The magnetic survey of Tasmania

Read before the Royal Society of Tasmania, 13 August, 1900. Section 1. The History of Magnetic Observation in Tasmania. Section II. Magnetic work in Victoria and New Zealand. Section III. The work of the proposed Survey. From its southerly latitude, its situation relative to the great land-mass of Australia, and its position almost in antipodes to Great Britain, Tasmania is eminently fitted as a station for magnetic observations, and, recognising this, the Royal Society of London, in the early forties, fitted out a complete survey party, with the latest form of instruments, to investigate, under the superintendence of Lieut. Kay, R.N., the magnetic elements of Tasmania, and to determine the rate of variation of these elements

Note on Itacolumite or flexible sandstone

The existence of flexible sandstone appears to have been known of since 1780, when specimens were brought to Europe from Brazil hy the Marquis of Lavradio, Viceroy of Rio de Janeiro. The bed-rock in which the flexible sandstone occurs was found by Von Eschwege to be largely dereloped near Mt. Itacolunmi in the State of Villa Rica, Province of Mina Garaes, Brazil, and is described by him as a fissile sandstcme containing plates of talc, chlorite, and mica.This rock contains a little gold, and has been shown by Heusser and Claraz to be the parent source of the Brazilian\ud diamond

Tourmaline-bearing rocks of the Heemskirk district

The Heemskirk district was visited some weeks ago by one of the authors in the course of his official duties as Assistant Government Geologist. Most of the field observations then made have already been published in the report on the district recently issued by the Mines Department, but the necessity of writing these reports as soon as possible after the examination of the district in question is completed precludes the possibility of a minute examination into the microscopical character of the rocks prior to publication

The glacial beds of Little Peppermint Bay, Tasmania

Little Peppermint Bay is a small arm of the sea on the western side of D'Entrecasteaux Channel, abont 27 miles south of Hobart. The nearest point at which the Channel steamers call is Woodbridge, or Peppermint Bay, about half a mile south of the beds described in this paper.The prevailing beds in the locality belong to thePermo- Carboniferous series, and have, over a large area, a fairly uniform dip to the S.E., at about an angle of 30C. They are intruded into by two distinct types of igneous rocks, viz., the Oyster Cove porphyries and the diabase greenstone, and, near the contacts, are disturbed to a considerable extent

On certain calcareous nodules

The nodules described in the following paper occur in certain bands in the upper members of the strata disclosed at Duff's quarry, in Forster-street, New Town. The nodule-bearing bands appear to be unfossiliferous, but both above and below them are other bands carrying numerous fossil impressions, including Alethopteris australis, Thinnfeldia obtusifolia, Phyllotheca, &c. The whole series of bands is just below the horizon of the New Town Coal Measures. The beds in which the nodules are found are grey and blue-grey in colour, traversed by thin layers of darker hue, thus giving rise to a banded structure ; they may be described as a calcareous sandstone of fine texture, fairly tough, and showing little or no tendency to split along the planes of banding. Includes two photograph

Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody-drug Conjugate Targeting AXL-expressing Cancers

AXL, a tyrosine kinase receptor that is overexpressed in many solid and hematologic malignancies, facilitates cancer progression and is associated with poor clinical outcomes. Importantly, drug-induced expression of AXL results in resistance to conventional chemotherapy and targeted therapies. Together with its presence on multiple cell types in the tumor immune microenvironment, these features make it an attractive therapeutic target for AXL-expressing malignancies. ADCT-601 (mipasetamab uzoptirine) is an AXL-targeted antibody–drug conjugate (ADC) comprising a humanized anti-AXL antibody site specifically conjugated using GlycoConnect technology to PL1601, which contains HydraSpace, a Val-Ala cleavable linker and the potent pyrrolobenzodiazepine (PBD) dimer cytotoxin SG3199. This study aimed to validate the ADCT-601 mode of action and evaluate its efficacy in vitro and in vivo, as well as its tolerability and pharmacokinetics. ADCT-601 bound to both soluble and membranous AXL, and was rapidly internalized by AXL-expressing tumor cells, allowing release of PBD dimer, DNA interstrand cross-linking, and subsequent cell killing. In vivo, ADCT-601 had potent and durable antitumor activity in a wide variety of human cancer xenograft mouse models, including patient-derived xenograft models with heterogeneous AXL expression where ADCT-601 antitumor activity was markedly superior to an auristatin-based comparator ADC. Notably, ADCT-601 had antitumor activity in a monomethyl auristatin E–resistant lung-cancer model and synergized with the PARP inhibitor olaparib in a BRCA1-mutated ovarian cancer model. ADCT-601 was well tolerated at doses of up to 6 mg/kg and showed excellent stability in vivo. These preclinical results warrant further evaluation of ADCT-601 in the clinic

Topological data analysis reveals genotype-phenotype relationships in primary ciliary dyskinesia

Background: Primary ciliary dyskinesia (PCD) is a heterogeneous inherited disorder caused by mutations in approximately 50 cilia-related genes. PCD genotype-phenotype relationships have mostly arisen from small case series because existing statistical approaches to investigate relationships have been unsuitable for rare diseases. / Methods: We applied a topological data analysis (TDA) approach to investigate genotype-phenotype relationships in PCD. Data from separate training and validation cohorts included 396 genetically defined individuals carrying pathogenic variants in PCD genes. To develop the TDA models, twelve clinical and diagnostic variables were included. TDA-driven hypotheses were subsequently tested using traditional statistics. / Results: Disease severity at diagnosis measured by FEV1 z-score was (i) significantly worse in individuals with CCDC39 mutations compared to other gene mutations and (ii) better in those with DNAH11 mutations; the latter also reported less neonatal respiratory distress. Patients without neonatal respiratory distress had better preserved FEV1 at diagnosis. Individuals with DNAH5 mutations were phenotypically diverse. Cilia ultrastructure and beat pattern defects correlated closely to specific causative gene groups, confirming these tests can be used to support a genetic diagnosis. / Conclusions: This large scale multi-national study presents PCD as a syndrome with overlapping symptoms and variation in phenotype, according to genotype. TDA modelling confirmed genotype-phenotype relationships reported by smaller studies (e.g. FEV1 worse with CCDC39 mutations), and identified new relationships, including FEV1 preservation with DNAH11 mutations and diversity of severity with DNAH5 mutations

Enhanced effector function of cytotoxic cells in the induced sputum of COPD patients

<p>Abstract</p> <p>Background</p> <p>We have previously shown that NK (CD56⁺CD3^-) and NKT-like (CD56⁺CD3⁺) cells are reduced in both numbers and cytotoxicity in peripheral blood. The aim of the present study was to investigate their numbers and function within induced sputum.</p> <p>Methods</p> <p>Induced sputum cell numbers and intracellular granzyme B and perforin were analysed by flow cytometry. Immunomagnetically selected CD56⁺cells (NK and NKT-like cells) were used in an LDH release assay to determine cytotoxicity.</p> <p>Results</p> <p>The proportion of NK cells and NKT-like cells in smokers with COPD (COPD subjects) was significantly higher (12.7% and 3%, respectively) than in healthy smokers (smokers) (5.7%, p < 0.01; 1%, p < 0.001) and non-smoking healthy subjects (HNS) (4.2%, p < 0.001; 0.8%, p < 0.01). The proportions of NK cells and NKT-like cells expressing <it>both </it>perforin <it>and </it>granzyme B were also significantly higher in COPD subjects compared to smokers and HNS. CD56⁺cells from COPD subjects were significantly more cytotoxic (1414 biological lytic activity) than those from smokers (142.5; p < 0.01) and HNS (3.8; p < 0.001) and were inversely correlated to FEV₁. (r = -0.75; p = 0.0098).</p> <p>Conclusion</p> <p>We have shown an increased proportion of NK and NKT-like cells in the induced sputum of COPD subjects and have demonstrated that these cells are significantly more cytotoxic in COPD subjects than smokers and HNS.</p

Age differences in physiological responses to self-paced and incremental V˙O2max\dot V O_{2max} testing

Purpose: A self-paced maximal exercise protocol has demonstrated higher $\dot V O_{2max}$ values when compared against traditional tests. The aim was to compare physiological responses to this self-paced $\dot V O_{2max}$ protocol (SPV) in comparison to a traditional ramp $\dot V O_{2max}$ (RAMP) protocol in young (18–30 years) and old (50–75 years) participants. Methods: Forty-four participants (22 young; 22 old) completed both protocols in a randomised, counter-balanced, crossover design. The SPV included 5 × 2 min stages, participants were able to self-regulate their power output (PO) by using incremental ‘clamps’ in ratings of perceived exertion. The RAMP consisted of either 15 or 20 W min$^{−1}$. Results: Expired gases, cardiac output (Q), stroke volume (SV), muscular deoxyhaemoglobin (deoxyHb) and electromyography (EMG) at the vastus lateralis were recorded throughout. Results demonstrated significantly higher $\dot V O_{2max}$ in the SPV (49.68 ± 10.26 ml kg$^{−1}$ min$^{−1}$) vs. the RAMP (47.70 ± 9.98 ml kg$^{−1}$ min$^{−1}$) in the young, but not in the old group (>0.05). Q and SV were significantly higher in the SPV vs. the RAMP in the young (0.05). No differences seen in deoxyHb and EMG for either age groups (>0.05). Peak PO was significantly higher in the SPV vs. the RAMP in both age groups (<0.05). Conclusion: Findings demonstrate that the SPV produces higher $\dot V O_{2max}$, peak Q and SV values in the young group. However, older participants achieved similar $\dot V O_{2max}$ values in both protocols, mostly likely due to age-related differences in cardiovascular responses to incremental exercise, despite them achieving a higher physiological workload in the SPV

The interaction of Thrombospondins with extracellular matrix proteins

The thrombospondins (TSPs) are a family of five matricellular proteins that appear to function as adapter molecules to guide extracellular matrix synthesis and tissue remodeling in a variety of normal and disease settings. Various TSPs have been shown to bind to fibronectin, laminin, matrilins, collagens and other extracellular matrix (ECM) proteins. The importance of TSP-1 in this context is underscored by the fact that it is rapidly deposited at the sites of tissue damage by platelets. An association of TSPs with collagens has been known for over 25 years. The observation that the disruption of the TSP-2 gene in mice leads to collagen fibril abnormalities provided important in vivo evidence that these interactions are physiologically important. Recent biochemical studies have shown that TSP-5 promotes collagen fibril assembly and structural studies suggest that TSPs may interact with collagens through a highly conserved potential metal ion dependent adhesion site (MIDAS). These interactions are critical for normal tissue homeostasis, tumor progression and the etiology of skeletal dysplasias