Theileria's Strategies and Effector Mechanisms for Host Cell Transformation: From Invasion to Immortalization.

One of the first events that follows invasion of leukocytes by Theileria sporozoites is the destruction of the surrounding host cell membrane and the rapid association of the intracellular parasite with host microtubules. This is essential for the parasite to establish its niche within the cytoplasm of the invaded leukocyte and sets Theileria spp. apart from other members of the apicomplexan phylum such as Toxoplasma gondii and Plasmodium spp., which reside within the confines of a host-derived parasitophorous vacuole. After establishing infection, transforming Theileria species (T. annulata, T. parva) significantly rewire the signaling pathways of their bovine host cell, causing continual proliferation and resistance to ligand-induced apoptosis, and conferring invasive properties on the parasitized cell. Having transformed its target cell, Theileria hijacks the mitotic machinery to ensure its persistence in the cytoplasm of the dividing cell. Some of the parasite and bovine proteins involved in parasite-microtubule interactions have been fairly well characterized, and the schizont expresses at least two proteins on its membrane that contain conserved microtubule binding motifs. Theileria-encoded proteins have been shown to be translocated to the host cell cytoplasm and nucleus where they have the potential to directly modify signaling pathways and host gene expression. However, little is known about their mode of action, and even less about how these proteins are secreted by the parasite and trafficked to their target location. In this review we explore the strategies employed by Theileria to transform leukocytes, from sporozoite invasion until immortalization of the host cell has been established. We discuss the recent description of nuclear pore-like complexes that accumulate on membranes close to the schizont surface. Finally, we consider putative mechanisms of protein and nutrient exchange that might occur between the parasite and the host. We focus in particular on differences and similarities with recent discoveries in T. gondii and Plasmodium species

How climate policies can translate to tangible change: Evidence from eleven low- and lower-middle income countries

Formally adopting climate change mitigation policies does not necessarily translate to tangible change on the ground. Here, we analyse 31 semi-structured interviews with climate policy government officials and consultants from 11 low-income and lower-middle income countries (LMICs) as well as the respective climate policy context, and find high average degrees of perceived discrepancies between formally adopted climate change mitigation policies and their actual implementation. Our results suggest that for our LMIC sample, both the global political process to limit climate change and domestic environmental threats have been key to drive the formal adoption of climate change mitigation policies, but have had limited effect on implementation. By contrast, momentum for implementation of climate change mitigation initiatives and projects on the ground emerges where climate policies are firmly embedded within economic and social development policies, the economy and society are comparably well-positioned to embrace the associated change, and where they have been governed by cross-ministerial institutions capable of implementing wider climate-compatible development pathways. Thus, to help translate climate policy into action, national LMIC governments and the international community need to find context-specific ways to successfully integrate climate with economic and social development policies, identify and build on feasible opportunities and competitive advantages through which the local economy can benefit from green growth, build adequate social capital, and actively create institutional spaces and processes for well-equipped and meaningful cross-ministerial co-beneift governance. The importance of unlocking co-benefits for implementing climate policies underlines both the urgency with which the international community needs to increase finance for LMICs for climate change mitigation, as well as the associated development opportunities

Quantification of myocardial blood flow with 82Rb positron emission tomography: clinical validation with 15O-water

Purpose: Quantification of myocardial blood flow (MBF) with generator-produced 82Rb is an attractive alternative for centres without an on-site cyclotron. Our aim was to validate 82Rb-measured MBF in relation to that measured using 15O-water, as a tracer 100% of which can be extracted from the circulation even at high flow rates, in healthy control subject and patients with mild coronary artery disease (CAD). Methods: MBF was measured at rest and during adenosine-induced hyperaemia with 82Rb and 15O-water PET in 33 participants (22 control subjects, aged 30 ± 13years; 11 CAD patients without transmural infarction, aged 60 ± 13years). A one-tissue compartment 82Rb model with ventricular spillover correction was used. The 82Rb flow-dependent extraction rate was derived from 15O-water measurements in a subset of 11 control subjects. Myocardial flow reserve (MFR) was defined as the hyperaemic/rest MBF. Pearson's correlation r, Bland-Altman 95% limits of agreement (LoA), and Lin's concordance correlation ρ c (measuring both precision and accuracy) were used. Results: Over the entire MBF range (0.66-4.7ml/min/g), concordance was excellent for MBF (r = 0.90, [82Rb-15O-water] mean difference ± SD = 0.04 ± 0.66ml/min/g, LoA = −1.26 to 1.33ml/min/g, ρ c = 0.88) and MFR (range 1.79-5.81, r = 0.83, mean difference = 0.14 ± 0.58, LoA = −0.99 to 1.28, ρ c = 0.82). Hyperaemic MBF was reduced in CAD patients compared with the subset of 11 control subjects (2.53 ± 0.74 vs. 3.62 ± 0.68ml/min/g, p = 0.002, for 15O-water; 2.53 ± 1.01 vs. 3.82 ± 1.21ml/min/g, p = 0.013, for 82Rb) and this was paralleled by a lower MFR (2.65 ± 0.62 vs. 3.79 ± 0.98, p = 0.004, for 15O-water; 2.85 ± 0.91 vs. 3.88 ± 0.91, p = 0.012, for 82Rb). Myocardial perfusion was homogeneous in 1,114 of 1,122 segments (99.3%) and there were no differences in MBF among the coronary artery territories (p > 0.31). Conclusion: Quantification of MBF with 82Rb with a newly derived correction for the nonlinear extraction function was validated against MBF measured using 15O-water in control subjects and patients with mild CAD, where it was found to be accurate at high flow rates. 82Rb-derived MBF estimates seem robust for clinical research, advancing a step further towards its implementation in clinical routin

Patterns of airway obstruction of non-acquired origin in children with and without major congenital anomalies.

Major congenital anomalies are known to play a role in the management and prognosis of airway obstruction. Most studies assess acquired forms of airway obstruction. Data on congenital or otherwise non-acquired forms of airway obstruction is sparse. In this retrospective, single-institution cohort study, we sought to evaluate and compare the patterns of airway obstruction in children with and without major congenital anomalies, and to assess the impact of management and outcome, irrespective of aetiology. Fifty-five patients were included, 23 with and 32 without underlying major congenital anomalies. Multilevel airway obstruction (usually affecting the nasopharynx, oropharynx, and the trachea) was more common in children with congenital anomalies (91% vs. 41%, p < .001). Consequently, these children required more frequent and earlier surgical management, especially tracheostomy and adenotonsillar surgery.Conclusions: Major congenital anomalies are associated with multilevel airway obstruction and poor functional prognosis. A simple clinical definition considering impact of major congenital anomalies on development and growth may help guide management plans following endoscopic evaluation of the entire airway and flanked by multidisciplinary discussions. What is Known: • Children with major comorbidities display increased disease severity and more prevalent multilevel airway obstruction • Previous studies include both children with acquired and non-acquired forms of airway obstruction; therefore, the actual impact major comorbidities in children with non-acquired causes of airway obstruction remain unclear. What is New: • A total of 42% children in this study population had major comorbidities with and impact on growth and/or psychomotor development, with a higher prevalence of multilevel airway obstruction and worse rates of functional improvement/recovery. • Children with major comorbidities require tracheostomy more often and earlier than those without major comorbidities, and remain tracheostomy-dependent for a longer time

Atomic structures of fibrillar segments of hIAPP suggest tightly mated β-sheets are important for cytotoxicity.

hIAPP fibrils are associated with Type-II Diabetes, but the link of hIAPP structure to islet cell death remains elusive. Here we observe that hIAPP fibrils are cytotoxic to cultured pancreatic β-cells, leading us to determine the structure and cytotoxicity of protein segments composing the amyloid spine of hIAPP. Using the cryoEM method MicroED, we discover that one segment, 19-29 S20G, forms pairs of β-sheets mated by a dry interface that share structural features with and are similarly cytotoxic to full-length hIAPP fibrils. In contrast, a second segment, 15-25 WT, forms non-toxic labile β-sheets. These segments possess different structures and cytotoxic effects, however, both can seed full-length hIAPP, and cause hIAPP to take on the cytotoxic and structural features of that segment. These results suggest that protein segment structures represent polymorphs of their parent protein and that segment 19-29 S20G may serve as a model for the toxic spine of hIAPP

Temperature-dependent 2D-3D growth transition of ultra-thin Pt films deposited by PLD

During the growth of metal thin films on dielectric substrates at a given deposition temperature T, the film's morphology is conditioned by the magnitude and asymmetry of up- and downhill diffusion. Any severe change of this mechanism leads to a growth instability, which induces an alteration of the thin film morphology. In order to study this mechanism, ultra-thin Pt films were deposited via pulsed laser deposition (PLD) onto yttria-stabilized-zirconia single crystals at different deposition temperatures. The morphological evolution of Pt thin films has been investigated by means of scanning electron microscopy (SEM), atomic force microscopy (AFM) and standard image analysis techniques. The experimentally obtained morphologies are compared to simulated thin film structures resulting from a two-dimensional kinetic Monte Carlo (KMC) approach. Two main observations have been made: i) Thin Pt films deposited onto zirconia undergo a growth transition from two-dimensional to three-dimensional growth at T > 573 K. The growth transition and related morphological changes are a function of the deposition temperature. ii) A critical cluster size of i\ast = 4 in combination with an asymmetric Ehrlich-Schwoebel (ES) barrier favoring the uphill diffusion of atoms allows for a computational reproduction of the experimentally obtained film morphologies.Comment: 7 pages, 6 figures, 1 tabl

COVID-19 Patients Require Prolonged Extracorporeal Membrane Oxygenation Support for Survival Compared With Non-COVID-19 Patients

OBJECTIVES: To investigate the ICU survival of venovenous extracorporeal membrane oxygenation (ECMO) patients suffering from COVID-19–related acute respiratory distress syndrome (ARDS) versus ECMO patients without COVID-19 (non-COVID-19)–related ARDS. DESIGN: Preliminary analysis of data from two prospective ECMO trials and retrospective analysis of a cohort of ARDS ECMO patients. SETTING: Single-center ICU. PATIENTS: Adult ARDS ECMO patients, 16 COVID-19 versus 23 non-COVID-19 patients. Analysis of retrospective data from 346 adult ARDS ECMO patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: COVID-19 and non-COVID-19 ARDS patients did not differ with respect to preexisting disease or body mass index. ICU survival rate was 62% for COVID-19 ECMO patients and 70% for non-COVID-19 ECMO patients. COVID-19 ECMO survivors were supported with ECMO for a median of 43 days (interquartile range [IQR], 18–58 d) versus 16 days (IQR, 19–39 d; p = 0.03) for non-COVID-19 patients. The median duration of ECMO therapy for all ARDS patients between 2007 and 2018 was 15 days (IQR, 6–28 d). The subgroup of patients suffering from any viral pneumonia received ECMO support for a median of 16 days (IQR, 9–27 d), survivors of influenza pneumonia received ECMO support for 13 days (IQR, 7–25 d). CONCLUSIONS: COVID-19 patients required significant longer ECMO support compared with patients without COVID-19 to achieve successful ECMO weaning and ICU survival

The cataract and glucosuria associated monocarboxylate transporter MCT12 is a new creatine transporter

Creatine transport has been assigned to creatine transporter 1 (CRT1), encoded by mental retardation associated SLC6A8. Here, we identified a second creatine transporter (CRT2) known as monocarboxylate transporter 12 (MCT12), encoded by the cataract and glucosuria associated gene SLC16A12. A non-synonymous alteration in MCT12 (p.G407S) found in a patient with age-related cataract (ARC) leads to a significant reduction of creatine transport. Furthermore, Slc16a12 knockout (KO) rats have elevated creatine levels in urine. Transport activity and expression characteristics of the two creatine transporters are distinct. CRT2 (MCT12)-mediated uptake of creatine was not sensitive to sodium and chloride ions or creatine biosynthesis precursors, breakdown product creatinine or creatine phosphate. Increasing pH correlated with increased creatine uptake. Michaelis-Menten kinetics yielded a Vmax of 838.8 pmol/h/oocyte and a Km of 567.4 µm. Relative expression in various human tissues supports the distinct mutation-associated phenotypes of the two transporters. SLC6A8 was predominantly found in brain, heart and muscle, while SLC16A12 was more abundant in kidney and retina. In the lens, the two transcripts were found at comparable levels. We discuss the distinct, but possibly synergistic functions of the two creatine transporters. Our findings infer potential preventive power of creatine supplementation against the most prominent age-related vision impaired conditio