The role of BST2/tetherin in feline retrovirus infection

Pathogenic retroviral infections of mammals have induced the evolution of cellular anti-viral restriction factors and have shaped their biological activities. This intrinsic immunity plays an important role in controlling viral replication and imposes a barrier to viral cross-species transmission. Well-studied examples of such host restriction factors are TRIM5α, an E3 ubiquitin ligase that binds incoming retroviral capsids in the cytoplasm via its C-terminal PRY/SPRY (B30.2) domain and targets them for proteasomal degradation, and APOBEC3 proteins, cytidine deaminases that induce hypermutation and impair viral reverse transcription. Tetherin (BST-2, CD317) is an interferon-inducible transmembrane protein that potently inhibits the release of nascent retrovirus particles in single-cycle replication assays. However, whether the primary biological activity of tetherin in vivo is that of a restriction factor remains uncertain as recent studies on human tetherin suggest that it is unable to prevent spreading infection of human immunodeficiency virus type 1 (HIV-1). The feline tetherin homologue resembles human tetherin in amino acid sequence, protein topology and anti-viral activity. Transiently expressed feline tetherin displays potent inhibition of feline immunodeficiency virus (FIV) and HIV-1 particle release. However, stable ectopic expression of feline tetherin in a range of feline cell lines has no inhibitory effect on the growth of either primary or cell culture-adapted strains of FIV. By comparing and contrasting the activities of the felid and primate tetherins against their respective immunodeficiency-causing lentiviruses we may gain insight into the contribution of tetherins to the control of lentiviral replication and the evolution of lentiviral virulence

Decision under normative uncertainty

While ordinary decision theory focuses on empirical uncertainty, real decision-makers also face normative uncertainty: uncertainty about value itself. From a purely formal perspective, normative uncertainty is comparable to (Harsanyian or Rawlsian) identity uncertainty in the 'original position', where one's future values are unknown. A comprehensive decision theory must address twofold uncertainty -- normative and empirical. We present a simple model of twofold uncertainty, and show that the most popular decision principle -- maximising expected value (`Expectationalism') -- has different formulations, namely Ex-Ante Expectationalism, Ex-Post Expectationalism, and hybrid theories. These alternative theories recommend different decisions, reasoning modes, and attitudes to risk. But they converge under an interesting (necessary and sufficient) condition

Expected Value Under Normative Uncertainty

Maximising expected value is the classic doctrine in choice theory under empirical uncertainty, and a prominent proposal in the emerging philosophical literature on normative uncertainty, i.e., uncertainty about the standard of evaluation. But how should Expectationalism be stated in general, when we can face both uncertainties simultaneously , as is common in life? Surprisingly, different possibilities arise, ranging from Ex-Ante to Ex-Post Expectationalism, with several hybrid versions. The difference lies in the perspective from which expectations are taken, or equivalently the amount of uncertainty packed into the prospect evaluated. Expectationalism thus faces the classic dilemma between ex-ante and ex-post approaches, familiar elsewhere in ethics and aggregation theory under uncertainty. We analyse the spectrum of expectational theories, showing that they reach diverging evaluations, use different modes of reasoning, take different attitudes to normative risk as well as empirical risk, but converge under an interesting (necessary and sufficient) condition

Ablative fast pyrolysis of biomass: A new demonstration project in California, USA

California is the fifth largest economy in the world and has about 40 million inhabitants. The California federal government has decided to stick to the Paris climate change agreement by 2030. For many years, California has been feeling the effects of global warming caused by the largest tree extinction in modern history, a five-year dry spell and resulting bark beetle plague, and severe forest fires coupled with heavy winds, heavy rains, and rising sea levels. California is therefore promoting the use of biogenic fuels in the transport sector. In spring 2017, there was a grant funding opportunity from the California Energy Commission (CEC) in the program: Research and Demonstration to Decarbonize Transportation Fuels . Funding supported innovative processes for production of bio-intermediate fuels. to be further used for the generation of sustainable low-carbon fungible biofuels in California\u27s transport sector. In order to meet the given budget, a modular pyrolysis system with an ablative reactor was proposed by the authors. The advantage over fluidized bed processes lies in the better space-time yield, i.e. the systems can be kept small and fit in standardized shipping containers, since neither a fluid heat carrier nor a cycle gas is needed. After careful consideration of the submitted project proposals, our concept was considered worthy of support so that in October 2018 the contracts could be signed. The project duration is 3.5 years. The American business partner is Biogas Energy, Richmond, CA. According to the contract, the pyrolysis plant must produce at least 50,000 gallons (about 190,000 L) of bio-oil. At the beginning of the 21st century, there were two patents on ablative fast pyrolysis reactors. On the one hand the BtO process of PYTEC GmbH, Hamburg with a disk reactor (Fig. 1a), on the other hand the drum reactor, consisting of stator and rotor, Aston University, Birmingham, UK (Figs. 1b, c). In both systems wood chips are pressed against a hot, rotating surface (about 600 ° C) of the reactor. While the disk reactor of PYTEC needs a complex, multiple feeder system which was implemented in a pilot plant with a capacity of 250 kg/h, the drum reactor comes with a conventional two-stage lock hopper system, since only in the reactor the wood chips are being pressed between the walls of the stator and the rotor using a special blade system. The latter fast pyrolysis reactor system was brought to pilot maturity in recent years by Energolesprom (ELP), Kazan, RU and is now being used after some modifications in California. The plant, with a throughput of 500 kg/h, will be built on the site of Western Place Management Authorities close to Sacramento. Expected start of operation is summer 2020. For start-up demolition wood will be the preferred feedstock. Later on biomass from forestry and agriculture will be processed. Please click Additional Files below to see the full abstract

Restriction of the felid lentiviruses by a synthetic feline TRIM5-CypA fusion

Gene therapy approaches to the treatment of HIV infection have targeted both viral gene expression and the cellular factors that are essential for virus replication. However, significant concerns have been raised regarding the potential toxic effects of such therapies, the emergence of resistant viral variants and unforeseen biological consequences such as enhanced susceptibility to unrelated pathogens. Novel restriction factors formed by the fusion of the tripartite motif protein (TRIM5) and cyclophilin A (CypA), or "TRIMCyps", offer an effective antiviral defence strategy with a very low potential for toxicity. In order to investigate the potential therapeutic utility of TRIMCyps in gene therapy for AIDS, a synthetic fusion protein between feline TRIM5 and feline CypA was generated and transduced into cells susceptible to infection with feline immunodeficiency virus (FIV). The synthetic feline TRIMCyp was highly efficient at preventing infection with both HIV and FIV and the cells resisted productive infection with FIV from either the domestic cat or the puma. Feline TRIMCyp and FIV infection of the cat offers a unique opportunity to evaluate TRIMCyp-based approaches to genetic therapy for HIV infection and the treatment of AIDS

RAD54 family translocases counter genotoxic effects of RAD51 in human tumor cells.

The RAD54 family DNA translocases have several biochemical activities. One activity, demonstrated previously for the budding yeast translocases, is ATPase-dependent disruption of RAD51-dsDNA binding. This activity is thought to promote dissociation of RAD51 from heteroduplex DNA following strand exchange during homologous recombination. In addition, previous experiments in budding yeast have shown that the same activity of Rad54 removes Rad51 from undamaged sites on chromosomes; mutants lacking Rad54 accumulate nonrepair-associated complexes that can block growth and lead to chromosome loss. Here, we show that human RAD54 also promotes the dissociation of RAD51 from dsDNA and not ssDNA. We also show that translocase depletion in tumor cell lines leads to the accumulation of RAD51 on chromosomes, forming complexes that are not associated with markers of DNA damage. We further show that combined depletion of RAD54L and RAD54B and/or artificial induction of RAD51 overexpression blocks replication and promotes chromosome segregation defects. These results support a model in which RAD54L and RAD54B counteract genome-destabilizing effects of direct binding of RAD51 to dsDNA in human tumor cells. Thus, in addition to having genome-stabilizing DNA repair activity, human RAD51 has genome-destabilizing activity when expressed at high levels, as is the case in many human tumors

Clinical Trial Designs and Measures in Hereditary Spastic Paraplegias

Hereditary spastic paraplegias (HSPs) are a large group of genetically-diverse neurologic disorders characterized clinically by a common feature of lower extremity spasticity and gait difficulties. Current therapies are predominantly symptomatic, and even then usually provide inadequate relief of symptoms. Going forward, HSP therapeutics development requires a systematic analysis of quantifiable measures and tools to assess treatment response. This review summarizes promising therapeutic targets, assessment measures, and previous clinical trials for the HSPs. Oxidative stress, signaling pathways, microtubule dynamics, and gene rescue/replacement have been proposed as potential treatment targets or modalities. Quantitative evaluation of pre-clinical rodent HSP models emphasize rotarod performance, foot base angle, grip strength, stride length, beam walking, critical speed, and body weight. Clinical measures of HSP in humans include 10-m gait velocity, the Spastic Paraplegia Rating Scale (SPRS), Ashworth Spasticity Scale, Fugl-Meyer Scale, timed up-and-go, and the Gillette Functional Assessment Questionnaire. We conducted a broad search for past clinical trials in HSPs and identified trials that investigated pharmacological agents including atorvastatin, gabapentin, L-threonine, botulinum toxin, dalfampridine, methylphenidate, and baclofen. We provide recommendations for future HSP treatment directions based on these prior research experiences as well as regulatory insight

Congress of neurological surgeons systematic review and evidence-based guidelines update on the role of chemotherapeutic management and antiangiogenic treatment of newly diagnosed glioblastoma in adults

QUESTION: What is the role of temozolomide in the management of adult patients (aged 65 and under) with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Concurrent and post-irradiation Temozolomide (TMZ) in combination with radiotherapy and post-radiotherapy as described by Stupp et al. is recommended to improve both PFS and OS in adult patients with newly diagnosed GBM. There is no evidence that alterations in the dosing regimen have additional beneficial effect. QUESTION: Is there benefit to adjuvant temozolomide treatment in elderly patients (\u3e 65 years old?). TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: Adjuvant TMZ treatment is suggested as a treatment option to improve PFS and OS in adult patients (over 70 years of age) with newly diagnosed GBM. QUESTION: What is the role of local regional chemotherapy with BCNU biodegradable polymeric wafers in adult patients with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level III: There is insufficient evidence for the use of BCNU wafers following resection in patients with newly diagnosed glioblastoma who undergo the Stupp protocol after surgery. Further studies of higher quality are suggested to understand the role of BCNU wafer and other locoregional therapy in the setting of Stupp Protocol. QUESTION: What is the role of bevacizumab in the adult patient with newly diagnosed glioblastoma? TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. RECOMMENDATION: Level I: Bevacizumab in general is not recommended in the initial treatment of adult patients with newly diagnosed GBM. It continues to be strongly recommended that patients with newly diagnosed GBM be enrolled in properly designed clinical trials to assess the benefit of novel chemotherapeutic agents compared to standard therapy

THE COGNITIVE OVERRIDE OF ANXIETY IS ACCOMPLISHED BY SOCIAL FAMILIARITY AND IS MEDIATED BY THE MEDIAL PREFRONTAL CORTEX.

poster abstractIn rats, social familiarity can alleviate anxiety-like behavior observed in the social interaction test. We propose that a neural circuit that includes the medial Prefrontal Cortex (mPFC) and Basolateral Amygdala (BLA), in which the mPFC processes social cues of familiarity and suppresses BLA outputs that lead to anxiety-like behavior, regulate this social familiarity effect. To investigate the effect of social familiarity on anxiety, we developed the Social Interaction-Habituation (SI-h) paradigm, consisting of a 5 min social interaction test repeated daily with the experimental rat exposed to the same partner rat on each test day. As the experimental rat becomes “familiar” with the partner rat, a significant increase in SI time is observed by day 5 compared to day 1, producing a SI-familiarity effect (SI-f). This SI-f effect is dependent on the presence of an anxiogenic stimulus (bright light), and familiarity to a partner rat. No increases in SI times were observed in rats when the SI-h test was performed under dark conditions or when exposed to novel partners on days 1-5. After establishing SI-f, exposure to a novel partner significantly reduces SI times, suggesting the SI-f effect is a result of recognition of the familiar partner rat. Re-exposure to the original partner in a new environment produces an enhanced SI-f effect; SI time significantly increases from day 1 by day 3. Bilateral inhibition of the mPFC with a GABAA agonist blocks the anxiolytic SI-f effect. Exposure to the same partner 24 hours following mPFC inhibition, SI times increase significantly higher than day 1. These data indicate that the mPFC activity is necessary for expression of the SI-f effect