HIV-1 Pre-Integration Complexes Selectively Target Decondensed Chromatin in the Nuclear Periphery

Integration of the double-stranded DNA copy of the HIV-1 genome into host chromosomal DNA is a requirement for efficient viral replication. Integration preferentially occurs within active transcription units, however chromosomal site specificity does not correlate with any strong primary sequence. To investigate whether the nuclear architecture may affect viral integration we have developed an experimental system where HIV-1 viral particles can be visualized within the nuclear compartment. Fluorescently labeled HIV-1 virions were engineered by fusing integrase, the viral protein that catalyzes the integration reaction, to fluorescent proteins. Viral tests demonstrate that the infectivity of fluorescent virions, including the integration step, is not altered as compared to wild-type virus. 3-D confocal microscopy allowed a detailed analysis of the spatial and temporal distribution of the pre-integration complexes (PICs) within the nucleus at different moments following infection; the fluorescently labeled PICs preferentially distribute in decondensed areas of the chromatin with a striking positioning in the nuclear periphery, while heterochromatin regions are largely disfavored. These observations provide a first indication of how the nuclear architecture may initially orient the selection of retroviral integration sites

CovidNeuroOnc: A UK multicenter, prospective cohort study of the impact of the COVID-19 pandemic on the neuro-oncology service

BackgroundThe COVID-19 pandemic has profoundly affected cancer services. Our objective was to determine the effect of the COVID-19 pandemic on decision making and the resulting outcomes for patients with newly diagnosed or recurrent intracranial tumors.MethodsWe performed a multicenter prospective study of all adult patients discussed in weekly neuro-oncology and skull base multidisciplinary team meetings who had a newly diagnosed or recurrent intracranial (excluding pituitary) tumor between 01 April and 31 May 2020. All patients had at least 30-day follow-up data. Descriptive statistical reporting was used.ResultsThere were 1357 referrals for newly diagnosed or recurrent intracranial tumors across 15 neuro-oncology centers. Of centers with all intracranial tumors, a change in initial management was reported in 8.6% of cases (n = 104/1210). Decisions to change the management plan reduced over time from a peak of 19% referrals at the start of the study to 0% by the end of the study period. Changes in management were reported in 16% (n = 75/466) of cases previously recommended for surgery and 28% of cases previously recommended for chemotherapy (n = 20/72). The reported SARS-CoV-2 infection rate was similar in surgical and non-surgical patients (2.6% vs. 2.4%, P > .9).ConclusionsDisruption to neuro-oncology services in the UK caused by the COVID-19 pandemic was most marked in the first month, affecting all diagnoses. Patients considered for chemotherapy were most affected. In those recommended surgical treatment this was successfully completed. Longer-term outcome data will evaluate oncological treatments received by these patients and overall survival

Spatiotemporal scaling of North American continental interior wetlands: implications for shorebird conservation

Within interior North America, erratic weather patterns and heterogeneous wetland complexes cause wide spatio-temporal variation in the resources available to migrating shorebirds. Identifying the pattern-generating components of landscape-level resources and the scales at which shorebirds respond to these patterns will better facilitate conservation efforts for these species. We constructed descriptive models that identified weather variables associated with creating the spatio-temporal patterns of shorebird habitat in ten landscapes in north-central Oklahoma. We developed a metric capable of measuring the dynamic composition and configuration of shorebird habitat in the region and used field data to empirically estimate the spatial scale at which shorebirds respond to the amount and configuration of habitat. Precipitation, temperature, solar radiation and wind speed best explained the incidence of wetland habitat, but relationships varied among wetland types. Shorebird occurrence patterns were best explained by habitat density estimates at a 1.5 km scale. This model correctly classified 86 % of shorebird observations. At this scale, when habitat density was low, shorebirds occurred in 5 % of surveyed habitat patches but occurrence reached 60 % when habitat density was high. Our results suggest scale dependence in the habitat-use patterns of migratory shorebirds. We discuss potential implications of our results and how integrating this information into conservation efforts may improve conservation strategies and management practices

Effects of platelet rich plasma (PRP) on human gingival fibroblast, osteoblast and periodontal ligament cell behaviour

The use of platelet rich plasma (PRP, GLO) has been used as an adjunct to various regenerative dental procedures. The aim of the present study was to characterize the influence of PRP on human gingival fibroblasts, periodontal ligament (PDL) cells and osteoblast cell behavior in vitro

Iterative Structure-Based Peptide-Like Inhibitor Design against the Botulinum Neurotoxin Serotype A

The botulinum neurotoxin serotype A light chain (BoNT/A LC) protease is the catalytic component responsible for the neuroparalysis that is characteristic of the disease state botulism. Three related peptide-like molecules (PLMs) were designed using previous information from co-crystal structures, synthesized, and assayed for in vitro inhibition against BoNT/A LC. Our results indicate these PLMS are competitive inhibitors of the BoNT/A LC protease and their Ki values are in the nM-range. A co-crystal structure for one of these inhibitors was determined and reveals that the PLM, in accord with the goals of our design strategy, simultaneously involves both ionic interactions via its P1 residue and hydrophobic contacts by means of an aromatic group in the P2′ position. The PLM adopts a helical conformation similar to previously determined co-crystal structures of PLMs, although there are also major differences to these other structures such as contacts with specific BoNT/A LC residues. Our structure further demonstrates the remarkable plasticity of the substrate binding cleft of the BoNT/A LC protease and provides a paradigm for iterative structure-based design and development of BoNT/A LC inhibitors

Comparative study on cellular entry of incinerated ancient gold particles (Swarna Bhasma) and chemically synthesized gold particles

Gold nanoparticles (AuNPs) are used for a number of imaging and therapeutic applications in east and western part of the world. For thousands of years, the traditional Indian Ayurvedic approach to healing involves the use of incinerated gold ash, prepared with a variety of plant extracts and minerals depending on the region. Here, we describe the characterization of incinerated gold particles (IAuPs) in HeLa (human cells derived from cervical cancer) and HFF-1 (human foreskin fibroblast cells) in comparison to synthesized citrate-capped gold nanoparticles (AuNPs). We found that while individual IAuP crystallites are around 60 nm in size, they form large aggregates with a mean diameter of 4711.7 nm, some of which can enter cells. Fewer cells appeared to have IAuPs compared to AuNPs, although neither type of particle was toxic to cells. Imaging studies revealed that IAuPs were in vesicles, cytosol, or in the nucleus. We found that their nuclear accumulation likely occurred after nuclear envelope breakdown during cell division. We also found that larger IAuPs entered cells via macropinocytosis, while smaller particles entered via clathrin-dependent receptor-mediated endocytosis

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR