA repair pathway or amplification of CCNE1, and iv) uncommon mutations in genes involving mismatch DNA repair and in the AT-rich interactive domain-containing protein (ARID1A), phosphatidylinositol 3-kinase (PI3K), K-Ras/B-Raf, Wnt, and protein phosphatase 2A pathways.^3,4 HGSCs are the most common type of epithelial ovarian cancer and are the primary focus of this review (Figure 1).Open in a separate windowFigure 1The tissue origins and major molecular pathway alterations in different types of ovarian epithelial cancer. ARID, AT-rich interactive domain-containing protein; CCNE, G1/S-specific cyclin-E; ErbB, extracellular region binding protein; HR DDR, homologous recombination DNA damage repair; MEK (alias mitogen-activated protein kinase, MAPK); PIK3CA, phosphatidylinositol 3-kinase catalytic subunit α; PTEN, phosphatase and tensin homologue.The tissue origin of HGSC has eluded investigators for decades, given that attempts to demonstrate its ovarian origin were mostly unsuccessful. Kuhn and Hacking⁵ felt that a crisis of confidence occurs when puzzles arise that repeatedly resist solutions. During a crisis, the paradigm is subjected to testing and might be rejected. Here, the crisis of confidence is whether epithelial ovarian cancer indeed arises from the ovary. It has become increasingly clear in recent years that many HGSCs develop from the epithelial precursor lesions on the fallopian tubes rather than from the ovary, which, in humans, is largely devoid of Müllerian epithelium. This new paradigm of ovarian cancer genesis was based on the original observation of dysplastic epithelium in the fallopian tube in women carrying BRCA1 and BRCA2 germline mutations.6, 7, 8 Serous tubal intraepithelial carcinoma (STIC) is the immediate precursor of HGSC. STIC is characterized by a continuation of nonciliated tubal epithelial cells showing marked nuclear atypia, mitotic figures, apoptotic bodies, loss of cellular polarization, a p53 staining abnormality (pattern compatible with either missense or deletion mutations), and an increased Ki-67 labeling index8, 9, 10, 11, 12 (Figure 2). The tubal paradigm proposes that STIC formation precedes HGSC, and that the STIC can become invasive into the underlying tubal mucosa, and, more often, that the STIC cells can detach from the fallopian tube surface and spread directly onto the peritoneal surface enclosing ovary, bowel, peritoneal wall, and omentum. Natural selection equips the emigrated STIC cells to survive and reproduce within certain tissue environmental niches to grow tumor nodules and cause tumor ascites (Figure 2). Because of proximity to the fimbriated ends of fallopian tubes and friendly environment (enriched blood supply as an example), ovaries are usually the first stop for STIC cells to arrive and develop into an ovarian HGSC. However, STIC cells or tubal epithelium with early serous proliferation may bypass ovarian tissues and lodge into peritoneal surface or omentum to form the peritoneal primary HGSC.¹³Open in a separate windowFigure 2Paradigm of fallopian tube as the origin of high-grade serous carcinomas (HGSCs). Multiple fallopian tube lesions including serous tubal intraepithelial carcinoma (STIC) (yellow lines in the fimbriated end) and p53 signature (blue lines) can occur at the fimbriated end. STIC is presumed to be the immediate precursor of HGSC. STIC cells can become invasive in the fallopian tube, and detach from the fallopian tube surface, spreading onto the peritoneal surface, enclosing ovary, bowel, peritoneal wall, and omentum. Natural selection favors emigrated STIC cells that can survive and reproduce within a certain tissue-environmental niche which grow into tumor nodules and cause tumor ascites. Illustration by Lydia Gredd, M.A., C.M.I., © 2020 I. Shih at JHU; used with permission.In addition to STIC, the p53 signature is another lesion on fallopian tube epithelium; it is defined by a small stretch of 10 to 30 normal-appearing epithelial cells with an intense p53 immunostaining pattern compatible with a missense TP53 mutation.14, 15, 16 Sequencing results have confirmed such mutations in all p53 signatures analyzed.17, 18, 19 p53 Signature lesions are morphologically indistinguishable from the adjacent TP53 wild-type epithelium by hematoxylin and eosin staining, and can be detected only by p53 immunostaining.     

Targeting mitochondrial dysfunction in MAIT cells limits IL-17 production in obesity

Subject terms: Translational immunology, Inflammation

Mucosal-associated invariant T (MAIT) cells are a population of evolutionarily conserved “innate” T cells that express the invariant T-cell receptor (TCR) α-chain Vα7.2-Jα33. MAIT cells are capable of rapidly producing several cytokines, including interferon gamma (IFNy), tumour necrosis factor alpha (TNFa) and interleukin 17 (IL-17).¹ MAIT cells, in particular IL-17-producing subsets, have been implicated in numerous chronic inflammatory diseases including rheumatoid arthritis, ankylosing spondylitis and psoriasis.² We have previously described alterations in MAIT cell cytokine profiles in obesity, including reduced IFNy production and elevated IL-17 production.³ More recently, we have reported alterations in MAIT cell metabolism in patients with obesity that underpin the loss of IFNy production by MAIT cells.⁴ The mechanism(s) driving the increase in type-17 MAIT cells in obesity is not fully understood. A pair of recent studies have linked type-17 inflammation to dysfunctional mitochondria; Zhang et al.⁵ demonstrated that reactive oxygen species (ROS) from the mitochondria (mROS) could be linked to the initiation of type-17 inflammation,⁵ while Nicholas et al. linked changes in mitochondrial metabolism to Th17 inflammation in type 2 diabetes patients.⁶ The role of dysregulated mitochondria in IL-17-producing MAIT cells is currently unknown and may represent a novel therapeutic target in obesity and beyond. To test this hypothesis, we first confirmed the presence of a type-17 MAIT cell phenotype using RNA sequencing, intracellular staining for flow cytometry and enzyme-linked immunosorbent assay in a cohort of patients with severe obesity (body mass index >40). MAIT cells isolated from patients with obesity displayed an IL-17-related gene signature (Fig. 1a) and increases in both the percentage of MAIT cells producing IL-17 and the quantity of IL-17 produced (Fig. 1b, c). Using our sequencing data, we next investigated mROS-related gene expression and showed an elevated mROS signature in MAIT cells from patients with obesity (Fig. 1d). To confirm these observations, we measured mROS levels in MAIT cells from the patients with obesity using the specific mROS dye MitoSox. We observed elevated mROS levels in the MAIT cells from patients with obesity when compared with MAIT cells from healthy age and sex-matched controls (Fig. 1e). We also demonstrated an elevated mitochondrial membrane potential in obese MAIT cells using JC-1 staining but did not find a difference in mitochondrial mass (Fig. 1f, g), further supporting the concept of dysregulated mitochondria, as a high membrane potential has been linked to elevated ROS levels and dysfunction in conventional T cells.⁷ In chronic hepatitis B infection, targeting mitochondrial dysfunction with antioxidants restores the antiviral activity of exhausted CD8+ T cells.⁸ With the elevated levels of mROS noted in the MAIT cells from patients with obesity, we next utilised the mitochondria-targeted antioxidant MitoTEMPO and asked whether the mitochondrial dysfunction of obese MAIT cells could be reversed. We showed reduced IL-17 production by MitoTEMPO-treated MAIT cells from obese patients (Fig. 1h). However, we did not observe any changes in IFNy production (Fig. 1i). To verify this reduction in the IL-17-producing MAIT cell frequency following treatment with MitoTEMPO, we investigated a second mitochondrial antioxidant, mitoquinone (MitoQ),⁹ and similar to MitoTEMPO, MitoQ induced a reduction in the IL-17-producing MAIT cell frequency (Fig. 1j). Finally, we investigated the impact of the endogenous antioxidant glutathione (GSH), which is crucial in the maintenance of the intracellular redox balance, and demonstrated a robust reduction in IL-17 production by MAIT cells from patients with obesity (Fig. 1k). Type-17 MAIT cells are linked to the pathogenesis of many chronic conditions ranging from obesity and liver fibrosis to arthritis and even cancer,^2,10 highlighting the therapeutic potential of targeting type-17 MAIT cells. Collectively, our data link dysregulated mitochondria to IL-17 production in MAIT cells in patients with obesity and highlight a potential novel therapeutic strategy using mitochondria-targeted antioxidants in chronic inflammatory conditions where type-17 MAIT cells are implicated in the pathogenesis.Open in a separate windowFig. 1Targeting mitochondrial ROS in obese MAIT cells reduces IL-17 levels. a Heatmap displaying the mean counts of IL-17-related genes in MAIT cells isolated from lean (n = 5) or obese (n = 4) adults. b Scatter plot displaying the frequencies of IL-17-producing MAIT cells (resting or stimulated with TCR beads and 50 ng/ml IL-12/IL-18) in lean and obese cohorts. c Scatter plot displaying the levels of IL-17 produced by MAIT cells (resting or stimulated with TCR beads and 50 ng/ml IL-12/IL-18) from lean and obese cohorts. d Heatmap displaying the mean counts of ROS-related genes in MAIT cells isolated from lean (n = 5) or obese (n = 4) adults. e Representative histograms and a scatter plot displaying the expression of mROS (MitoSox) in MAIT cells from lean and obese cohorts. f Scatter plot displaying the mitochondrial membrane potential (JC-1) of MAIT cells from lean and obese cohorts. g Scatter plot displaying the mitochondrial mass (MitoTracker) of MAIT cells from lean and obese cohorts. h, i Scatter plot displaying the impact of MitoTEMPO treatment on the frequencies of IL-17- and IFNy-producing MAIT cells (stimulated with TCR beads and 50 ng/ml IL-12/IL-18) in patients with obesity (n = 20). j Scatter plot displaying the impact of MitoQ treatment on the frequency of IL-17-producing MAIT cells (stimulated with TCR beads and 50 ng/ml IL-12/IL-18) in patients with obesity (n = 8). k Scatter plot displaying the impact of glutathione (GSH) treatment on IL-17 production by MAIT cells from patients with obesity (stimulated with TCR beads and 50 ng/ml IL-12/IL-18) (n = 3). Data are representative of a minimum of three independent experiments unless otherwise stated. Significant differences are indicated by *p < 0.05, **p < 0.01 and ***p < 0.001     

Understanding the Role of Blood Vessels in the Neurologic Manifestations of Coronavirus Disease 2019 (COVID-19)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally identified as an outbreak in Wuhan, China, toward the end of 2019 and quickly became a global pandemic, with a large death toll. Originally identified as a respiratory disease, similar to previously discovered SARS and Middle East respiratory syndrome (MERS), concern has since been raised about the effects of SARS-CoV-2 infection on the vasculature. This viral-vascular involvement is of particular concern with regards to the small vessels present in the brain, with mounting evidence demonstrating that SARS-CoV-2 is capable of crossing the blood-brain barrier. Severe symptoms, termed coronavirus disease 2019 (COVID-19), often result in neurologic complications, regardless of patient age. These neurologic complications range from mild to severe across all demographics; however, the long-term repercussions of neurologic involvement on patient health are still unknown.

Currently, there are approximately 140 million confirmed infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide, and about 3,000,000 deaths associated with SARS-CoV-2 infection (Johns Hopkins University & Medicine, Coronavirus Resource Center, https://coronavirus.jhu.edu, last accessed April 17, 2021) manifesting as severe coronavirus disease 2019, or coronavirus disease 2019 (COVID-19). Approximately 15% of individuals affected by COVID-19 develop severe disease, and 6% are critically ill, resulting in respiratory failure and/or multiple organ dysfunction or failure.¹ The original outbreak of SARS-CoV-2 infection originated from Wuhan, Hubei province, China, in late 2019.^2,3Genomic characterization indicates that bats and rodents are the likely gene sources of α- and β-coronaviruses (CoVs), whereas γ- and δ-CoVs likely arise from avian sources.⁴ To date, seven human coronaviruses have been identified with the ability to cause respiratory, enteric, hepatic, and neurologic diseases in different animal species, including cattle and cats. These viruses are responsible for about 5% to 10% of acute respiratory infections, including the common cold.^4,5 SARS-CoV-2 is a member of the β- coronaviruses and is closely related to severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) with high sequence homology.⁶ These coronaviruses appear to infect the respiratory and gastrointestinal tract, with patients presenting symptoms of fever, cough, and shortness of breath, whereas less common symptoms include diarrhea, vomiting, and nausea.⁷ In addition, cytokine release syndrome was found to be the major cause of morbidity in patients infected with SARS-CoV and MERS-CoV.⁸Aside from the respiratory system, with acute respiratory distress syndrome affecting roughly one-third of COVID-19 hospitalized patients,⁹ COVID-19 appears to also involve multiple organ systems with pathologic manifestations, including the heart, kidney, and brain.10, 11, 12, 13, 14 Because of the multiorgan involvement of COVID-19, it has been hypothesized that COVID-19 is a vascular disease that primarily affects endothelial cells.^15,16 These organs, and their associated blood vessels, may be affected by direct viral tissue injury and localized disordered cytokine release.¹⁷ This direct injury and release of inflammatory and apoptosis inducing mediators leads to localized microvascular inflammation, which triggers endothelial activation, leading to vasodilation and prothrombotic conditions, which cause increased patient mortality.¹⁸Viral infections of the brain are less common than those of other organs as they involve penetration of the blood-brain barrier (BBB). Several viruses, including polio and West Nile virus, are able to cause neurologic complications, but the reasons why they occur in <1 in 100 patients are not understood.¹⁹ The route of entry of the virus into the brain, such as in the blood supply, or by direct infection of vascular endothelial cells, plays a role in the number and type of neurologic symptoms presented by the patient.^19,20 Investigations into MERS-CoV indicated that viral particles enter the bloodstream and are able to infect endothelial cells.²¹ In the case of SARS-CoV-2, viral-like particles have been seen in brain capillary endothelium and actively budding across endothelial cells.²²Although the route of entry of the virus may still be unknown, recent publications have highlighted neurologic manifestations that have been observed in 42% of COVID-19 patients at disease onset, 63% during hospitalization, and 82% at some time during the course of the disease.^23,24 In addition, a significant link was seen between magnetic resonance imaging abnormalities and persistent neurologic deficits, which continued 3 months after disease onset in 55% of patients.²³This review explores the role of the vasculature, specifically within the context of the neurologic manifestations of COVID-19. Herein, the neurologic manifestations reported with SARS-CoV-2 infection are reviewed. The evidence that suggests blood vessels are involved in SARS-CoV-2 infection is surveyed. Finally, the multiple pathologic processes (thromboembolic, inflammatory, and secondary processes) within blood vessels that may contribute to the neurologic manifestations of COVID-19 infection are considered.     

Genomic analyses provide insights into peach local adaptation and responses to climate change

The environment has constantly shaped plant genomes, but the genetic bases underlying how plants adapt to environmental influences remain largely unknown. We constructed a high-density genomic variation map of 263 geographically representative peach landraces and wild relatives. A combination of whole-genome selection scans and genome-wide environmental association studies (GWEAS) was performed to reveal the genomic bases of peach adaptation to diverse climates. A total of 2092 selective sweeps that underlie local adaptation to both mild and extreme climates were identified, including 339 sweeps conferring genomic pattern of adaptation to high altitudes. Using genome-wide environmental association studies (GWEAS), a total of 2755 genomic loci strongly associated with 51 specific environmental variables were detected. The molecular mechanism underlying adaptive evolution of high drought, strong UVB, cold hardiness, sugar content, flesh color, and bloom date were revealed. Finally, based on 30 yr of observation, a candidate gene associated with bloom date advance, representing peach responses to global warming, was identified. Collectively, our study provides insights into molecular bases of how environments have shaped peach genomes by natural selection and adds candidate genes for future studies on evolutionary genetics, adaptation to climate changes, and breeding.

Environmental adaptation is fundamental to species survival and conservation of biodiversity, especially under threats of climate change (Blanquart et al. 2013). Unlike animals, which can escape from hostile environments, plants are sessile and have to adapt by shaping and/or fixing genetic variants that are conducive for survival. Generally, climate is the major selective pressure driving adaptive evolution, resulting in different ecotypes within a single species (Fournier-Level et al. 2011; Hancock et al. 2011). However, the mechanisms underlying how climate shapes plant genomes remain largely unclear. Recently, identifying adaptive variants and understanding molecular mechanism of adaptation across a genome have become tractable due to the advances of sequencing technologies. Recent studies have sought to elucidate genetic bases of adaptation through genome-wide identification of selective sweeps as well as loci that associate with climate variables in several species, including Arabidopsis thaliana (Fournier-Level et al. 2011), pine (Eckert et al. 2010a,b; Dillon et al. 2013; De La Torre et al. 2019), rice (Qiu et al. 2017), sorghum (Lasky et al. 2015), soybean (Lu et al. 2017, 2020), spruce (Holliday et al. 2010; Yeaman et al. 2016), poplar (Evans et al. 2014; Holliday et al. 2016; Wang et al. 2018; Zhang et al. 2019), and fruit fly (Castellano et al. 2018; Chen et al. 2020). In addition, genomic loci or genes controlling adaptive traits and their adaptive evolution patterns have been revealed through association studies or genetic mapping (Pelgas et al. 2011; Yan et al. 2013; Lu et al. 2017; Navarro et al. 2017; Wang et al. 2018; Shi et al. 2020). However, very few studies have focused on genetic bases of adaptation in domesticated perennial fruit crops. Domesticated crops have adapted to diverse climates during domestication and subsequent spread and show local adaptation through long-term natural selection. Landraces and wild relatives harbor great genetic diversity and an abundance of resistance genes, which provide excellent resources for breeding initiatives. This is especially the case with accessions originating from stressful environments (Bolger et al. 2014). However, a cost of domestication is that many resistance-related genes have been lost (Li et al. 2018; Gao et al. 2019; Wang et al. 2020). In addition, global climate change is driving decreases in productivity and changes of distribution in several crop species (Wheeler and von Braun 2013). Therefore, it is of great importance to identify adaptive genes that can contribute to crop improvement, species survival, and global food security in the face of environmental deterioration.Peach is an important temperate fruit species, with a global yield of 24.5 million tons in 2018 (FA OSTAT; http://www.fao.org/faostat). It is also an important model system for the Rosaceae family, members of which provide one of the world''s main resources of fruits. Peach originated in southwestern China, and its landraces and wild relatives are widespread in both temperate and subtropical regions, as well as in wet and dry climates (Wang et al. 2012). Moreover, peach and its wild relatives can also be found in extremely harsh environments, such as high altitude, severe cold, and high drought regions. On the grounds of wide distributions, peach can be regarded as an excellent material for studying adaptation genetics. Peach has a relatively small genome size (∼227.4 Mb), and genomic analyses have identified a number of loci and genes associated with human selection and agronomically important traits (Falchi et al. 2013; Verde et al. 2013; Cao et al. 2014, 2016, 2019; Li et al. 2019; Zhou et al. 2021), such as fruit size, sugar content, fruit shape, flesh color, etc. However, there have been few studies describing genomic loci associated with environmental adaptation and natural selection.Our previous studies have revealed the impacts of human selection on peach genomes (Cao et al. 2014, 2019; Li et al. 2019). In this study, we focused on how natural selection shapes the genomes and how peaches have adapted to different environments. We analyzed genomes of a wide collection of 263 peach accessions from a broad range of geographical origins and associated with diverse climates (Fig. 1A), spanning mild and extreme environments, using the resequencing data with an average depth of 5.7× (Supplemental Table S1). We deciphered adaptive patterns across the peach genome by combining the identification of signatures of selective sweeps with genome-wide association studies of environmental variables and adaptive traits. Finally, we also identified a candidate gene associated with peach responses to global warming, based on observations over a 30-yr period.Open in a separate windowFigure 1.Distribution of the 263 peach accessions and demographic history of the seven ecotypes. (A) Geographic distribution of 263 peach accessions used in this study. Each accession is represented by a dot on the world map. Seven ecotypes are highlighted using solid circles with different colors. (B) Demographic history of the seven peach groups. Ancestral population size was inferred using the PSMC model. Three periods, the last glacial maximum (LGM, ∼20 KYA), Naynayxungla Glaciation (NG, 0.5∼0.78 MYA), and Xixiabangma Glaciation (XG, 0.8∼0.17 MYA), are shaded in green, red, and blue, respectively.     

Novel Functions of the Septin Cytoskeleton: Shaping Up Tissue Inflammation and Fibrosis

Chronic inflammatory diseases cause profound alterations in tissue homeostasis, including unchecked activation of immune and nonimmune cells leading to disease complications such as aberrant tissue repair and fibrosis. Current anti-inflammatory therapies are often insufficient in preventing or reversing these complications. Remodeling of the intracellular cytoskeleton is critical for cell activation in inflamed and fibrotic tissues; however, the cytoskeleton has not been adequately explored as a therapeutic target in inflammation. Septins are GTP-binding proteins that self-assemble into higher order cytoskeletal structures. The septin cytoskeleton exhibits a number of critical cellular functions, including regulation of cell shape and polarity, cytokinesis, cell migration, vesicle trafficking, and receptor signaling. Surprisingly, little is known about the role of the septin cytoskeleton in inflammation. This article reviews emerging evidence implicating different septins in the regulation of host-pathogen interactions, immune cell functions, and tissue fibrosis. Targeting of the septin cytoskeleton as a potential future therapeutic intervention in human inflammatory and fibrotic diseases is also discussed.

Acute and chronic inflammation result in dramatic changes in tissue homeostasis. These changes include altered cellular composition and interactions between immune and nonimmune cells in affected tissues, as well as the perturbed biochemical environment driven by the release of various pro- and anti-inflammatory mediators.^1,2 Similarly, the physical properties of affected tissues change due to acute and chronic inflammation-induced development of edema, aberrant tissue remodeling, and fibrosis.^3,4 On a cellular level, inflammatory states result in functional adaptations toward accelerated recognition and elimination of the invaded pathogens, as well as enhanced production of extracellular matrix and tissue turnover.^2,5,6 These alterations of cellular function in inflamed tissues are mediated by reprograming of the fundamental molecular processes, including gene expression, protein synthesis, vesicle trafficking, and cytoskeletal assembly.The cytoskeleton is a critical regulator of the architecture and function of eukaryotic cells. It comprises various filamentous structures formed via self-assembly and the polymerization of specialized proteins.⁷ The four components of the cytoskeleton include: actin filaments, microtubules, intermediate filaments, and septin polymers. These cytoskeletal elements play crucial roles in mediating housekeeping and specialized functions in multiple cell types. Examples include regulation of cell shape and size, cell division, migration, cell–cell interactions, protein uptake and secretion, receptor signaling, etc.7, 8, 9 Defects in the assembly and remodeling of different cytoskeletal elements play major roles in the development of various diseases, which is exemplified by tumor progression and metastasis.^7,10,11 The cytoskeletal regulation of tissue inflammation has also been extensively investigated. For example, the actin cytoskeleton controls the inflammatory response by regulating activation of immune cells and permeability of epithelial and endothelial barriers.12, 13, 14 Microtubules regulate pathogens sensing by inflammasomes,¹⁵ assembly of the immune synapse,¹⁶ and vascular leakage in the inflamed tissues.¹⁷ Finally, intermediate filaments have been implicated in glial cell activation during neural inflammation¹⁸ and development of inflammatory skin disorders.¹⁹ Although the roles of actin filaments, microtubules, and intermediate filament in tissue inflammation has attracted significant attention, the role of the fourth cytoskeletal element, the septin cytoskeleton, in modulating the inflammatory response remains poorly understood. This review addresses this knowledge gap by summarizing existing evidence for the involvement of the septin cytoskeleton in inflammation and tissue fibrosis and outlining possible mechanisms of such involvement.     

Integrin β1 Establishes Liver Microstructure and Modulates Transforming Growth Factor β during Liver Development and Regeneration

A unique and complex microstructure underlies the diverse functions of the liver. Breakdown of this organization, as occurs in fibrosis and cirrhosis, impairs liver function and leads to disease. The role of integrin β1 was examined both in establishing liver microstructure and recreating it after injury. Embryonic deletion of integrin β1 in the liver disrupts the normal development of hepatocyte polarity, specification of cell–cell junctions, and canalicular formation. This in turn leads to the expression of transforming growth factor β (TGF-β) and widespread fibrosis. Targeted deletion of integrin β1 in adult hepatocytes prevents recreation of normal hepatocyte architecture after liver injury, with resultant fibrosis. In vitro, integrin β1 is essential for canalicular formation and is needed to prevent stellate cell activation by modulating TGF-β. Taken together, these findings identify integrin β1 as a key determinant of liver architecture with a critical role as a regulator of TGF-β secretion. These results suggest that disrupting the hepatocyte–extracellular matrix interaction is sufficient to drive fibrosis.

The homogeneous appearance of the liver belies a complex microstructure essential for proper function. A fenestrated endothelium provides minimal resistance to blood flow to maintain low portal pressure and allows filtered plasma to bathe hepatocytes, permitting nutrient exchange and release of synthetic products. At the apical hepatocyte surface, a specialized canalicular network conveys bile out of the liver for secretion into the intestine.Establishing precise microstructure is thus critical for liver function. The role of hepatocyte–extracellular matrix (ECM) interactions in the development of liver microstructure was therefore examined in the current study.Integrins play an essential role in hepatocyte–ECM interactions. They are single-pass transmembrane receptors that function as adhesion molecules on the cell surface and mediate cell–matrix and cell–cell interactions.¹ They exist on the hepatocyte surface as heterodimers of an α and β subunit and contain a short cytoplasmic tail responsible for chemical signaling and physical force transduction through links to the actin cytoskeleton.² Component subunits exhibit high selectivity in their interactions. In particular, integrin receptors on hepatocytes bind collagen I, laminin, and fibronectin.3, 4, 5Integrin signaling involves a multiprotein complex that is recruited to and becomes associated with the intracellular portion of the protein. Although heterogeneous, signaling often involves focal adhesion kinase (FAK) as a platform for various phosphorylation events, including autophosphorylation, as well as signaling involving Src-family kinase, integrin-linked kinases, and paxillin.6, 7, 8 Principal integrin pairs expressed by hepatocytes are α1β1, α5β1, and a9β1.^9,10 The α1β1 heterodimer predominantly binds collagen IV, the α5β1 receptor binds fibronectin, and the α9β1 receptor binds to a non-RGD (Arg-Gly-Asp) site on tenascin.^11,12 Data on specific roles for integrins in the liver are limited to a few reports. α5β1 integrins sense tauroursodeoxycholic acid and become active in response to cell swelling.¹³ Mice with transgene-mediated osteopontin expression in hepatocytes develop fibrotic livers.¹⁴ Disruption of integrin-linked kinase in hepatocytes leads to increased deposition of ECM.¹⁵ Integrin β1 is essential for liver regeneration, but its effect on fibrosis has not been determined.¹⁶ In humans, hepatitis C is associated with increased expression of various integrins, including β1, α1, α5, and α6, which reflect disease severity.¹⁷ Expression of integrin α6 occurs in a variety of chronic liver diseases.¹⁸A critical role for integrins after injury is also suggested by the known role of ECM during injury response. ECM remodeling via matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is critical in recreating normal liver architecture. MMP-2, MMP-3, and MMP-14 are expressed by stellate cells during activation.^19,20 MMP-9 is expressed in hepatocytes and Kupffer cells after setting of injury.²¹ TIMP-1 modulates liver MMPs, and both TIMP-1 and TIMP-2 are expressed in hepatocytes during injury.22, 23, 24To determine how hepatocyte integrins help establish liver microstructure and re-establish it after liver injury, models were created to assess the consequences of hepatocyte-specific deletion of integrin β1 from before birth and in the adult mice after injury. Hepatocyte size and shape, interactions between hepatocytes and other cells, and signaling pathways relevant to integrin signaling and fibrosis were investigated.