Exploring energy sufficiency: New challenges and options in times of crisis

The war in Ukraine is changing the political landscape at breakneck speed. How should politics and society react to high energy prices and a precarious dependence on fossil fuels imports? Can modern societies get by with much less energy? Energy sufficiency can play an important role in answering these questions. The contributions in this Special topic explore sufficiency as an interdisciplinary research topic for energy modeling, scenarios, and policy.The war in Ukraine is changing the political landscape at breakneck speed. How should politics and society react to high energy prices and a precarious dependence on fossil fuels imports? Can modern societies get by with much less energy? Energy sufficiency can play an important role in answering these questions. The contributions in this Special topic explore sufficiency as an interdisciplinary research topic for energy modeling, scenarios, and policy

Exploring energy sufficiency : new challenges and options in times of crisis

The war in Ukraine is changing the political landscape at breakneck speed. How should politics and society react to high energy prices and a precarious dependence on fossil fuels imports? Can modern societies get by with much less energy? Energy sufficiency can play an important role in answering these questions. The contributions in this Special topic explore sufficiency as an interdisciplinary research topic for energy modeling, scenarios, and policy

Association of polymorphisms in the LEDGF/p75 gene (PSIP1) with susceptibility to HIV-1 infection and disease progression

OBJECTIVE: LEDGF/p75, encoded by the PSIP1 gene, interacts with HIV-1 integrase and targets HIV-1 integration into active genes. We investigated the influence of polymorphisms in PSIP1 on HIV-1 acquisition and disease progression in black South Africans. METHODS: Integrase binding domain of LEDGF/p75 was sequenced in 126 participants. Four haplotype tagging SNPs rs2277191, rs1033056, rs12339417 and rs10283923 referred to as SNP1, SNP2, SNP3 and SNP4, respectively, and one exonic SNP rs61744944 (SNP5, Q472L) were genotyped in 195 HIV-1 seronegative, 52 primary and 403 chronically infected individuals using TaqMan assays. LEDGF/p75 expression was quantified by real-time RT-PCR. The impact of Q472L mutation on the interaction with HIV_1 IN was measured by AlphaScreen. RESULTS: rs2277191 (SNP1) A was more frequent among seropositives (P = 0.06, Fisher's exact test). Among individuals followed longitudinally SNP1A trended towards association with higher likelihood of HIV-1 acquisition [relative hazard (RH) = 2.21, P = 0.08; Cox model] and it was also associated with rapid disease progression (RH = 5.98, P = 0.04; Cox model) in the recently infected (primary infection) cohort. rs12339417 (SNP3)C was associated with slower decline of CD4(+) T cells (P = 0.02) and lower messenger RNA (mRNA) levels of LEDGF/p75 (P < 0.01). Seroconverters had higher preinfection mRNA levels of LEDGF/p75 (P < 0.01) and these levels decreased after HIV-1 infection (P = 0.02). CONCLUSIONS: Genetic variants of PSIP1 may affect HIV-1 outcomes. Further studies are needed to confirm the effect of genetic variation of PSIP1 on HIV-1 pathogenesis in different cohorts

Energy sufficiency: Conceptual considerations, modeling, and scenarios for less energy consumption

The war in Ukraine is changing the political landscape at breakneck speed. How should politics and society react to high energy prices and a precarious dependence on fossil fuels imports? Can modern societies get by with much less energy? Energy sufficiency can play an important role in answering these questions. The contributions in this Special topic explore sufficiency as an interdisciplinary research topic for energy modeling, scenarios, and policy.The war in Ukraine is changing the political landscape at breakneck speed. How should politics and society react to high energy prices and a precarious dependence on fossil fuels imports? Can modern societies get by with much less energy? Energy sufficiency can play an important role in answering these questions. The contributions in this Special topic explore sufficiency as an interdisciplinary research topic for energy modeling, scenarios, and policy

Role of LEDGF/p75 (PSIP1) in oncogenesis:Insights in molecular mechanism and therapeutic potential

Aberrant gene expression due to dysfunction in proteins involved in transcriptional regulation is a hallmark of tumor development. Indeed, targeting transcriptional regulators represents an emerging approach in cancer therapeutics. Lens epithelium-derived growth factor (LEDGF/p75, PSIP1) is a co-transcriptional activator that tethers several proteins to the chromatin. LEDGF/p75 has been implicated in diseases such as HIV infection and KMT2A-rearranged leukemia. Notably, LEDGF/p75 is upregulated in various human cancers including prostate and breast cancer. In this review, we discuss the essential role of LEDGF/p75 in different malignancies and explore its mechanistic contribution to tumorigenesis revealing its potential as a therapeutic target for chemotherapy.</p

Interplay between HIV Entry and Transportin-SR2 Dependency

<p>Abstract</p> <p>Background</p> <p>Transportin-SR2 (TRN-SR2, TNPO3, transportin 3) was previously identified as an interaction partner of human immunodeficiency virus type 1 (HIV-1) integrase and functions as a nuclear import factor of HIV-1. A possible role of capsid in transportin-SR2-mediated nuclear import was recently suggested by the findings that a chimeric HIV virus, carrying the murine leukemia virus (MLV) capsid and matrix proteins, displayed a transportin-SR2 independent phenotype, and that the HIV-1 N74D capsid mutant proved insensitive to transportin-SR2 knockdown.</p> <p>Results</p> <p>Our present analysis of viral specificity reveals that TRN-SR2 is not used to the same extent by all lentiviruses. The DNA flap does not determine the TRN-SR2 requirement of HIV-1. We corroborate the TRN-SR2 independent phenotype of the chimeric HIV virus carrying the MLV capsid and matrix proteins. We reanalyzed the HIV-1 N74D capsid mutant in cells transiently or stably depleted of transportin-SR2 and confirm that the N74D capsid mutant is independent of TRN-SR2 when pseudotyped with the vesicular stomatitis virus glycoprotein (VSV-G). Remarkably, although somewhat less dependent on TRN-SR2 than wild type virus, the N74D capsid mutant carrying the wild type HIV-1 envelope required TRN-SR2 for efficient replication. By pseudotyping with envelopes that mediate pH-independent viral uptake including HIV-1, measles virus and amphotropic MLV envelopes, we demonstrate that HIV-1 N74D capsid mutant viruses retain partial dependency on TRN-SR2. However, this dependency on TRN-SR2 is lost when the HIV N74D capsid mutant is pseudotyped with envelopes mediating pH-dependent endocytosis, such as the VSV-G and Ebola virus envelopes.</p> <p>Conclusion</p> <p>Here we discover a link between the viral entry of HIV and its interaction with TRN-SR2. Our data confirm the importance of TRN-SR2 in HIV-1 replication and argue for careful interpretation of experiments performed with VSV-G pseudotyped viruses in studies on early steps of HIV replication including the role of capsid therein.</p

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN

Virus Evolution Reveals an Exclusive Role for LEDGF/p75 in Chromosomal Tethering of HIV

Retroviruses by definition insert their viral genome into the host cell chromosome. Although the key player of retroviral integration is viral integrase, a role for cellular cofactors has been proposed. Lentiviral integrases use the cellular protein LEDGF/p75 to tether the preintegration complex to the chromosome, although the existence of alternative host proteins substituting for the function of LEDGF/p75 in integration has been proposed. Truncation mutants of LEDGF/p75 lacking the chromosome attachment site strongly inhibit HIV replication by competition for the interaction with integrase. In an attempt to select HIV strains that can overcome the inhibition, we now have used T-cell lines that stably express a C-terminal fragment of LEDGF/p75. Despite resistance development, the affinity of integrase for LEDGF/p75 is reduced and replication kinetics in human primary T cells is impaired. Detection of the integrase mutations A128T and E170G at key positions in the LEDGF/p75–integrase interface provides in vivo evidence for previously reported crystallographic data. Moreover, the complementary inhibition by LEDGF/p75 knockdown and mutagenesis at the integrase–LEDGF/p75 interface points to the incapability of HIV to circumvent LEDGF/p75 function during proviral integration. Altogether, the data provide a striking example of the power of viral molecular evolution. The results underline the importance of the LEDGF/p75 HIV-1 interplay as target for innovative antiviral therapy. Moreover, the role of LEDGF/p75 in targeting integration will stimulate research on strategies to direct gene therapy vectors into safe landing sites