The nature of carbon monoxide adsorption on platinum group metal catalysts

The nature of carbon monoxide adsorption on alumina supported platinum group metal catalysts was investigated using in-situ infra-red spectroscopy. Both adsorption and thermal desorption studies were made and the results combined to give a complete picture of the bonding schemes observed for each metal. In light of the conclusions drawn from this research, bimetallic samples were then investigated. The observations from these experiments were explained by comparison with the results from the constituent metals. When attempting to study the bonding schemes in more detail using an enhanced method of data collection, anomalous results were obtained. It was proposed that the species formed would be alumina carbonates, this was proven correct by comparison with the results from a standard preparation of these groups. Standard techniques for the analysis of catalysts and the treatment of results were developed during the course of this work

Inverse kinematics of concentric tube steerable needles

Abstract-Prior papers have introduced steerable needles composed of precurved concentric tubes. The curvature and extent of these needles can be controlled by the relative rotation and translation of the individual tubes. Under certain assumptions on the geometry and design of these needles, the forward kinematics problem can be solved in closed form by means of algebraic equations. The inverse kinematics problem, however, is not as straightforward owing to the nonlinear map between relative tube displacements and needle tip configuration as well as to the multiplicity of solutions as the number of tubes increases. This paper presents a general approach to solving the inverse kinematics problem using a pseudoinverse solution together with gradients of nullspace potential functions to enforce geometric and mechanical constraints

Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia

Primary ciliary dyskinesia (PCD) is characterized by chronic airway disease, reduced fertility, and randomization of the left/right body axis. It is caused by defects of motile cilia and sperm flagella. We screened a cohort of affected individuals that lack an obvious axonemal defect for pathogenic variants using whole exome capture, next generation sequencing, and bioinformatic analysis assuming an autosomal recessive trait. We identified one subject with an apparently homozygous nonsense variant [(c.1762C\u3eT), p.(Arg588*)] in the uncharacterized CFAP57 gene. Interestingly, the variant results in the skipping of exon 11 (58 amino acids), which may be due to disruption of an exonic splicing enhancer. In normal human nasal epithelial cells, CFAP57 localizes throughout the ciliary axoneme. Nasal cells from the PCD patient express a shorter, mutant version of CFAP57 and the protein is not incorporated into the axoneme. The missing 58 amino acids include portions of WD repeats that may be important for loading onto the intraflagellar transport (IFT) complexes for transport or docking onto the axoneme. A reduced beat frequency and an alteration in ciliary waveform was observed. Knockdown of CFAP57 in human tracheobronchial epithelial cells (hTECs) recapitulates these findings. Phylogenetic analysis showed that CFAP57 is highly conserved in organisms that assemble motile cilia. CFAP57 is allelic with the BOP2/IDA8/FAP57 gene identified previously in Chlamydomonas reinhardtii. Two independent, insertional fap57 Chlamydomonas mutant strains show reduced swimming velocity and altered waveforms. Tandem mass tag (TMT) mass spectroscopy shows that FAP57 is missing, and the g inner dyneins (DHC7 and DHC3) and the d inner dynein (DHC2) are reduced, but the FAP57 paralog FBB7 is increased. Together, our data identify a homozygous variant in CFAP57 that causes PCD that is likely due to a defect in the inner dynein arm assembly process

Cyclic strain induces dualmode endothelial-mesenchymal transformation of the cardiac valve

Endothelial-mesenchymal transformation (EMT) is a critical event for the embryonic morphogenesis of cardiac valves. Inducers of EMT during valvulogenesis include VEGF, TGF-β1, and wnt/β-catenin (where wnt refers to the wingless-type mammary tumor virus integration site family of proteins), that are regulated in a spatiotemporal manner. EMT has also been observed in diseased, strain-overloaded valve leaflets, suggesting a regulatory role for mechanical strain. Although the preponderance of studies have focused on the role of soluble mitogens, we asked if the valve tissue microenvironment contributed to EMT. To recapitulate these microenvironments in a controlled, in vitro environment, we engineered 2D valve endothelium from sheep valve endothelial cells, using microcontact printing to mimic the regions of isotropy and anisotropy of the leaflet, and applied cyclic mechanical strain in an attempt to induce EMT. We measured EMT in response to both low (10%) and high strain (20%), where low-strain EMT occurred via increased TGF-β1 signaling and high strain via increased wnt/β-catenin signaling, suggesting dual strain-dependent routes to distinguish EMT in healthy versus diseased valve tissue. The effect was also directionally dependent, where cyclic strain applied orthogonal to axis of the engineered valve endothelium alignment resulted in severe disruption of cell microarchitecture and greater EMT. Once transformed, these tissues exhibited increased contractility in the presence of endothelin-1 and larger basal mechanical tone in a unique assay developed to measure the contractile tone of the engineered valve tissues. This finding is important, because it implies that the functional properties of the valve are sensitive to EMT. Our results suggest that cyclic mechanical strain regulates EMT in a strain magnitude and directionally dependent manner. tight junctions | cytokines | activated myofibroblast C ardiac valves are sophisticated structures that function in a complex mechanical environment, opening and closing more than 3 billion times during the average human lifetime (1). Initially considered passive flaps of tissue, it is now acknowledged that valves contain a highly heterogeneous population of endothelial (VEC) and interstitial (VIC) cells. The VICs exist as synthetic, myofibroblast, or smooth muscle-like phenotypes (2, 3) and alter their tone in response to vasoactive mediators (4-7). The VECs line the surface of the valve leaflet and are unique in their ability to undergo endothelial-mesenchymal transformation (EMT), a process that is crucial for valvulogenesis (8, 9). Recent clinical evidence of EMT has been observed in pathologies such as ischemic cardiomyopathy and concomitant mitral regurgitation and is correlated with increased leaflet mechanical strains (10, 11). These pathological strains can be oriented obliquely to cell and tissue orientation (12, 13), suggesting the possible interaction between mechanical forces and tissue architecture in regulating EMT. Prior work has focused on the regulation of EMT via soluble factors. Modulation of VEGF and increases in wnt/β-catenin and TGF-β1 expression, among other factors, direct EMT during valvulogenesis (8, 14) and in the mature valve (15, 16). Additionally, mechanical forces are known to modulate valve remodeling and disease progression (17, 18). However, the influence of mechanical forces and its synergy with tissue architecture in influencing cardiac valve EMT is unknown. During embryonic development, valve morphogenesis has been correlated with an increase in fluid shear stresses, mechanical strains, and altered geometry of the developing heart (19-22). These observations potentially suggests interaction between mechanical forces and the factors that regulate EMT. Additionally, it is also unknown if EMT results in a functional change of the VEC to a contractile myofibroblast-like VIC. We hypothesized that cyclic strain may potentiate valve EMT in a manner dependent on cell orientation and the direction of applied strain. We developed an in vitro model that combines cyclic stretching of engineered valve endothelium reconstituted from primary sheep VECs for biochemical and expression studies. In addition, we present a functional assay for EMT using valve thin films (vTFs), a biohybrid construct of the engineered valve endothelium on an elastomer thin film that is deformed during tissue contraction. We report strain-dependent dual-mode EMT, with TGF-β1 signaling triggering EMT under low strain (10%) and wnt/β-catenin signaling under high strain (20%). We also report strain-dependent increased contractility of transformed VEC tissues when treated with endothelin-1, suggesting transformation of the normally noncontractile VEC to a contractile VIC-like cell

A scoping review of trauma informed approaches in acute, crisis, emergency, and residential mental health care

Experiences of trauma in childhood and adulthood are highly prevalent among service users accessing acute, crisis, emergency, and residential mental health services. These settings, and restraint and seclusion practices used, can be extremely traumatic, leading to a growing awareness for the need for trauma informed care (TIC). The aim of TIC is to acknowledge the prevalence and impact of trauma and create a safe environment to prevent re-traumatisation. This scoping review maps the TIC approaches delivered in these settings and reports related service user and staff experiences and attitudes, staff wellbeing, and service use outcomes.We searched seven databases (EMBASE; PsycINFO; MEDLINE; Web of Science; Social Policy and Practice; Maternity and Infant Care Database; Cochrane Library Trials Register) between 24/02/2022-10/03/2022, used backwards and forwards citation tracking, and consulted academic and lived experience experts, identifying 4244 potentially relevant studies. Thirty-one studies were included.Most studies (n = 23) were conducted in the USA and were based in acute mental health services (n = 16). We identified few trials, limiting inferences that can be drawn from the findings. The Six Core Strategies (n = 7) and the Sanctuary Model (n = 6) were the most commonly reported approaches. Rates of restraint and seclusion reportedly decreased. Some service users reported feeling trusted and cared for, while staff reported feeling empathy for service users and having a greater understanding of trauma. Staff reported needing training to deliver TIC effectively.TIC principles should be at the core of all mental health service delivery. Implementing TIC approaches may integrate best practice into mental health care, although significant time and financial resources are required to implement organisational change at scale. Most evidence is preliminary in nature, and confined to acute and residential services, with little evidence on community crisis or emergency services. Clinical and research developments should prioritise lived experience expertise in addressing these gaps

Climatic variability over the last 30,000 years recorded in La Piscina de Yuriria, a Central Mexican Crater lake

The Trans-Mexican Volcanic Belt provides an excellent setting for reconstruction of late Quaternary climate from different natural archives. Moreover human impact on the landscape since the mid Holocene provides a good opportunity to investigate the complex interplay of natural and anthropogenic forcing of landscape change. However despite the wealth of records, understanding of the environmental history of the region and its wider significance for climate change across the northern neotropics remains incomplete. We present a radiocarbon-dated, multiple-proxy (sedimentology, sedimentary geochemistry, ostracods, diatoms, stable isotopes) record of climatic and environmental change based on the lacustrine sediments from La Piscina de Yuriria, a hydrologically-closed volcanic crater in the northern TMVB. Much of the last glacial interval was characterised by low effective moisture associated with a weakened North American Monsoon (NAM) although the interval from 30,000 to 27,500 aBP experienced abrupt changes in rainfall. The period corresponding to the late glacial stadial was also dry and the lake may have dried out at this time. There was a change to wetter but variable conditions during the early Holocene as the NAM strengthened. Progressive drying during the later Holocene was accompanied by phases of catchment disturbance, which were partly the result of human impact

Sperm-Associated Antigen 6 (SPAG6) Deficiency and Defects in Ciliogenesis and Cilia Function: Polarity, Density, and Beat

SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered

John Newsom-Davis: clinician-scientist and so much more

John Newsom-Davis was born in 1932 and died, aged 74, in 2007. After national service in the Royal Air Force, he read Natural Sciences at Cambridge. Following clinical studies at the Middlesex Hospital, he began research into respiratory neurophysiology with Tom Sears at the National Hospital, Queen Square, in London, and spent 1 year with Fred Plum at Cornell University in New York. After neurology specialist training at Queen Square, he became the director of the Batten Unit, continuing his interest in respiratory physiology. There he began to work on myasthenia gravis in collaboration with Ricardo Miledi at University College London and in 1978, after performing the first studies on plasma exchange in that disease, he established a myasthenia gravis research group at the Royal Free Hospital. There he investigated the role of the thymus in this disease and demonstrated an autoimmune basis for the Lambert Eaton myasthenic syndrome and ‘seronegative’ myasthenia. He was awarded the first Medical Research Council Clinical Research Professorship in 1979 but moved to Oxford in 1987 when he was elected Action Research Professor of Neurology. While at Oxford, he continued to run a very successful multidisciplinary group, researched further into the thymic abnormalities and cellular immunology of myasthenia, identified antibody-mediated mechanisms in acquired neuromyotonia, and began the molecular work that identified the genetic basis for many forms of congenital myasthenic syndrome. Meanwhile, he was also involved in university and college governance and contributed widely to the Medical Research Council, government committees, research charities and the Association of British Neurologists. Among many honours, he was elected Fellow of the Royal Society in 1991, appointed Commander of the British Empire in 1996 and made a Foreign Associate Member of the Institute of Medicine of the United States in 2001. Nearing and following retirement from Oxford, where he continued to see patients with myasthenia, he was the President of the Association of British Neurologists and Editor of Brain, and led a National Institutes of Health-funded international trial of thymectomy

Fluorinated Adenosine A2A Receptor Antagonists Inspired by Preladenant as Potential Cancer Immunotherapeutics

Antagonism of the adenosine A2A receptor on T cells blocks the hypoxia-adenosinergic pathway to promote tumor rejection. Using an in vivo immunoassay based on the Concanavalin A mouse model, a series of A2A antagonists were studied and identified preladenant as a potent lead compound for development. Molecular modeling was employed to assist drug design and subsequent synthesis of analogs and those of tozadenant, including fluorinated polyethylene glycol PEGylated derivatives. The efficacy of the analogs was evaluated using two in vitro functional bioassays, and compound 29, a fluorinated triethylene glycol derivative of preladenant, was confirmed as a potential immunotherapeutic agent

Upper limits on the strength of periodic gravitational waves from PSR J1939+2134

The first science run of the LIGO and GEO gravitational wave detectors presented the opportunity to test methods of searching for gravitational waves from known pulsars. Here we present new direct upper limits on the strength of waves from the pulsar PSR J1939+2134 using two independent analysis methods, one in the frequency domain using frequentist statistics and one in the time domain using Bayesian inference. Both methods show that the strain amplitude at Earth from this pulsar is less than a few times $10^{-22}$.Comment: 7 pages, 1 figure, to appear in the Proceedings of the 5th Edoardo Amaldi Conference on Gravitational Waves, Tirrenia, Pisa, Italy, 6-11 July 200