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The Journal of Chemical Physics Jun 2024Drachmann's regularization approach is implemented for floating explicitly correlated Gaussians (fECGs) and molecular systems. Earlier applications of drachmannized...
Drachmann's regularization approach is implemented for floating explicitly correlated Gaussians (fECGs) and molecular systems. Earlier applications of drachmannized relativistic corrections for molecular systems were hindered due to the unknown analytic matrix elements of 1/rix1/rjy-type operators with fECGs. In the present work, one of the 1/r factors is approximated by a linear combination of Gaussians, which results in calculable integrals. The numerical approach is found to be precise and robust over a range of molecular systems and nuclear configurations, and thus, it opens the route toward an automated evaluation of high-precision relativistic corrections over potential energy surfaces of polyatomic systems. Furthermore, the newly developed integration approach makes it possible to construct the matrix representation of the square of the electronic Hamiltonian relevant for energy lower-bound as well as time-dependent computations of molecular systems with a flexible and high-precision fECG basis representation.
PubMed: 38828828
DOI: 10.1063/5.0213079 -
The Protein Journal May 2024Hemoglobin (Hb) is the key metalloprotein within red blood cells involved in oxygen transportation from lungs to body cells. The heme-iron atom inherent within Hb...
Hemoglobin (Hb) is the key metalloprotein within red blood cells involved in oxygen transportation from lungs to body cells. The heme-iron atom inherent within Hb effectuates the mechanism of oxygen transportation and carbon dioxide removal. Structural investigations on avian Hb are limited when compared with the enormous work has been carried out on mammalian Hb. Here, the crystal structure of T-state methemoglobin (T-metHb) from domestic duck (Anas platyrhynchos), a low oxygen affinity avian species, determined to 2.1Å resolution is presented. Duck T-metHb crystallized in the orthorhombic space group C222 with unit cell parameters a = 59.89, b = 109.42 and c = 92.07Å. The final refined model with R-factor: 19.5% and R: 25.2% was obtained. The structural analysis reveals that duck T-metHb adopts a unique quaternary structure that is distinct from any of the avian liganded Hb structures. Moreover, it closely resembles the deoxy Hb of bar-headed goose, a high oxygen-affinity species. Besides the amino acid αPro119 located in the α1β1 interface, a unique quaternary structure with a constrained heme environment is attributed for the intrinsic low oxygen-affinity of duck Hb. This study reports the first protein crystal structure of low oxygen-affinity avian T-metHb from Anas platyrhynchos.
PubMed: 38767790
DOI: 10.1007/s10930-024-10206-z -
Chemosphere Jul 2024Arsenic, ubiquitous in various industrial processes and consumer products, presents both essential functions and considerable toxicity risks, driving extensive research...
Arsenic, ubiquitous in various industrial processes and consumer products, presents both essential functions and considerable toxicity risks, driving extensive research into safer applications. Our investigation, drawing from 7182 arsenic-containing molecules in the Cambridge Structural Database (CSD), outlines their diverse bonding patterns. Notably, 51% of these molecules exhibit cyclic connections, while 49% display acyclic ones. Arsenic forms eight distinct bonding types with other elements, with significant interactions observed, particularly with phenyl rings, O and F moieties. Top interactions involve carbon, nitrogen, oxygen, fluorine, sulfur, and arsenic itself. We meticulously evaluated average bond lengths under three conditions: without an R-factor cut-off, with R-factor ≤0.075, and with R-factor ≤0.05, supporting the credibility of our results. Comparative analysis with existing literature data enriches our understanding of arsenic's bonding behaviour. Our findings illuminate the structural attributes, molecular coordination, geometry, and bond lengths of arsenic with 68 diverse atoms, enriching our comprehension of arsenic chemistry. These revelations not only offer a pathway for crafting innovative and safer arsenic-based compounds but also foster the evolution of arsenic detoxification mechanisms, tackling pivotal health and environmental challenges linked to arsenic exposure across different contexts.
Topics: Arsenic; Data Mining; Databases, Chemical; Molecular Structure; Arsenicals
PubMed: 38763400
DOI: 10.1016/j.chemosphere.2024.142349 -
Nucleic Acids Research May 2024Emerging evidence indicates that arginine methylation promotes the stability of arginine-glycine-rich (RGG) motif-containing RNA-binding proteins (RBPs) and regulates...
Emerging evidence indicates that arginine methylation promotes the stability of arginine-glycine-rich (RGG) motif-containing RNA-binding proteins (RBPs) and regulates gene expression. Here, we report that post-translational modification of FXR1 enhances the binding with mRNAs and is involved in cancer cell growth and proliferation. Independent point mutations in arginine residues of FXR1's nuclear export signal (R386 and R388) and RGG (R453, R455 and R459) domains prevent it from binding to RNAs that form G-quadruplex (G4) RNA structures. Disruption of G4-RNA structures by lithium chloride failed to bind with FXR1, indicating its preference for G4-RNA structure containing mRNAs. Furthermore, loss-of-function of PRMT5 inhibited FXR1 methylation both in vivo and in vitro, affecting FXR1 protein stability, inhibiting RNA-binding activity and cancer cell growth and proliferation. Finally, the enhanced crosslinking and immunoprecipitation (eCLIP) analyses reveal that FXR1 binds with the G4-enriched mRNA targets such as AHNAK, MAP1B, AHNAK2, HUWE1, DYNC1H1 and UBR4 and controls its mRNA expression in cancer cells. Our findings suggest that PRMT5-mediated FXR1 methylation is required for RNA/G4-RNA binding, which promotes gene expression in cancer cells. Thus, FXR1's structural characteristics and affinity for RNAs preferentially G4 regions provide new insights into the molecular mechanism of FXR1 in oral cancer cells.
PubMed: 38709899
DOI: 10.1093/nar/gkae319 -
Communications Biology Apr 2024Bacterial cooperation and antagonism mediated by secretion systems are among the ways in which bacteria interact with one another. Here we report the discovery of an...
Bacterial cooperation and antagonism mediated by secretion systems are among the ways in which bacteria interact with one another. Here we report the discovery of an antagonistic property of a type IV secretion system (T4SS) sourced from a conjugative plasmid, RP4, using engineering approaches. We scrutinized the genetic determinants and suggested that this antagonistic activity is independent of molecular cargos, while we also elucidated the resistance genes. We further showed that a range of Gram-negative bacteria and a mixed bacterial population can be eliminated by this T4SS-dependent antagonism. Finally, we showed that such an antagonistic property is not limited to T4SS sourced from RP4, rather it can also be observed in a T4SS originated from another conjugative plasmid, namely R388. Our results are the first demonstration of conjugative T4SS-dependent antagonism between Gram-negative bacteria on the genetic level and provide the foundation for future mechanistic studies.
Topics: Plasmids; Type IV Secretion Systems; Conjugation, Genetic; Gram-Negative Bacteria; Escherichia coli
PubMed: 38664513
DOI: 10.1038/s42003-024-06192-8 -
Scientific Reports Apr 2024Antimicrobial resistance genes (ARG), such as extended-spectrum β-lactamase (ESBL) and carbapenemase genes, are commonly carried on plasmids. Plasmids can transmit...
Antimicrobial resistance genes (ARG), such as extended-spectrum β-lactamase (ESBL) and carbapenemase genes, are commonly carried on plasmids. Plasmids can transmit between bacteria, disseminate globally, and cause clinically important resistance. Therefore, targeting plasmids could reduce ARG prevalence, and restore the efficacy of existing antibiotics. Cobalt complexes possess diverse biological activities, including antimicrobial and anticancer properties. However, their effect on plasmid conjugation has not been explored yet. Here, we assessed the effect of four previously characterised bis(N-picolinamido)cobalt(II) complexes lacking antibacterial activity on plasmid conjugation in Escherichia coli and Klebsiella pneumoniae. Antimicrobial susceptibility testing of these cobalt complexes confirmed the lack of antibacterial activity in E. coli and K. pneumoniae. Liquid broth and solid agar conjugation assays were used to screen the activity of the complexes on four archetypical plasmids in E. coli J53. The cobalt complexes significantly reduced the conjugation of RP4, R6K, and R388 plasmids, but not pKM101, on solid agar in E. coli J53. Owing to their promising activity, the impact of cobalt complexes was tested on the conjugation of fluorescently tagged extended-spectrum β-lactamase encoding pCTgfp plasmid in E. coli and carbapenemase encoding pKpQILgfp plasmid in K. pneumoniae, using flow cytometry. The complexes significantly reduced the conjugation of pKpQILgfp in K. pneumoniae but had no impact on pCTgfp conjugation in E. coli. The cobalt complexes did not have plasmid-curing activity, suggesting that they target conjugation rather than plasmid stability. To our knowledge, this is the first study to report reduced conjugation of clinically relevant plasmids with cobalt complexes. These cobalt complexes are not cytotoxic towards mammalian cells and are not antibacterial, therefore they could be optimised and employed as inhibitors of plasmid conjugation.
Topics: Animals; Agar; Anti-Bacterial Agents; Anti-Infective Agents; beta-Lactamases; Escherichia coli; Klebsiella Infections; Klebsiella pneumoniae; Mammals; Microbial Sensitivity Tests; Plasmids
PubMed: 38582880
DOI: 10.1038/s41598-024-58895-x -
Thrombosis Research May 2024The hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with...
Reduced plasma factor X is associated with a lack of response to recombinant activated factor VII in patients with hemophilia A and inhibitor, but does not impair emicizumab-driven hemostasis in vitro.
BACKGROUND
The hemostatic effect of recombinant (r) factor (F)VIIa after repetitive intermittent administration may be attenuated in patients with hemophilia A (PwHA) with inhibitors (PwHAwI) creating a clinically unresponsive status, although mechanism(s) remain to be clarified. In patients receiving prophylaxis treatment with emicizumab, concomitant rFVIIa is sometimes utilized in multiple doses for surgical procedures or breakthrough bleeding.
AIM AND METHODS
We identified 'unresponsiveness' to rFVIIa, based on global coagulation function monitored using rotational thromboelastometry (ROTEM) in 11 PwHAwI and 5 patients with acquired HA, and investigated possible mechanisms focusing on the association between plasma FX levels and rFVIIa-mediated interactions.
RESULTS
Our data demonstrated that FX antigen levels were lower in the rFVIIa-unresponsive group than in the rFVIIa-responsive group (0.46 ± 0.14 IU/mL vs. 0.87 ± 0.15 IU/mL, p < 0.01). This relationship was further examined by thrombin generation assays using a FX-deficient PwHAwI plasma model. The addition of FX with rFVIIa was associated with increased peak thrombin (PeakTh) generation. At low levels of FX (<0.5 IU/mL), rFVIIa failed to increase PeakTh to the normal range, consistent with clinical rFVIIa-unresponsiveness. In the presence of emicizumab (50 μg/mL), PeakTh was increased maximally to 80 % of normal, even at low levels of FX (0.28 IU/mL).
CONCLUSIONS
Unresponsiveness to rFVIIa was associated with reduced levels of FX in PwHAwI. Emicizumab exhibited in vitro coagulation potential in the presence of FX at concentrations that appeared to limit the clinical response to rFVIIa therapy.
Topics: Female; Humans; Male; Antibodies, Bispecific; Antibodies, Monoclonal, Humanized; Blood Coagulation; Factor VIIa; Factor X; Hemophilia A; Hemostasis; Recombinant Proteins; Thrombelastography
PubMed: 38547693
DOI: 10.1016/j.thromres.2024.03.023 -
The Science of the Total Environment May 2024The water sector is facing unprecedented pressures as increased environmental and anthropogenic challenges, such as climate change and rapid urbanization, impact the... (Review)
Review
The water sector is facing unprecedented pressures as increased environmental and anthropogenic challenges, such as climate change and rapid urbanization, impact the availability and predictability of safe drinking water. There is a need for practitioners and policymakers to integrate water security and resilience (WS&R) factors into programming to sustain investments in drinking water systems to support associated economic, security, and public health benefits. In response to intensifying impacts from WS&R risks, communities around the world are developing adaptive strategies, and a critical review of these strategies may provide lessons that can be implemented at scale. In this critical review, we systematically screened over 9000 peer-reviewed and grey literature articles and extracted data from relevant studies that propose, pilot, and/or evaluate adaptations in low- and middle-income countries (LMICs) and evaluated the suitability of each adaptation for different contexts. We created a portfolio of adaptive strategies from over 75 LMICs to inform practitioners and policymakers in enhancing the resilience of drinking water systems. Over 20 adaptations were identified, including strategies such as stormwater management, wastewater reuse, non-revenue water reductions, water pricing, and public awareness campaigns. We categorized adaptations by function (improving water management, augmenting existing supplies, reducing water demand) and scale (household, municipal, regional) to provide recommendations tailored to local needs. For each adaptation, we highlighted associated strengths, weaknesses, barriers to adoption, and enabling environments for successful implementation. We propose a novel decision-support tool, called STEP WS&R, that provides a consistent and replicable process for informing high-level investment and policy choices around WS&R. This critical review presents recommendations for practitioners and policymakers to invest in WS&R adaptations, catered to shared risks and contexts.
PubMed: 38460697
DOI: 10.1016/j.scitotenv.2024.171520 -
Communications Biology Mar 2024The increasing rate of carbapenem-resistant bacteria within healthcare environments is an issue of great concern that needs urgent attention. This resistance is driven...
The increasing rate of carbapenem-resistant bacteria within healthcare environments is an issue of great concern that needs urgent attention. This resistance is driven by metallo-β-lactamases (MBLs), which can catalyse the hydrolysis of almost all clinically available β-lactams and are resistant to all the clinically utilized β-lactamase inhibitors. In this study, an uncharacterized MBL is identified in a multidrug resistant isolate of the opportunistic pathogen, Chryseobacterium indologenes. Sequence analysis predicts this MBL (CIM-1) to be a lipoprotein with an atypical lipobox. Characterization of CIM-1 reveals it to be a high-affinity carbapenemase with a broad spectrum of activity that includes all cephalosporins and carbapenems. Results also shown that CIM-1 is potentially a membrane-associated MBL with an uncharacterized lipobox. Using prediction tools, we also identify more potentially lipidated MBLs with non-canonical lipoboxes highlighting the necessity of further investigation of lipidated MBLs.
Topics: Anti-Bacterial Agents; R Factors; beta-Lactamases; Bacterial Proteins
PubMed: 38454015
DOI: 10.1038/s42003-024-05940-0 -
Acta Crystallographica Section B,... Apr 2024The binary CdYb phase representing the Tsai-type category of the icosahedral quasicrystals is solved by the assignment of a unique atomic decoration to rhombohedral...
The binary CdYb phase representing the Tsai-type category of the icosahedral quasicrystals is solved by the assignment of a unique atomic decoration to rhombohedral units in the Ammann-Kramer-Neri tiling. The unique decoration is found for units with an edge length of 24.1 Å and 3m internal point symmetry. The structural refinement was carried out for two underlying tilings generated by the projection method for 6D space. The difference lies in the location of the origin point which for one tiling is in the vertex and for the second one in the center of the 6D unit cell. The two tilings exhibit mutual duality. The choice of the tiling has a minor effect on the final structural model as both converge to an R factor of ∼11.5%. The main difference is related to the treatment of the Cd4 tetrahedral motif which is either orientationally ordered and aligned with the threefold axis or disordered and modeled as a partially occupied icosahedron. Both models can be presented as a covering by rhombic triacontahedral clusters with identical positions of clusters within rhombohedral units. The shell structure is Tsai-type in the case of the first tiling and Bergman-type for the other.
PubMed: 38441050
DOI: 10.1107/S2052520624000763