Enabling Vaccine Delivery Platforms and Adjuvants for Malaria

Enabling vaccine delivery platforms and adjuvants with promising attributes for malaria vaccine development are reviewed within the framework of accessibility, efficacy, clinical status, cost, and cold-chain considerations. An emphasis is placed on commercially available platforms and adjuvants including virus-like particle, nanoparticle, microneedle, and mRNA vaccine delivery platforms as well as lipid vesicle, microparticle, and emulsion-based adjuvants. Strategies for addressing complications of vaccine delivery in endemic regions due to concatenate vaccination and infection, and parasite immune avoidance mechanisms are presented. Additionally, recent findings regarding how malaria infection triggers inflammatory pathways and T cell exhaustion along with negative impacts to the development of effective memory responses are described in a context relevant to vaccine development

Experimental, Numerical and Analytical Characterization of Slosh Dynamics Applied to In-Space Propellant Storage, Management and Transfer

Experimental and numerical results are presented from a new cryogenic fluid slosh program at the Florida Institute of Technology (FIT). Water and cryogenic liquid nitrogen are used in various ground-based tests with an approximately 30 cm diameter spherical tank to characterize damping, slosh mode frequencies, and slosh forces. The experimental results are compared to a computational fluid dynamics (CFD) model for validation. An analytical model is constructed from prior work for comparison. Good agreement is seen between experimental, numerical, and analytical results

Pre-Erythrocytic Vaccine Candidates in Malaria

A vaccine providing sterile immunity against malaria has been shown to be possible with antigens from the pre-erythrocytic stages of malaria. Therefore, it is reasonable to focus vaccine development efforts on the pre-erythrocytic stages, consisting of both sporozoites and liver stage parasites, where it is expected that sterile immunity against the parasite can be elicited to block the development of blood stage infection, clinical disease, and resulting parasite transmission. Accordingly, we will review the preclinical and clinical studies of malaria pre-erythrocytic efforts as well as highlight the advances, trends, and roadblocks encountered in these efforts

Evidence formulti-cycle sedimentation and provenance constraints from

Laser ablation ICP-MS U–Pb analyses were conducted on detrital zircons of Triassic sandstone and conglomerate from the Lusitanian basin in order to: i) document the age spectra of detrital zircon; ii) compare U–Pb detrital zircon ages with previous published data obtained from Upper Carboniferous, Ordovician, Cambrian and Ediacaran sedimentary rocks of the pre-Mesozoic basement of western Iberia; iii) discuss potential sources; and iv) test the hypothesis of sedimentary recycling. U–Pb dating of zircons established a maximum depositional age for this deposit as Permian (ca. 296Ma),which is about sixty million years older compared to the fossil content recognized in previous studies (Upper Triassic). The distribution of detrital zircon ages obtained points to common source areas: the Ossa–Morena and Central Iberian zones that outcrop in and close to the Porto–Tomar fault zone. The high degree of immaturity and evidence of little transport of the Triassic sediment suggests that granite may constitute primary crystalline sources. The Carboniferous age of ca. 330 Ma for the best estimate of crystallization for a granite pebble in a Triassic conglomerate and the Permian–Carboniferous ages (ca. 315Ma) found in detrital zircons provide evidence of the denudation of Variscan and Cimmerian granites during the infilling of continental rift basins in western Iberia. The zircon age spectra found in Triassic strata are also the result of recycling from the Upper Carboniferous Buçaco basin,which probably acted as an intermediate sediment repository.U–Pb data in this study suggest that the detritus from the Triassic sandstone and conglomerate of the Lusitanian basin is derived fromlocal source areas with features typical of Gondwana,with no sediment from external sources from Laurussia or southwestern Iberia

Sedimentary record of the amalgamation and break-up of Pangaea: U-Pb detrital zircon geochronology and provenance of Carboniferous-Triassic siliciclastic rocks (SW Iberia)

In SW Iberia there is a basal unconformity where Triassic sandstones overlie previously deformed Carboniferous turbidites. This important stratigraphic boundary records the transition from the final stages of Pangaea’s amalgamation to the initial stages of break-up. U-Pb dating of detrital zircon from Carboniferous greywackes of the South Portuguese Zone and Triassic sandstones of the Algarve and Alentejo basins was carried out to conduct a study of sedimentary provenance. The radiometric ages obtained by LA-ICP-MS show that most of the samples have common age spectra which are typical of North Gondwana sources: Archean and Paleoproterozoic ages characteristic of the West African craton, Neoproterozoic ages associated with Cadomian and Pan-African orogenies, and Cambrian ages related to the intra-continental rifting of North Gondwana. The only exception is a Visean immature greywacke that was probably derived from Devonian magmatic arcs related to the Variscan orogeny. Very rare pre-Devonian zircons indicate faint contributions from recycled sediments. In contrast the Serpukhovian to Moscovian greywackes are derived from felsic mature source rocks and include Proterozoic and Paleozoic detrital zircons suggesting recycling of an old basement. They also include Ordovician and Silurian detrital zircons, the ages of which have no correspondence in North Gondwana, and thus indicate an external source (Laurussia?). U-Pb ages younger than Ordovician are significant in the Triassic sandstone of the Alentejo basin and resemble the zircon populations of the Serpukhovian to Moscovian greywackes from the South Portuguese Zone. U-Pb ages younger than Neoproterozoic are poorly represented in the zircon population of the Triassic sandstone from the Algarve basin, which rests unconformably upon Moscovian turbidites, pointing to Upper Devonian quartzites of the South Portuguese Zone as probable sources, since they are dominated by Precambrian detrital zircons. These differences occurring in the Triassic basins suggest that detrital zircon populations could be derived from two independent sources and paleo-drainage systems due to complex crustal-block extension architecture

Thrombectomy for Large‐Vessel Occlusion With Pretreatment Intracranial Hemorrhage

Background Many patients treated with endovascular thrombectomy (EVT) in clinical practice would not have qualified for inclusion in the initial clinical trials demonstrating benefit for EVT, yet likely will benefit from reperfusion. One such subset for which data are sparse is patients with emergent large‐vessel occlusion and concomitant intracranial hemorrhage (ICH). The objective of this report is to document patients who underwent thrombectomy for large‐vessel occlusion in the presence of concomitant ICH and evaluate their clinical characteristics and outcomes. Methods We retrospectively reviewed prospectively collected patient records at 4 comprehensive stroke centers from 2012 to 2019. Patients were identified who had pre‐EVT ICH. Data collected included baseline patient demographics and laboratory values, stroke characteristics, ICH radiographic variables, antiplatelet/anticoagulant/thrombolytic medication use, and procedural factors. The primary safety outcome was any worsening of ICH on neuroimaging obtained 24 hours after EVT. Results Eight patients were identified who underwent thrombectomy with concomitant ICH. The mean age was 71.9 years (range, 37–90). Median National Institutes of Health Stroke Scale score was 25 (interquartile range, 16.5–28.8), and 5 (63%) received tissue plasminogen activator. All patients underwent EVT and had mTICI2B or greater reperfusion. In 7 patients (88%), the initial ICH remained stable on postprocedure imaging. In 1 patient who received intravenous antiplatelet agents during thrombectomy, the hemorrhagic transformation was radiographically increased but without clinical correlate or mass effect. Conclusions In a multi‐institution evaluation of 8 patients with ICH at the time of thrombectomy, 1 patient had radiographic worsening of hemorrhage, and no patient experienced clinical worsening related to hemorrhage progression. These findings suggest that thrombectomy may be safe in this population

Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma

The molecular basis for the inverse relationship between differentiation and tumorigenesis is unknown. The function of runx2, a master regulator of osteoblast differentiation belonging to the runt family of tumor suppressor genes, is consistently disrupted in osteosarcoma cell lines. Ectopic expression of runx2 induces p27KIP1, thereby inhibiting the activity of S-phase cyclin complexes and leading to the dephosphorylation of the retinoblastoma tumor suppressor protein (pRb) and a G1 cell cycle arrest. Runx2 physically interacts with the hypophosphorylated form of pRb, a known coactivator of runx2, thereby completing a feed-forward loop in which progressive cell cycle exit promotes increased expression of the osteoblast phenotype. Loss of p27KIP1 perturbs transient and terminal cell cycle exit in osteoblasts. Consistent with the incompatibility of malignant transformation and permanent cell cycle exit, loss of p27KIP1 expression correlates with dedifferentiation in high-grade human osteosarcomas. Physiologic coupling of osteoblast differentiation to cell cycle withdrawal is mediated through runx2 and p27KIP1, and these processes are disrupted in osteosarcoma

Variable Anisotropic Brain Electrical Conductivities in Epileptogenic Foci

Source localization models assume brain electrical conductivities are isotropic at about 0.33 S/m. These assumptions have not been confirmed ex vivo in humans. This study determined bidirectional electrical conductivities from pediatric epilepsy surgery patients. Electrical conductivities perpendicular and parallel to the pial surface of neocortex and subcortical white matter (n = 15) were measured using the 4-electrode technique and compared with clinical variables. Mean (±SD) electrical conductivities were 0.10 ± 0.01 S/m, and varied by 243% from patient to patient. Perpendicular and parallel conductivities differed by 45%, and the larger values were perpendicular to the pial surface in 47% and parallel in 40% of patients. A perpendicular principal axis was associated with normal, while isotropy and parallel principal axes were linked with epileptogenic lesions by MRI. Electrical conductivities were decreased in patients with cortical dysplasia compared with non-dysplasia etiologies. The electrical conductivity values of freshly excised human brain tissues were approximately 30% of assumed values, varied by over 200% from patient to patient, and had erratic anisotropic and isotropic shapes if the MRI showed a lesion. Understanding brain electrical conductivity and ways to non-invasively measure them are probably necessary to enhance the ability to localize EEG sources from epilepsy surgery patients

Galectin-1 prevents pathological vascular remodeling in atherosclerosis and abdominal aortic aneurysm

Pathological vascular remodeling is the underlying cause of atherosclerosis and abdominal aortic aneurysm (AAA). Here, we analyzed the role of galectin-1 (Gal-1), a β-galactoside-binding protein, as a therapeutic target for atherosclerosis and AAA. Mice lacking Gal-1 (Lgals1 −/− ) developed severe atherosclerosis induced by pAAV/D377Y-mPCSK9 adenovirus and displayed higher lipid levels and lower expression of contractile markers of vascular smooth muscle cells (VSMCs) in plaques than wild-type mice. Proteomic analysis of Lgals1 −/− aortas showed changes in markers of VSMC phenotypic switch and altered composition of mitochondrial proteins. Mechanistically, Gal-1 silencing resulted in increased foam cell formation and mitochondrial dysfunction in VSMCs, while treatment with recombinant Gal-1 (rGal-1) prevented these effects. Furthermore, rGal-1 treatment attenuated atherosclerosis and elastase-induced AAA, leading to higher contractile VSMCs in aortic tissues. Gal-1 expression decreased in human atheroma and AAA compared to control tissue. Thus, Gal-1-driven circuits emerge as potential therapeutic strategies in atherosclerosis and AAA. Galectin-1 plays an essential role in prevention of atherosclerosis and abdominal aortic aneurysm

Aneuploidy Detection in Pigs Using Comparative Genomic Hybridization: From the Oocytes to Blastocysts

Data on the frequency of aneuploidy in farm animals are lacking and there is the need for a reliable technique which is capable of detecting all chromosomes simultaneously in a single cell. With the employment of comparative genomic hybridization coupled with the whole genome amplification technique, this study brings new information regarding the aneuploidy of individual chromosomes in pigs. Focus is directed on in vivo porcine blastocysts and late morulas, 4.7% of which were found to carry chromosomal abnormality. Further, ploidy abnormalities were examined using FISH in a sample of porcine embryos. True polyploidy was relatively rare (1.6%), whilst mixoploidy was presented in 46.8% of embryos, however it was restricted to only a small number of cells per embryo. The combined data indicates that aneuploidy is not a prevalent cause of embryo mortality in pigs