Comparison of HTLV-associated myelopathy (HAM) in HIV-positive and HIV-negative patients at a tertiary South African hospital

Background. HTLV-1 associated myelopathy (HAM), or tropical spastic paraparesis, is caused by a retrovirus, the human T-cell lymphotropic virus (HTLV). Although patients with HAM and HIV infection have been described, to our knowledge no direct comparison has been made between patients who are HIV positive and suffering from HAM (HHAM) v. those who are HIV negative and suffering from HAM.Aim. We aimed to compare clinical and radiological findings in HIV-positive and -negative patients with HAM.Methods. Adult patients who presented to the Neurology Unit at the Steve Biko Academic Hospital from May 2005 to June 2012 with a progressive myelopathy and HTLV seropositivity were retrospectively identified and their clinical and radiological data were collected and reviewed.Results. 21 patients with HAM were identified, of whom 9 were HIV-positive and 11 HIV-negative. One patient, whose HIV status had not been established, was not included in the study. Although the trend did not reach statistical significance, co-infected patients tended to present at an earlier age (HHAM 6/9 (66%) <40 years old; HAM 2/11 (18%) <40 years old) and presented to hospital earlier (HHAM 6/9 (66%) < 3 years symptomatic; HAM 7/11 (63%) > 3 years symptomatic). Cord atrophy occurred in 7/8 dually infected patients and 8/10 HIV-negative patients.Conclusion. Although the study is limited by the small number of patients, co-infected patients tended to have a younger age of onset and to present to hospital sooner, and thoracic cord atrophy was very common

Decomposition Rates of Organic Material across Herbivore Treatments in a Nutrient-Rich Semi-Arid Sodic Savanna

Decomposition is a major determinant of terrestrial nutrient cycling and therefore an important regulator of ecosystem structure and function. It has been widely documented that large mammalian herbivores (LMH) act as a significant driver of changes to aboveground structure and modifications to edaphic properties. Little is known about the role of herbivory, and particularly the loss thereof, in mediating essential ecological processes in a herbivore-adapted system. The Nkuhlu exclosures, a large-scale, long-term exclusion experiment in the Kruger National Park, South Africa, provided an opportunity to explore the effects of herbivory and/or its long-term exclusion on decomposition and stabilisation of detrital plant material. An extended, site-specific version of the Tea Bag Index approach was used to quantify decomposition rate (k) and stabilisation factor (S) of standardised litter substrate. Two hundred and fifty tea bags (125 green and 125 rooibos tea bags) applied in a paired tea bag design were exposed to three herbivore treatments along the sodic zone of the Nkuhlu exclosures and removed after three months of incubation. Decomposition rates (k) were highest in the presence of LMH and lowest in their absence. Conversely, stabilisation factor (S) was significantly higher in treatments from which herbivores have been excluded for ~18 years. Our study provides evidence that LMH can influence essential ecological processes such as decomposition and stabilisation of detrital plant material. Moreover, results confirmed that ecosystems that evolved with herbivores, are sensitive to herbivore loss as it reduces decomposition rates of plant detritus and hence, decelerates ecosystem nutrient cycling

In Vitro and In Vivo Evidence that Thrombospondin-1 (TSP-1) Contributes to Stirring- and Shear-Dependent Activation of Platelet-Derived TGF-β1

Thrombospondin 1 (TSP-1), which is contained in platelet α-granules and released with activation, has been shown to activate latent TGF-β1 in vitro, but its in vivo role is unclear as TSP-1-null (Thbs1−/−) mice have a much less severe phenotype than TGF-β1-null (Tgfb1−/−) mice. We recently demonstrated that stirring and/or shear could activate latent TGF-β1 released from platelets and have now studied these methods of TGF-β1 activation in samples from Thbs1−/− mice, which have higher platelet counts and higher levels of total TGF-β1 in their serum than wild type mice. After either two hours of stirring or shear, Thbs1−/− samples demonstrated less TGF-β1 activation (31% and 54% lower levels of active TGF-β1 in serum and platelet releasates, respectively). TGF-β1 activation in Thbs1−/− mice samples was normalized by adding recombinant human TSP-1 (rhTSP-1). Exposure of platelet releasates to shear for one hour led to near depletion of TSP-1, but this could be prevented by preincubating samples with thiol-reactive agents. Moreover, replenishing rhTSP-1 to human platelet releasates after one hour of stirring enhanced TGF-β1 activation. In vivo TGF-β1 activation in carotid artery thrombi was also partially impaired in Thbs1−/− mice. These data indicate that TSP-1 contributes to shear-dependent TGF-β1 activation, thus providing a potential explanation for the inconsistent in vitro data previously reported as well as for the differences in phenotypes of Thbs1−/− and Tgfb1−/− mice

Re-engineering The Clinical Research Enterprise in Response to COVID-19: The Clinical Translational Science Award (CTSA) experience and proposed playbook for future pandemics

The 2020 COVID-19 pandemic has had a profound impact on the clinical research enterprises at the 60 Clinical and Translational Science Award (CTSA) Hubs throughout the nation. There was simultaneously a need to expand research to obtain crucial data about disease prognosis and therapy and enormous limitations on conducting research as localities and institutions limited travel and person-to-person contact. These imperatives resulted in major changes in the way research was conducted, including expediting Institutional Review Board review, shifting to remote interactions with participants, centralizing decision-making in prioritizing research protocols, establishing biobanks, adopting novel informatics platforms, and distributing study drugs in unconventional ways. National CTSA Steering Committee meetings provided an opportunity to share best practices and develop the idea of capturing the CTSA program experiences in a series of papers. Here we bring together the recommendations from those papers in a list of specific actions that research sites can take to strengthen operations and prepare for similar future public health emergencies. Most importantly, creative innovations developed in response to the COVID-19 pandemic deserve serious consideration for adoption as new standards, thus converting the painful trauma of the pandemic into “post-traumatic growth” that makes the clinical research enterprise stronger, more resilient, and more effective

Adenovirus type 5 exerts genome-wide control over cellular programs governing proliferation, quiescence, and survival

The effects of the adenovirus Ad5 on basic host cell programs, such as cell-cycle regulation, were studied in a microarray analysis of human fibroblasts. About 2,000 genes were up- or down-regulated after Ad5 infection and Ad5 infection was shown to induce reversal of the quiescence program and recapitulation of the core serum response

RNA Interference and Single Particle Tracking Analysis of Hepatitis C Virus Endocytosis

Hepatitis C virus (HCV) enters hepatocytes following a complex set of receptor interactions, culminating in internalization via clathrin-mediated endocytosis. However, aside from receptors, little is known about the cellular molecular requirements for infectious HCV entry. Therefore, we analyzed a siRNA library that targets 140 cellular membrane trafficking genes to identify host genes required for infectious HCV production and HCV pseudoparticle entry. This approach identified 16 host cofactors of HCV entry that function primarily in clathrin-mediated endocytosis, including components of the clathrin endocytosis machinery, actin polymerization, receptor internalization and sorting, and endosomal acidification. We next developed single particle tracking analysis of highly infectious fluorescent HCV particles to examine the co-trafficking of HCV virions with cellular cofactors of endocytosis. We observe multiple, sequential interactions of HCV virions with the actin cytoskeleton, including retraction along filopodia, actin nucleation during internalization, and migration of internalized particles along actin stress fibers. HCV co-localizes with clathrin and the ubiquitin ligase c-Cbl prior to internalization. Entering HCV particles are associated with the receptor molecules CD81 and the tight junction protein, claudin-1; however, HCV-claudin-1 interactions were not restricted to Huh-7.5 cell-cell junctions. Surprisingly, HCV internalization generally occurred outside of Huh-7.5 cell-cell junctions, which may reflect the poorly polarized nature of current HCV cell culture models. Following internalization, HCV particles transport with GFP-Rab5a positive endosomes, which is consistent with trafficking to the early endosome. This study presents technical advances for imaging HCV entry, in addition to identifying new host cofactors of HCV infection, some of which may be antiviral targets.</p

Molecular Determinants and Dynamics of Hepatitis C Virus Secretion

The current model of hepatitis C virus (HCV) production involves the assembly of virions on or near the surface of lipid droplets, envelopment at the ER in association with components of VLDL synthesis, and egress via the secretory pathway. However, the cellular requirements for and a mechanistic understanding of HCV secretion are incomplete at best. We combined an RNA interference (RNAi) analysis of host factors for infectious HCV secretion with the development of live cell imaging of HCV core trafficking to gain a detailed understanding of HCV egress. RNAi studies identified multiple components of the secretory pathway, including ER to Golgi trafficking, lipid and protein kinases that regulate budding from the trans-Golgi network (TGN), VAMP1 vesicles and adaptor proteins, and the recycling endosome. Our results support a model wherein HCV is infectious upon envelopment at the ER and exits the cell via the secretory pathway. We next constructed infectious HCV with a tetracysteine (TC) tag insertion in core (TC-core) to monitor the dynamics of HCV core trafficking in association with its cellular cofactors. In order to isolate core protein movements associated with infectious HCV secretion, only trafficking events that required the essential HCV assembly factor NS2 were quantified. TC-core traffics to the cell periphery along microtubules and this movement can be inhibited by nocodazole. Sub-populations of TC-core localize to the Golgi and co-traffic with components of the recycling endosome. Silencing of the recycling endosome component Rab11a results in the accumulation of HCV core at the Golgi. The majority of dynamic core traffics in association with apolipoprotein E (ApoE) and VAMP1 vesicles. This study identifies many new host cofactors of HCV egress, while presenting dynamic studies of HCV core trafficking in infected cells.</p

Time preferences and risk aversion: tests on domain differences

The design and evaluation of environmental policy requires the incorporation of time and risk elements as many environmental outcomes extend over long time periods and involve a large degree of uncertainty. Understanding how individuals discount and evaluate risks with respect to environmental outcomes is a prime component in designing effective environmental policy to address issues of environmental sustainability, such as climate change. Our objective in this study is to investigate whether subjects' time preferences and risk aversion across the monetary domain and the environmental domain differ. Crucially, our experimental design is incentivized: in the monetary domain, time preferences and risk aversion are elicited with real monetary payoffs, whereas in the environmental domain, we elicit time preferences and risk aversion using real (bee-friendly) plants. We find that subjects' time preferences are not significantly different across the monetary and environmental domains. In contrast, subjects' risk aversion is significantly different across the two domains. More specifically, subjects (men and women) exhibit a higher degree of risk aversion in the environmental domain relative to the monetary domain. Finally, we corroborate earlier results, which document that women are more risk averse than men in the monetary domain. We show this finding to, also, hold in the environmental domain

The DExD/H box ATPase Dhh1 functions in translational repression, mRNA decay, and processing body dynamics

Dhh1 is a critical determinant in whether mRNAs are translated, stored, or decayed