Pharmaceuticals have emerged as a major group of environmental contaminants over the past decade but relatively little is known about their occurrence in freshwaters compared to other pollutants. We ...present a global-scale analysis of the presence of 203 pharmaceuticals across 41 countries and show that contamination is extensive due to widespread consumption and subsequent disposal to rivers. There are clear regional biases in current understanding with little work outside North America, Europe, and China, and no work within Africa. Within individual countries, research is biased around a small number of populated provinces/states and the majority of research effort has focused upon just 14 compounds. Most research has adopted sampling techniques that are unlikely to provide reliable and representative data. This analysis highlights locations where concentrations of antibiotics, cardiovascular drugs, painkillers, contrast media, and antiepileptic drugs have been recorded well above thresholds known to cause toxic effects in aquatic biota. Studies of pharmaceutical occurrence and effects need to be seen as a global research priority due to increasing consumption, particularly among societies with aging populations. Researchers in all fields of environmental management need to work together more effectively to identify high risk compounds, improve the reliability and coverage of future monitoring studies, and develop new mitigation measures.
Histone modifications regulate chromatin-dependent processes, yet the mechanisms by which they contribute to specific outcomes remain unclear. H3K4me3 is a prominent histone mark that is associated ...with active genes and promotes transcription through interactions with effector proteins that include initiation factor TFIID. We demonstrate that H3K4me3-TAF3 interactions direct global TFIID recruitment to active genes, some of which are p53 targets. Further analyses show that (1) H3K4me3 enhances p53-dependent transcription by stimulating preinitiation complex (PIC) formation; (2) H3K4me3, through TAF3 interactions, can act either independently or cooperatively with the TATA box to direct PIC formation and transcription; and (3) H3K4me3-TAF3/TFIID interactions regulate gene-selective functions of p53 in response to genotoxic stress. Our findings indicate a mechanism by which H3K4me3 directs PIC assembly for the rapid induction of specific p53 target genes.
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► H3K4me3 facilitates global TFIID recruitment to the core promoters of active genes ► By stimulating PIC formation, H3K4me3 enhances p53-dependent activation ► H3K4me3 acts both independently of and cooperatively with the TATA box ► Interactions between H3K4me3 and TAF3/TFIID regulate gene-selective functions of p53
H3K4me3 plays a causal role in transcription by recruiting the TAF3 subunit of TFIID to promoters and facilitating the assembly of the transcriptional preinitiation complex. This activity is required for the activation of rapidly induced genes, including some p53 targets.
The major obstacle to curing HIV infection is the persistence of cells with intact proviruses that can produce replication-competent virus. This HIV reservoir is believed to exist primarily in CD4+ ...T-cells and is stable despite years of suppressive antiretroviral therapy. A potential mechanism for HIV persistence is clonal expansion of infected cells, but how often such clones carry replication-competent proviruses has been controversial. Here, we used single-genome sequencing to probe for identical HIV sequence matches among viruses recovered in different viral outgrowth cultures and between the sequences of outgrowth viruses and proviral or intracellular HIV RNA sequences in uncultured blood mononuclear cells from eight donors on suppressive ART with diverse proviral populations. All eight donors had viral outgrowth virus that was fully susceptible to their current ART drug regimen. Six of eight donors studied had identical near full-length HIV RNA sequences recovered from different viral outgrowth cultures, and one of the two remaining donors had identical partial viral sequence matches between outgrowth virus and intracellular HIV RNA. These findings provide evidence that clonal expansion of HIV-infected cells is an important mechanism of reservoir persistence that should be targeted to cure HIV infection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but ...some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of human cells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequences is transcribed from integrated DNA copies of viral sequences, generating viral-host chimeric transcripts. The integration and transcription of viral sequences may thus contribute to the detection of viral RNA by PCR in patients after infection and clinical recovery. Because we have detected only subgenomic sequences derived mainly from the 3' end of the viral genome integrated into the DNA of the host cell, infectious virus cannot be produced from the integrated subgenomic SARS-CoV-2 sequences.
Advances in technology have made it possible to analyze integration sites in cells from HIV-infected patients. A significant fraction of infected cells in patients on long-term therapy are clonally ...expanded; in some cases the integrated viral DNA contributes to the clonal expansion of the infected cells. Although the large majority (>95%) of the HIV proviruses in treated patients are defective, expanded clones can carry replication-competent proviruses, and cells from these clones can release infectious virus. As discussed in this Perspective, it is likely that cells that produce virus are strongly selected against in vivo, and cells with replication competent proviruses expand and survive because only a small fraction of the cells produce virus. These findings have implications for strategies that are intended to eliminate the reservoir of infected cells that has made it almost impossible to cure HIV-infected patients.
HIV remains largely incurable because the viral DNA integrates into long-lived cells where the provirus remains quiescent. Hughes and Coffin present their perspective on what controls the specificity of HIV integration, with particular emphasis on its importance in the generation and persistence of HIV-infected cells on long-term antiretroviral therapy.
We introduce a second quantization scheme based on quasinormal modes, which are the dissipative modes of leaky optical cavities and plasmonic resonators with complex eigenfrequencies. The theory ...enables the construction of multiplasmon or multiphoton Fock states for arbitrary three-dimensional dissipative resonators and gives a solid understanding to the limits of phenomenological dissipative Jaynes-Cummings models. In the general case, we show how different quasinormal modes interfere through an off-diagonal mode coupling and demonstrate how these results affect cavity-modified spontaneous emission. To illustrate the practical application of the theory, we show examples using a gold nanorod dimer and a hybrid dielectric-metal cavity structure.
HIV-1 reverse transcription Hu, Wei-Shau; Hughes, Stephen H
Cold Spring Harbor perspectives in medicine,
10/2012, Letnik:
2, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Reverse transcription and integration are the defining features of the Retroviridae; the common name "retrovirus" derives from the fact that these viruses use a virally encoded enzyme, reverse ...transcriptase (RT), to convert their RNA genomes into DNA. Reverse transcription is an essential step in retroviral replication. This article presents an overview of reverse transcription, briefly describes the structure and function of RT, provides an introduction to some of the cellular and viral factors that can affect reverse transcription, and discusses fidelity and recombination, two processes in which reverse transcription plays an important role. In keeping with the theme of the collection, the emphasis is on HIV-1 and HIV-1 RT.
Research addressing the occurrence, fate and effects of pharmaceuticals in the aquatic environment has expanded rapidly over the past two decades, primarily due to the development of improved ...chemical analysis methods. Significant research gaps still remain, however, including a lack of longer term, repeated monitoring of rivers, determination of temporal and spatial changes in pharmaceutical concentrations, and inputs from sources other than wastewater treatment plants (WWTPs), such as combined sewer overflows (CSOs). In addressing these gaps it was found that the five pharmaceuticals studied were routinely (51–94% of the time) present in effluents and receiving waters at concentrations ranging from single ng to μg L−1. Mean concentrations were in the tens to hundreds ng L−1 range and CSOs appear to be a significant source of pharmaceuticals to water courses in addition to WWTPs. Receiving water concentrations varied throughout the day although there were no pronounced peaks at particular times. Similarly, concentrations varied throughout the year although no consistent patterns were observed. No dissipation of the study compounds was found over a 5 km length of river despite no other known inputs to the river. In conclusion, pharmaceuticals are routinely present in semi-rural and urban rivers and require management alongside more traditional pollutants.
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Pharmaceuticals were routinely present in effluent and receiving waters.Mean concentrations were in the range of tens to hundreds ng l-1.Peak concentrations reached almost 5 μg l-1.Combined sewer overflows (CSOs) are a source of pharmaceuticals.No dissipation of pharmaceuticals was found over a 5 km length of river.
A range of pharmaceuticals were routinely present in effluent and receiving waters and were not found to dissipate over a 5 km length of river.
We present a quasinormal-mode (QNM) theory for coupled loss and gain resonators working in the vicinity of an exceptional point. Assuming linear media, which can be fully quantified using the complex ...pole properties of the QNMs, we show how the QNMs yield a quantitatively accurate model to a full classical dipole spontaneous-emission response in Maxwell’s equations at a variety of spatial positions and frequencies (under linear response). We also develop an intuitive QNM coupled-mode theory, which can be used to accurately model such systems using only the QNMs of the bare resonators, where the hybrid QNMs of the complete system are automatically obtained. Near a lossy exceptional point, whose general properties are broadened and corrected through use of QNM theory, we analytically show how the QNMs yield a Lorentzian-like and a Lorentzian-squared-like response for the spontaneous-emission line shape consistent with other works. However, using rigorous analytical and numerical solutions for microdisk resonators, we demonstrate that the general line shapes are far richer than what has been previously predicted. Indeed, the classical picture of spontaneous emission can take on a wide range of positive and negative Purcell factors from the hybrid modes of the coupled loss-gain system. The negative Purcell factors are unphysical and signal a clear breakdown of the classical dipole picture of spontaneous emission in such media, though the concept of a negative local density of states is correct. This finding has enabled a quantum fix to the decay of a two-level-system dipole emitter in amplifying and lossy media Franke et al., Phys. Rev. Lett. 127, 013602 (2021), and we further show and discuss the impact of this fix using the QNMs of the microdisk resonators. We also show the rich spectral features of the Green’s function propagators, which can be used to model various physical observables, such as photon detection.
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