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"Thomas, Kseniya"
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Ladies of Letterpress : a gallery of prints with 80 removable posters
\"Who can resist the tactile charm of letterpress? Not many, judging by its ever-rising popularity among artists and designers working with old-school printing methods. The Ladies of Letterpress features the best work of the members of Ladies of Letterpress, an international organization that champions the work of women printers. Valuable as a handy resource, it includes a wide range of pieces, from greeting cards to broadsides and posters, printed in a variety of type and illustration styles. Each piece is accompanied by details of paper, inks, and press used in its printing, and a profile of its printer. Whether you're drawn to elegant greeting cards, humorous note cards, or calendars and posters, you're sure to find inspiration in this volume. And when you do, there are eighty detachable pages just begging to be pinned up\"-- Provided by publisher.
Book
Tissue-Engineered Lungs for in Vivo Implantation
Because adult lung tissue has limited regeneration capacity, lung transplantation is the primary therapy for severely damaged lungs. To explore whether lung tissue can be regenerated in vitro, we treated lungs from adult rats using a procedure that removes cellular components but leaves behind a scaffold of extracellular matrix that retains the hierarchical branching structures of airways and vasculature. We then used a bioreactor to culture pulmonary epithelium and vascular endothelium on the acellular lung matrix. The seeded epithelium displayed remarkable hierarchical organization within the matrix, and the seeded endothelial cells efficiently repopulated the vascular compartment. In vitro, the mechanical characteristics of the engineered lungs were similar to those of native lung tissue, and when implanted into rats in vivo for short time intervals (45 to 120 minutes) the engineered lungs participated in gas exchange. Although representing only an initial step toward the ultimate goal of generating fully functional lungs in vitro, these results suggest that repopulation of lung matrix is a viable strategy for lung regeneration.
Journal Article
CD8+ T cells induce cachexia during chronic viral infection
Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8
+
T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8
+
T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8
+
T cell response and required T cell–intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8
+
T cells in IAC.
Cachexia manifests in cancer, chronic inflammation and infections. Bergthaler and colleagues show that CD8
+
T cells mediate infection-associated cachexia in a manner dependent on T cell–intrinsic type I IFN signaling and antigen recognition.
Journal Article
Cue-reactivity to distal cues in individuals at risk for gaming disorder
Gaming disorder (GD) is a disorder due to addictive behaviors (ICD-11). Cue-reactivity and craving are relevant mechanisms in the development and maintenance of addictive behaviors. When confronted with cues showing in-game content (proximal cues) individuals with higher symptom severity show increased cue-reactivity. Based on conditioning and addiction theories on incentive sensitization, cue-reactivity responses may generalize to more distal cues, e.g. when individuals at risk of developing a GD are confronted with a starting page of an online game. In cue-reactivity paradigms so far, only proximal gaming cues have been used.
We investigated the effect of distal gaming cues compared to gaming-unrelated control cues on cue-reactivity and craving in 88 individuals with non-problematic use of online games (nPGU) and 69 individuals at risk for GD (rGD). The distal cues showed the use of an electronic device (e.g., desktop PC or smartphone) whose screen showed starting pages of either games (target cues), shopping- or pornography sites (control cues) from a first-person perspective.
We found significantly higher urge and arousal ratings as well as longer viewing times for gaming-related compared to gaming-unrelated control cues in rGD compared to nPGU. Valence ratings did not differ between groups.
The results demonstrate that already distal gaming-specific cues lead to cue-reactivity and craving in rGD. This finding indicates that based on conditioning processes, cue-reactivity and craving develop during the course of GD and generalize to cues that are only moderately related to the specific gaming activity.
•distal gaming cues in contrast to proximal do not show in-game contents.•distal cues may trigger cue-reactivity in individuals at risk of gaming disorder.•risk users had higher urge and arousal ratings for gaming compared to control cues.•both groups had longer viewing times for gaming compared to control cues.
Journal Article
A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals
The CD2–CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a ‘CD2 corolla’. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2–CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2–CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8
+
tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.
The adhesion receptor CD2 plays an important role in the full activation of T cells. Dustin and colleagues show that CD2 occupies a region in the periphery of the immunological synapse where it amplifies cognate antigen signals, whereas the presence of PD-1 disrupts this effect.
Journal Article
Complex Interplay Between MAZR and Runx3 Regulates the Generation of Cytotoxic T Lymphocyte and Memory T Cells
The BTB zinc finger transcription factor MAZR (also known as PATZ1) controls, partially in synergy with the transcription factor Runx3, the development of CD8 lineage T cells. Here we explored the role of MAZR as well as combined activities of MAZR/Runx3 during cytotoxic T lymphocyte (CTL) and memory CD8 + T cell differentiation. In contrast to the essential role of Runx3 for CTL effector function, the deletion of MAZR had a mild effect on the generation of CTLs in vitro . However, a transcriptome analysis demonstrated that the combined deletion of MAZR and Runx3 resulted in much more widespread downregulation of CTL signature genes compared to single Runx3 deletion, indicating that MAZR partially compensates for loss of Runx3 in CTLs. Moreover, in line with the findings made in vitro , the analysis of CTL responses to LCMV infection revealed that MAZR and Runx3 cooperatively regulate the expression of CD8α, Granzyme B and perforin in vivo . Interestingly, while memory T cell differentiation is severely impaired in Runx3-deficient mice, the deletion of MAZR leads to an enlargement of the long-lived memory subset and also partially restored the differentiation defect caused by loss of Runx3. This indicates distinct functions of MAZR and Runx3 in the generation of memory T cell subsets, which is in contrast to their cooperative roles in CTLs. Together, our study demonstrates complex interplay between MAZR and Runx3 during CTL and memory T cell differentiation, and provides further insight into the molecular mechanisms underlying the establishment of CTL and memory T cell pools.
Journal Article
A highly divergent sample from a nearly extinct SARS-CoV-2 lineage in a patient with long-term COVID-19
Although COVID-19 is primarily an acute disease, there are cases of persistent infection, primarily in immunocompromised patients. It is hypothesized that at least some variants of concern (VOCs) have arisen in such persistent cases, with the virus \"spilling over\" into the general population after accumulating intra-host mutations. Additionally, a growing body of evidence hints at the gastrointestinal (GI) tract as a reservoir of long-term infection, at least in some cases.
We report the genomic analysis of a highly divergent SARS-CoV-2 sample obtained in October 2022 from an HIV+ patient with presumably long-term COVID-19 infection. Phylogenetic analysis indicates that the sample is characterized by a gain of 89 mutations since divergence from its nearest sequenced neighbor, which had been collected in September 2020 and belongs to the B.1.1 lineage, largely extinct by 2022. Of these mutations, 33 were nonsynonymous and occurred in the Spike protein. Of these, 17 are lineage-defining in some VOCs or are at sites where another mutation is lineage-defining in a VOC, and/or have been shown to be involved in antibody evasion, and/or have been detected in other cases of persistent COVID-19; these include some \"usual suspects,\" such as Spike:L452R, E484Q, K417T, Y453F, and N460K. Molecular clock analysis indicates that mutations in this lineage accumulated at an increased rate compared with the ancestral B.1.1 strain. This increase is driven by the accumulation of non-synonymous mutations, with an average dN/dS value of 2.2, indicating strong positive selection during within-patient evolution. Additionally, the presence of mutations that are rare in the general population samples but common in samples from wastewater suggests that the virus had persisted for at least some time in the GI tract.
Our analysis adds to the growing body of evidence that the evolution of SARS-CoV-2 in chronically infected patients can be a major source of novel epidemiologically important variants and points to the potential role of the GI tract in long-term infection.
Journal Article
Matrix-associated extracellular vesicles modulate human smooth muscle cell adhesion and directionality by presenting collagen VI
The extracellular matrix (ECM) supports blood vessel architecture and functionality and undergoes active remodelling during vascular repair and atherogenesis. Vascular smooth muscle cells (VSMCs) are essential for vessel repair and, via their secretome, can invade from the vessel media into the intima to mediate ECM remodelling. Accumulation of fibronectin (FN) is a hallmark of early vascular repair and atherosclerosis. Here, we show that FN stimulates human VSMCs to secrete small extracellular vesicles (sEVs) by activating the β1 integrin/FAK/Src pathway as well as Arp2/3-dependent branching of the actin cytoskeleton. We found that sEVs are trapped by the ECM in vitro and colocalise with FN in symptomatic atherosclerotic plaques in vivo. Functionally, ECM-trapped sEVs induced the formation of focal adhesions (FA) with enhanced pulling forces at the cellular periphery preventing cellular spreading and adhesion. Proteomic and GO pathway analysis revealed that VSMC-derived sEVs display a cell adhesion signature and are specifically enriched with collagen VI on the sEV surface. In vitro assays identified collagen VI as playing a key role in cell adhesion and invasion directionality. Taken together, our data suggests that the accumulation of FN is a key early event in vessel repair acting to promote secretion of collagen VI enriched sEVs by VSMCs. These sEVs stimulate directional invasion, most likely by triggering peripheral focal adhesion formation and actomyosin contraction to exert sufficient traction force to enable VSMC movement within the complex vascular ECM network.
Journal Article
Genetic insights into the social organization of Neanderthals
Genomic analyses of Neanderthals have previously provided insights into their population history and relationship to modern humans1-8, but the social organization of Neanderthal communities remains poorly understood. Here we present genetic data for 13 Neanderthals from two Middle Palaeolithic sites in the Altai Mountains of southern Siberia: 11 from Chagyrskaya Cave9,10 and 2 from Okladnikov Cave11—making this one of the largest genetic studies of a Neanderthal population to date. We used hybridization capture to obtain genome-wide nuclear data, as well as mitochondrial and Y-chromosome sequences. Some Chagyrskaya individuals were closely related, including a father-daughter pair and a pair of second-degree relatives, indicating that at least some of the individuals lived at the same time. Up to one-third of these individuals' genomes had long segments of homozygosity, suggesting that the Chagyrskaya Neanderthals were part of a small community. In addition, the Y-chromosome diversity is an order of magnitude lower than the mitochondrial diversity, a pattern that we found is best explained by female migration between communities. Thus, the genetic data presented here provide a detailed documentation of the social organization of an isolated Neanderthal community at the easternmost extent of their known range.
Journal Article
Immune Checkpoint Ligand PD-L1 Is Upregulated in Pulmonary Lymphangioleiomyomatosis
Pulmonary lymphangioleiomyomatosis (LAM) is a slow-progressing metastatic disease that is driven by mutations in the tumor suppressor tuberous sclerosis complex 1/2 (TSC1/2). Rapamycin inhibits LAM cell proliferation and is the only approved treatment, but it cannot cause the regression of existing lesions and can only stabilize the disease. However, in other cancers, immunotherapies such as checkpoint blockade against PD-1 and its ligand PD-L1 have shown promise in causing tumor regression and even curing some patients. Thus, we asked whether PD-L1 has a role in LAM progression. In vitro, PD-L1 expression in murine Tsc2-null cells is unaffected by mTOR inhibition with torin but can be upregulated by IFN-γ. Using immunohistochemistry and single-cell flow cytometry, we found increased PD-L1 expression both in human lung tissue from patients with LAM and in Tsc2-null lesions in a murine model of LAM. In this model, PD-L1 is highly expressed in the lung by antigen-presenting and stromal cells, and activated T cells expressing PD-1 infiltrate the affected lung. In vivo treatment with anti-PD-1 antibody significantly prolongs mouse survival in the model of LAM. Together, these data demonstrate that PD-1/PD-L1-mediated immunosuppression may occur in LAM, and suggest new opportunities for therapeutic targeting that may provide benefits beyond those of rapamycin.
Journal Article