Spatial associations of long-term exposure to diesel particulate matter with seasonal and annual mortality due to COVID-19 in the contiguous United States.

BACKGROUND: People with certain underlying respiratory and cardiovascular conditions might be at an increased risk for severe illness from COVID-19. Diesel Particulate Matter (DPM) exposure may affect the pulmonary and cardiovascular systems. The study aims to assess if DPM was spatially associated with COVID-19 mortality rates across three waves of the disease and throughout 2020. METHODS: We tested an ordinary least squares (OLS) model, then two global models, a spatial lag model (SLM) and a spatial error model (SEM) designed to explore spatial dependence, and a geographically weighted regression (GWR) model designed to explore local associations between COVID-19 mortality rates and DPM exposure, using data from the 2018 AirToxScreen database. RESULTS: The GWR model found that associations between COVID-19 mortality rate and DPM concentrations may increase up to 77 deaths per 100,000 people in some US counties for every interquartile range (0.21 µg/m3) increase in DPM concentration. Significant positive associations between mortality rate and DPM were observed in New York, New Jersey, eastern Pennsylvania, and western Connecticut for the wave from January to May, and in southern Florida and southern Texas for June to September. The period from October to December exhibited a negative association in most parts of the US, which seems to have influenced the year-long relationship due to the large number of deaths during that wave of the disease. CONCLUSIONS: Our models provided a picture in which long-term DPM exposure may have influenced COVID-19 mortality during the early stages of the disease. That influence appears to have waned over time as transmission patterns evolved.

Spatial Associations of Long-term Exposure to Diesel Particulate Matter with Seasonal and Annual Mortality Due to COVID-19 in the Contiguous United States.

Background People with certain underlying respiratory and cardiovascular conditions might be at an increased risk for severe illness from COVID-19. Diesel Particulate Matter (DPM) exposure may affect the pulmonary and cardiovascular systems. The study aims to assess if DPM was spatially associated with COVID-19 mortality across three waves of the disease and throughout 2020. Methods We tested an ordinary least square (OLS) model, then two global models, spatial lag model (SLM) and spatial error model (SEM), designed to explore spatial dependence, and a geographically weighted regression (GWR) model designed to explore local associations. Results The GWR model found that associations between COVID-19 deaths and DPM concentrations may increase up to 57, 36, 43, and 58 deaths per 100,000 people in some US counties for every 1 µg/m 3 increase in DPM concentration. Relative significant positive association are observed in New York, New Jersey, eastern Pennsylvania, and western Connecticut for the wave from January to May, and in southern Florida and southern Texas for June to September. The period from October to December exhibit a negative association in most parts of the US, which seems to have influenced the year-long relationship due to the large number of deaths during that wave of the disease. Conclusions Our models provided a picture in which long-term DPM exposure may have influenced COVID-19 mortality during the early stages of the disease, but that influence appears to have waned over time as transmission patterns evolved.

Characterization of the DdrD protein from the extremely radioresistant bacterium Deinococcus radiodurans.

Here, we report the in vitro and in vivo characterization of the DdrD protein from the extraordinary stress-resistant bacterium, D. radiodurans. DdrD is one of the most highly induced proteins following cellular irradiation or desiccation. We confirm that DdrD belongs to the Radiation Desiccation Response (RDR) regulon protein family whose expression is regulated by the IrrE/DdrO proteins after DNA damage. We show that DdrD is a DNA binding protein that binds to single-stranded DNA In vitro, but not to duplex DNA unless it has a 5' single-stranded extension. In vivo, we observed no significant effect of the absence of DdrD on the survival of D. radiodurans cells after exposure to γ-rays or UV irradiation in different genetic contexts. However, genome reassembly is affected in a ∆ddrD mutant when cells recover from irradiation in the absence of nutrients. Thus, DdrD likely contributes to genome reconstitution after irradiation, but only under starvation conditions. Lastly, we show that the absence of the DdrD protein partially restores the frequency of plasmid transformation of a ∆ddrB mutant, suggesting that DdrD could also be involved in biological processes other than the response to DNA damage.

In vivo and in vitro characterization of DdrC, a DNA damage response protein in Deinococcus radiodurans bacterium.

The bacterium Deinococcus radiodurans possesses a set of Deinococcus-specific genes highly induced after DNA damage. Among them, ddrC (dr0003) was recently re-annotated, found to be in the inverse orientation and called A2G07_00380. Here, we report the first in vivo and in vitro characterization of the corrected DdrC protein to better understand its function in irradiated cells. In vivo, the ΔddrC null mutant is sensitive to high doses of UV radiation and the ddrC deletion significantly increases UV-sensitivity of ΔuvrA or ΔuvsE mutant strains. We show that the expression of the DdrC protein is induced after γ-irradiation and is under the control of the regulators, DdrO and IrrE. DdrC is rapidly recruited into the nucleoid of the irradiated cells. In vitro, we show that DdrC is able to bind single- and double-stranded DNA with a preference for the single-stranded DNA but without sequence or shape specificity and protects DNA from various nuclease attacks. DdrC also condenses DNA and promotes circularization of linear DNA. Finally, we show that the purified protein exhibits a DNA strand annealing activity. Altogether, our results suggest that DdrC is a new DNA binding protein with pleiotropic activities. It might maintain the damaged DNA fragments end to end, thus limiting their dispersion and extensive degradation after exposure to ionizing radiation. DdrC might also be an accessory protein that participates in a single strand annealing pathway whose importance in DNA repair becomes apparent when DNA is heavily damaged.

Interaction of Yna1 and Yna2 Is Required for Nuclear Accumulation and Transcriptional Activation of the Nitrate Assimilation Pathway in the Yeast Hansenula polymorpha.

A few yeasts, including Hansenula polymorpha are able to assimilate nitrate and use it as nitrogen source. The genes necessary for nitrate assimilation are organised in this organism as a cluster comprising those encoding nitrate reductase (YNR1), nitrite reductase (YNI1), a high affinity transporter (YNT1), as well as the two pathway specific Zn(II)2Cys2 transcriptional activators (YNA1, YNA2). Yna1p and Yna2p mediate induction of the system and here we show that their functions are interdependent. Yna1p activates YNA2 as well as its own (YNA1) transcription thus forming a nitrate-dependent autoactivation loop. Using a split-YFP approach we demonstrate here that Yna1p and Yna2p form a heterodimer independently of the inducer and despite both Yna1p and Yna2p can occupy the target promoter as mono- or homodimer individually, these proteins are transcriptionally incompetent. Subsequently, the transcription factors target genes containing a conserved DNA motif (termed nitrate-UAS) determined in this work by in vitro and in vivo protein-DNA interaction studies. These events lead to a rearrangement of the chromatin landscape on the target promoters and are associated with the onset of transcription of these target genes. In contrast to other fungi and plants, in which nuclear accumulation of the pathway-specific transcription factors only occur in the presence of nitrate, Yna1p and Yna2p are constitutively nuclear in H. polymorpha. Yna2p is needed for this nuclear accumulation and Yna1p is incapable of strictly positioning in the nucleus without Yna2p. In vivo DNA footprinting and ChIP analyses revealed that the permanently nuclear Yna1p/Yna2p heterodimer only binds to the nitrate-UAS when the inducer is present. The nitrate-dependent up-regulation of one partner protein in the heterodimeric complex is functionally similar to the nitrate-dependent activation of nuclear accumulation in other systems.

DdrO is an essential protein that regulates the radiation desiccation response and the apoptotic-like cell death in the radioresistant Deinococcus radiodurans bacterium.

Deinococcus radiodurans is known for its extreme radioresistance. Comparative genomics identified a radiation-desiccation response (RDR) regulon comprising genes that are highly induced after DNA damage and containing a conserved motif (RDRM) upstream of their coding region. We demonstrated that the RDRM sequence is involved in cis-regulation of the RDR gene ddrB in vivo. Using a transposon mutagenesis approach, we showed that, in addition to ddrO encoding a predicted RDR repressor and irrE encoding a positive regulator recently shown to cleave DdrO in Deinococcus deserti, two genes encoding α-keto-glutarate dehydrogenase subunits are involved in ddrB regulation. In wild-type cells, the DdrO cell concentration decreased transiently in an IrrE-dependent manner at early times after irradiation. Using a conditional gene inactivation system, we showed that DdrO depletion enhanced expression of three RDR proteins, consistent with the hypothesis that DdrO acts as a repressor of the RDR regulon. DdrO-depleted cells loose viability and showed morphological changes evocative of an apoptotic-like response, including membrane blebbing, defects in cell division and DNA fragmentation. We propose that DNA repair and apoptotic-like death might be two responses mediated by the same regulators, IrrE and DdrO, but differently activated depending on the persistence of IrrE-dependent DdrO cleavage.

Roles of the Aspergillus nidulans homologues of Tup1 and Ssn6 in chromatin structure and cell viability.

For three different carbon catabolite repressible promoters, alcA, alcR and the bidirectional promoter prnD-prnB, a deletion of rcoA, the Aspergillus nidulans homologue of TUP1, does not result in carbon catabolite derepression. Surprisingly, it results in disruption of the chromatin default structure of alcR and prnD-prnB promoters. In these promoters, and at variance with the wild type, repression occurs in the absence of nucleosome positioning. For alcR, repression occurs together with a nucleosome pattern identical to that found under conditions of full expression, and for prnD-prnB it occurs with a novel pattern that does not correspond to the pattern seen under conditions of repression in a wild-type strain. Deletion of the putative RcoA partner, SsnF, is lethal in A. nidulans.

Patterns of nucleosomal organization in the alc regulon of Aspergillus nidulans: roles of the AlcR transcriptional activator and the CreA global repressor.

We have studied the chromatin organization of three promoters of the alc regulon of Aspergillus nidulans. No positioned nucleosomes are seen in the aldA (aldehyde dehydrogenase) promoter under any physiological condition tested by us. In the alcA (alcohol dehydrogenase I) and alcR (coding for the pathway-specific transcription factor) promoters, a pattern of positioned nucleosomes is seen under non-induced and non-induced repressed conditions. While each of these promoters shows a specific pattern of chromatin restructuring, in both cases induction results in loss of nucleosome positioning. Glucose repression in the presence of inducer results in a specific pattern of partial positioning in the alcA and alcR promoters. Loss of nucleosome positioning depends absolutely on the AlcR protein and it is very unlikely to be a passive result of the induction of transcription. In an alcR loss-of-function background and in strains carrying mutations of the respective AlcR binding sites of the alcA and alcR promoters, nucleosomes are fully positioned under all growth conditions. Analysis of mutant AlcR proteins establishes that all domains needed for transcriptional activation and chromatin restructuring are included within the first 241 residues. The results suggest a two-step process, one step resulting in chromatin restructuring, a second one in transcriptional activation. Partial positioning upon glucose repression shows a specific pattern that depends on the CreA global repressor. An alcR loss-of-function mutation is epistatic to a creA loss-of-function mutation, showing that AlcR does not act by negating a nucleosome positioning activity of CreA.