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"Carroll, P."
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A post-exceptionalist perspective on early American history : American Wests, global Wests, and Indian Wars
Challenging the still widely held notion that Ametrican history is somehow exceptional or unique, this book argues that early America is best understood as a settler-colonial supplanting society. As Kakel shows, this society undertook the violent theft of Indigenous land and resources on a massive scale, and was driven by a logic of elimination and a genocidal imperative to rid the new white settler living space of its existing Indigenous inhabitants.
Book
Discovery of the interstellar chiral molecule propylene oxide (CH₃CHCH₂O)
Life on Earth relies on chiral molecules—that is, species not superimposable on their mirror images. This manifests itself in the selection of a single molecular handedness, or homochirality, across the biosphere. We present the astronomical detection of a chiral molecule, propylene oxide (CH₃CHCH₂O), in absorption toward the Galactic center. Propylene oxide is detected in the gas phase in a cold, extended molecular shell around the embedded, massive protostellar clusters in the Sagittarius B2 star-forming region. This material is representative of the earliest stage of solar system evolution in which a chiral molecule has been found.
Journal Article
Beginners
\"Carver is one of the most celebrated short-story writers in American literature his style is both instantly recognizable and hugely influential and the pieces in \"What We Talk About\" . . ., which portray the gritty loves and lives of the American working class, are counted among the foundation stones of the contemporary short story. In this unedited text, we gain insight into the process of a great writer. These expansive stories illuminate the many dimensions of Carver s style, and are indispensable to our understanding of his legacy.\"--Provided by publisher.
Book
Detection of a pair density wave state in UTe2
Spin-triplet topological superconductors should exhibit many unprecedented electronic properties, including fractionalized electronic states relevant to quantum information processing. Although UTe
2
may embody such bulk topological superconductivity
1
–
11
, its superconductive order parameter Δ(
k
) remains unknown
12
. Many diverse forms for Δ(
k
) are physically possible
12
in such heavy fermion materials
13
. Moreover, intertwined
14
,
15
density waves of spin (SDW), charge (CDW) and pair (PDW) may interpose, with the latter exhibiting spatially modulating
14
,
15
superconductive order parameter Δ(
r
), electron-pair density
16
–
19
and pairing energy gap
17
,
20
–
23
. Hence, the newly discovered CDW state
24
in UTe
2
motivates the prospect that a PDW state may exist in this material
24
,
25
. To search for it, we visualize the pairing energy gap with μeV-scale energy resolution using superconductive scanning tunnelling microscopy (STM) tips
26
–
31
. We detect three PDWs, each with peak-to-peak gap modulations of around 10 μeV and at incommensurate wavevectors
P
i
=1,2,3
that are indistinguishable from the wavevectors
Q
i
=1,2,3
of the prevenient
24
CDW. Concurrent visualization of the UTe
2
superconductive PDWs and the non-superconductive CDWs shows that every
P
i
:
Q
i
pair exhibits a relative spatial phase
δϕ
≈ π. From these observations, and given UTe
2
as a spin-triplet superconductor
12
, this PDW state should be a spin-triplet PDW
24
,
25
. Although such states do exist
32
in superfluid
3
He, for superconductors, they are unprecedented.
A spin-triplet pair density wave is discovered in the candidate topological superconductor UTe
2
using superconductive scanning tunnelling microscopy tips.
Journal Article
Potentially Pathogenic Airway Bacteria and Neutrophilic Inflammation in Treatment Resistant Severe Asthma
Molecular microbiological analysis of airway samples in asthma has demonstrated an altered microbiome in comparison to healthy controls. Such changes may have relevance to treatment-resistant severe asthma, particularly those with neutrophilic airway inflammation, as bacteria might be anticipated to activate the innate immune response, a process that is poorly steroid responsive. An understanding of the relationship between airway bacterial presence and dominance in severe asthma may help direct alternative treatment approaches.
We aimed to use a culture independent analysis strategy to describe the presence, dominance and abundance of bacterial taxa in induced sputum from treatment resistant severe asthmatics and correlate findings with clinical characteristics and airway inflammatory markers.
Induced sputum was obtained from 28 stable treatment-resistant severe asthmatics. The samples were divided for supernatant IL-8 measurement, cytospin preparation for differential cell count and Terminal Restriction Fragment Length Polymorphism (T-RFLP) profiling for bacterial community analysis.
In 17/28 patients, the dominant species within the airway bacterial community was Moraxella catarrhalis or a member of the Haemophilus or Streptococcus genera. Colonisation with these species was associated with longer asthma disease duration (mean (SD) 31.8 years (16.7) vs 15.6 years (8.0), p = 0.008), worse post-bronchodilator percent predicted FEV1 (68.0% (24.0) vs 85.5% (19.7), p = 0.025) and higher sputum neutrophil differential cell counts (median (IQR) 80% (67-83) vs 43% (29-67), p = 0.001). Total abundance of these organisms significantly and positively correlated with sputum IL-8 concentration and neutrophil count.
Airway colonisation with potentially pathogenic micro-organisms in asthma is associated with more severe airways obstruction and neutrophilic airway inflammation. This altered colonisation may have a role in the development of an asthma phenotype that responds less well to current asthma therapies.
Journal Article
Immune checkpoint inhibitors in kidney transplant recipients: a multicentre, single-arm, phase 1 study
Most kidney transplant recipients with cancer stop or reduce immunosuppressive therapy before starting treatment with an immune checkpoint inhibitor, and approximately 40% of such patients will develop allograft rejection. Isolated immunosuppression reduction might be associated with organ rejection. Whether immunosuppression manipulation, immune checkpoint inhibition, or both, induce organ rejection is difficult to ascertain. The aim of this study was to examine the risk of allograft rejection with immune checkpoint inhibitor exposure when baseline immunosuppression was left unchanged.
We conducted a multicentre, single-arm, phase 1 study in three hospitals in Australia. Kidney transplant recipients aged 18 years or older with incurable, locally advanced cancer or defined metastatic solid tumours were eligible if they had a creatinine concentration of less than 180 mmol/L, no or low concentrations of donor-specific HLA antibodies, and an Eastern Cooperative Oncology Group status of 0–2. Patients received standard doses of nivolumab (3 mg/kg intravenously every 14 days for five cycles, then 480 mg every 28 days for up to 2 years). The primary endpoint was the proportion of patients with irretrievable allograft rejection and no evidence of tumour response. Primary outcome analyses and safety analyses were done in the modified intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Register, ANZCTR12617000741381, and is completed.
Between May 31, 2017, and Aug 6, 2021, 22 kidney transplant recipients with various solid tumours were screened and enrolled, four of whom chose not to proceed in the study and one of whom had unexpected disease progression. 17 patients (six [35%] women and 11 [65%] men; median age 67 years [IQR 59–71]) were allocated treatment with nivolumab and were included in the analyses. The trial was then stopped due to ongoing difficulties with running clinical trials during COVID-19 health restrictions. Patients were treated with a median of three infusions (IQR 2–10) and median follow-up was 28 months (IQR 16–34). No patients had irretrievable allograft rejection without evidence of tumour response. There were no treatment-related deaths or treatment-related serious adverse events. The most common grade 3 or grade 4 adverse events were decreased lymphocyte count in four (24%) patients, fever or infection in four (24%) patients, decreased haemoglobin in three (18%) patients, and increased creatinine in three (18%) patients.
Maintaining baseline immunosuppression before treatment with an immune checkpoint inhibitor in kidney transplant recipients might not affect expected efficacy and might reduce the risk of allograft rejection mediated by immune checkpoint inhibitors.
Bristol Myers Squibb.
Journal Article
Single-cell mutation analysis of clonal evolution in myeloid malignancies
Myeloid malignancies, including acute myeloid leukaemia (AML), arise from the expansion of haematopoietic stem and progenitor cells that acquire somatic mutations. Bulk molecular profiling has suggested that mutations are acquired in a stepwise fashion: mutant genes with high variant allele frequencies appear early in leukaemogenesis, and mutations with lower variant allele frequencies are thought to be acquired later
1
–
3
. Although bulk sequencing can provide information about leukaemia biology and prognosis, it cannot distinguish which mutations occur in the same clone(s), accurately measure clonal complexity, or definitively elucidate the order of mutations. To delineate the clonal framework of myeloid malignancies, we performed single-cell mutational profiling on 146 samples from 123 patients. Here we show that AML is dominated by a small number of clones, which frequently harbour co-occurring mutations in epigenetic regulators. Conversely, mutations in signalling genes often occur more than once in distinct subclones, consistent with increasing clonal diversity. We mapped clonal trajectories for each sample and uncovered combinations of mutations that synergized to promote clonal expansion and dominance. Finally, we combined protein expression with mutational analysis to map somatic genotype and clonal architecture with immunophenotype. Our findings provide insights into the pathogenesis of myeloid transformation and how clonal complexity evolves with disease progression.
The evolution of myeloid malignancies is investigated using combined single-cell sequencing and immunophenotypic analysis.
Journal Article
α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8
Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.
Journal Article
RNA-Seq Atlas of Glycine max: A guide to the soybean transcriptome
Background: Next generation sequencing is transforming our understanding of transcriptomes. It can determine the expression level of transcripts with a dynamic range of over six orders of magnitude from multiple tissues, developmental stages or conditions. Patterns of gene expression provide insight into functions of genes with unknown annotation. Results: The RNA Seq-Atlas presented here provides a record of high-resolution gene expression in a set of fourteen diverse tissues. Hierarchical clustering of transcriptional profiles for these tissues suggests three clades with similar profiles: aerial, underground and seed tissues. We also investigate the relationship between gene structure and gene expression and find a correlation between gene length and expression. Additionally, we find dramatic tissue-specific gene expression of both the most highly-expressed genes and the genes specific to legumes in seed development and nodule tissues. Analysis of the gene expression profiles of over 2,000 genes with preferential gene expression in seed suggests there are more than 177 genes with functional roles that are involved in the economically important seed filling process. Finally, the Seq-atlas also provides a means of evaluating existing gene model annotations for the Glycine max genome. Conclusions: This RNA-Seq atlas extends the analyses of previous gene expression atlases performed using Affymetrix GeneChip technology and provides an example of new methods to accommodate the increase in transcriptome data obtained from next generation sequencing. Data contained within this RNA-Seq atlas of Glycine max can be explored at http://www.soybase.org/soyseq.
Journal Article