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result(s) for
"Lundgren, K"
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Chickens
Presents general information about chickens, why people raise them, some of the various breeds, and how they grow from fertilized eggs to mature birds.
Book
Antigen-specific B cell depletion for precision therapy of mucosal pemphigus vulgaris
Desmoglein 3 chimeric autoantibody receptor T cells (DSG3-CAART) expressing the pemphigus vulgaris (PV) autoantigen DSG3 fused to CD137-CD3ζ signaling domains, represent a precision cellular immunotherapy approach for antigen-specific B cell depletion. Here, we present definitive preclinical studies enabling a first-in-human trial of DSG3-CAART for mucosal PV. DSG3-CAART specifically lysed human anti-DSG3 B cells from PV patients and demonstrated activity consistent with a threshold dose in vivo, resulting in decreased target cell burden, decreased serum and tissue-bound autoantibodies, and increased DSG3-CAART engraftment. In a PV active immune model with physiologic anti-DSG3 IgG levels, DSG3-CAART inhibited antibody responses against pathogenic DSG3 epitopes and autoantibody binding to epithelial tissues, leading to clinical and histologic resolution of blisters. DSG3 autoantibodies stimulated DSG3-CAART IFN-γ secretion and homotypic clustering, consistent with an activated phenotype. Toxicology screens using primary human cells and high-throughput membrane proteome arrays did not identify off-target cytotoxic interactions. These preclinical data guided the trial design for DSG3-CAART and may help inform CAART preclinical development for other antibody-mediated diseases.
Journal Article
A shared mechanism for Bacteroidota protein transport and gliding motility
Bacteria of the phylum Bacteroidota are major human commensals and pathogens in addition to being abundant members of the wider biosphere. Bacteroidota move by gliding and they export proteins using the Type 9 Secretion System (T9SS). Here we discover that gliding motility and the T9SS share an unprecedented mechanism of energisation in which outer membrane proteins are covalently attached by disulfide bonds to a moving internal track structure that propels them laterally through the membrane. We determined the structure of an exemplar Bacteroidota mobile track by obtaining the cryoEM structure of a 3 MDa circular mini-track from
Porphyromonas gingivalis
. Our discoveries identify a mechanistic and evolutionary link between gliding motility and T9SS-dependent protein transport.
Bacteria of the phylum
Bacteroidota
move by gliding and export proteins using a type-9 secretion system. Here, Liu et al. show that these two processes use a shared mechanism in which outer membrane proteins are covalently attached by disulfide bonds to a moving track structure inside the cell.
Journal Article
Hypoxia, Snail and incomplete epithelial–mesenchymal transition in breast cancer
Background:
Hypoxia is an element of the tumour microenvironment that impacts upon numerous cellular factors linked to clinical aggressiveness in cancer. One such factor, Snail, a master regulator of the epithelial–mesenchymal transition (EMT), has been implicated in key tumour biological processes such as invasion and metastasis. In this study we set out to investigate regulation of EMT in hypoxia, and the importance of Snail in cell migration and clinical outcome in breast cancer.
Methods:
Four breast cancer cell lines were exposed to 0.1% oxygen and expression of EMT markers was monitored. The migratory ability was analysed following Snail overexpression and silencing. Snail expression was assessed in 500 tumour samples from premenopausal breast cancer patients, randomised to either 2 years of tamoxifen or no adjuvant treatment.
Results:
Exposure to 0.1% oxygen resulted in elevated levels of Snail protein, along with changes in vimentin and E-cadherin expression, and in addition increased migration of MDA-MB-468 cells. Overexpression of Snail increased the motility of MCF-7, T-47D and MDA-MB-231 cells, whereas silencing of the protein resulted in decreased migratory propensity of MCF-7, MDA-MB-468 and MDA-MB-231 cells. Moreover, nuclear Snail expression was associated with tumours of higher grade and proliferation rate, but not with disease recurrence. Interestingly, Snail negativity was associated with impaired tamoxifen response (
P
=0.048).
Conclusions:
Our results demonstrate that hypoxia induces Snail expression but generally not a migratory phenotype, suggesting that hypoxic cells are only partially pushed towards EMT. Furthermore, our study supports the link between Snail and clinically relevant features and treatment response.
Journal Article
Histological evaluation of cardiac remodelling in equine athletes
Approximately 1–2 per 100,000 young athletes die from sudden cardiac death (SCD) and extreme exercise may be associated with myocardial scar and arrhythmias. Racehorses have a high prevalence of atrial fibrillation (AF) and SCD but the presence of myocardial scar and inflammation has not been evaluated. Cardiac tissues from the left (LAA) and right (RAA) atrial appendages, left ventricular anterior (LVAPM) and posterior (LVPPM) papillary muscles, and right side of the interventricular septum (IVS-R) were harvested from racehorses with sudden cardiac death (SCD, n = 16) or other fatal injuries (OFI, n = 17), constituting the athletic group (ATH, n = 33), and compared to sedentary horses (SED, n = 10). Horses in the ATH group had myocyte hypertrophy at all sites; increased fibrosis at all sites other than the LAA; increased fibroblast infiltration but a reduction in the overall extracellular matrix (ECM) volume in the RAA, LVAPM, and IVS-R compared to SED horses. In this horse model, athletic conditioning was associated with myocyte hypertrophy and a reduction in ECM. There was an excess of fibrocyte infiltration and focal fibrosis that was not present in non-athletic horses, raising the possibility of an exercise-induced pro-fibrotic substrate.
Journal Article
An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation
Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an
N
-methyl-
d
-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (
P
<0.001) and blood (
P
=0.001 and
P
<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.
Journal Article
Tests on anchorage of naturally corroded reinforcement in concrete
Many studies on the structural effects of corrosion in reinforcement have been conducted. However, most of them are based on artificially corroded test specimens. Thus, the knowledge available entails one major uncertainty, i.e. whether the results are reliable enough to be used for naturally corroded structures. The purpose of this study was to develop a test method and carry out experiments on naturally corroded specimens taken from an existing structure to investigate the anchorage capacity. Beam specimens were taken from the edge beams of a bridge at repair. The specimens showed corrosion-induced damage to a varying extent from no sign of corrosion to extensive cracking and spalling of the concrete cover. A four-point bending test indirectly supported by suspension hangers was chosen. The beams were strengthened with transverse reinforcement around the suspension hangers to avoid premature failure. Eight successful tests were carried out; in all these tests, diagonal shear cracks preceded a splitting induced pull-out failure; i.e. anchorage failure was achieved as intended. The results showed around 10 % lower capacity for the corroded specimens than for the reference ones. The average bond stress in the anchorage zone was estimated based on the applied load and available anchorage length. The stress was about 16 % lower in the beams with corrosion cracks, and 9 % lower in the beams with cover spalling compared to the reference specimens; there was also a larger variation among the damaged specimens than for the reference specimens. The results extend our knowledge concerning the structural behaviour of corroded reinforced concrete structures during field conditions.
Journal Article
Structure of the conjugation surface exclusion protein TraT
Conjugal transfer of plasmids between bacteria is a major route for the spread of antimicrobial resistance. Many conjugative plasmids encode exclusion systems that inhibit redundant conjugation. In incompatibility group F (IncF) plasmids surface exclusion is mediated by the outer membrane protein TraT. Here we report the cryoEM structure of the TraT exclusion protein complex from the canonical F plasmid of
Escherichia coli
. TraT is a hollow homodecamer shaped like a chef’s hat. In contrast to most outer membrane proteins, TraT spans the outer membrane using transmembrane α-helices. We develop a microscopy-based conjugation assay to probe the effects of directed mutagenesis on TraT. Our analysis provides no support for the idea that TraT has specific interactions with partner proteins. Instead, we infer that TraT is most likely to function by physical interference with conjugation. This work provides structural insight into a natural inhibitor of microbial gene transfer.
Chen et al. determined the cryo-EM structure of the TraT exclusion protein from the F plasmid of
E. coli
, revealing a unique hollow homodecameric architecture that includes α-helices traversing the outer membrane. Their work indicates that TraT might limit plasmid transfer via physical interference, offering insights into controlling antimicrobial resistance.
Journal Article
Hypoxia and breast cancer: prognostic and therapeutic implications
Hypoxia affects many important processes in tumour progression and is a key feature in the tumour microenvironment that needs to be taken into account when evaluating prognostics and therapeutic options for cancer patients. Hypoxia-regulating proteins, i.e. hypoxia inducible factors (HIFs), and associated gene products have been linked to certain tumour behaviours and might be useful as prognostic and predictive markers. Recently, hypoxia-driven gene products have been launched as novel cancer treatment targets with the potential to increase tumour-specific effects. Breast cancer consists of a multitude of different diseases with certain common characteristics, but also clearly disparate behaviours and genetic alterations. In this review we will summarise the role of hypoxia in breast cancer and specifically outline the importance of hypoxia and HIF-1alpha regarding prognostic and treatment-specific implications. (Part of a Multi-author Review).
Journal Article