The Value of Whole-Genome Sequencing for Mitochondrial DNA Population Studies: Strategies and Criteria for Extracting High-Quality Mitogenome Haplotypes

Whole-genome sequencing (WGS) data present a readily available resource for mitochondrial genome (mitogenome) haplotypes that can be utilized for genetics research including population studies. However, the reconstruction of the mitogenome is complicated by nuclear mitochondrial DNA (mtDNA) segments (NUMTs) that co-align with the mtDNA sequences and mimic authentic heteroplasmy. Two minimum variant detection thresholds, 5% and 10%, were assessed for the ability to produce authentic mitogenome haplotypes from a previously generated WGS dataset. Variants associated with NUMTs were detected in the mtDNA alignments for 91 of 917 (~8%) Swedish samples when the 5% frequency threshold was applied. The 413 observed NUMT variants were predominantly detected in two regions (nps 12,612–13,105 and 16,390–16,527), which were consistent with previously documented NUMTs. The number of NUMT variants was reduced by ~97% (400) using a 10% frequency threshold. Furthermore, the 5% frequency data were inconsistent with a platinum-quality mitogenome dataset with respect to observed heteroplasmy. These analyses illustrate that a 10% variant detection threshold may be necessary to ensure the generation of reliable mitogenome haplotypes from WGS data resources.     

Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol,Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents,and Carbonic Anhydrases I,II, VII,IX, and XII Inhibitors

A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with K_Is = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 µM) and derivative 32 (MIC range 13.80–55.20 µM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4’-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC₅₀ of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 µM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.     

Heparin-Functionalized Adsorbents Eliminate Central Effectors of Immunothrombosis,including Platelet Factor 4, High-Mobility Group Box 1 Protein and Histones

Inflammation and thrombosis are closely intertwined in numerous disorders, including ischemic events and sepsis, as well as coronavirus disease 2019 (COVID-19). Thrombotic complications are markers of disease severity in both sepsis and COVID-19 and are associated with multiorgan failure and increased mortality. Immunothrombosis is driven by the complement/tissue factor/neutrophil axis, as well as by activated platelets, which can trigger the release of neutrophil extracellular traps (NETs) and release further effectors of immunothrombosis, including platelet factor 4 (PF4/CXCL4) and high-mobility box 1 protein (HMGB1). Many of the central effectors of deregulated immunothrombosis, including activated platelets and platelet-derived extracellular vesicles (pEVs) expressing PF4, soluble PF4, HMGB1, histones, as well as histone-decorated NETs, are positively charged and thus bind to heparin. Here, we provide evidence that adsorbents functionalized with endpoint-attached heparin efficiently deplete activated platelets, pEVs, PF4, HMGB1 and histones/nucleosomes. We propose that this elimination of central effectors of immunothrombosis, rather than direct binding of pathogens, could be of clinical relevance for mitigating thrombotic complications in sepsis or COVID-19 using heparin-functionalized adsorbents.     

Human Chorionic Gonadotropin and Early Embryogenesis: Review

Human chorionic gonadotropin (hCG) has four major isoforms: classical hCG, hyperglycosylated hCG, free β subunit, and sulphated hCG. Classical hCG is the first molecule synthesized by the embryo. Its RNA is transcribed as early as the eight-cell stage and the blastocyst produces the protein before its implantation. This review synthetizes everything currently known on this multi-effect hormone: hCG levels, angiogenetic activity, immunological actions, and effects on miscarriages and thyroid function.     

Assessing the public health risk of microbial intrusion events in distribution systems: conceptual model, available data, and challenges

Low and negative pressure events in drinking water distribution systems have the potential to result in intrusion of pathogenic microorganisms if an external source of contamination is present (e.g., nearby leaking sewer main) and there is a pathway for contaminant entry (e.g., leaks in drinking water main). While the public health risk associated with such events is not well understood, quantitative microbial risk assessment can be used to estimate such risk. A conceptual model is provided and the state of knowledge, current assumptions, and challenges associated with the conceptual model parameters are presented. This review provides a characterization of the causes, magnitudes, durations and frequencies of low/negative pressure events; pathways for pathogen entry; pathogen occurrence in external sources of contamination; volumes of water that may enter through the different pathways; fate and transport of pathogens from the pathways of entry to customer taps; pathogen exposure to populations consuming the drinking water; and risk associated with pathogen exposure.     

Recent Advances in Reactive Extrusion Processing of Biodegradable Polymer‐Based Compositions

This review reports on recent advances in the design of biodegradable polymers built from petroleum and renewable resources using reactive extrusion processing. Reactive extrusion represents a unique tool to manufacture biodegradable polymers upon different types of reactive modification in a cost‐effective way. Partially based on our ongoing research, ring‐opening polymerization of biodegradable polyesters will be approached as well as the chemical modification of biodegradable polymers, particularly natural polymers. The development of environmentally friendly polymer blends as well as (nano)composites from natural polymers, including natural fibers and nanoclays, through reactive extrusion, as an efficient way to improve the interfacial adhesion between these components, will be also discussed.

     

The impact of polypropylene‐graft‐maleic anhydride on the crystallization and dynamic mechanical properties of isotactic polypropylene

Differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) were used to identify the mechanisms that lead to differences in the mechanical behavior of formulations of polypropylene blended with maleated polypropylene (MAPP) copolymers. MAPP lowered the melting temperature of PP indicating that less stable crystals were formed possibly because of cocrystallization of PP and MAPP. Crystallization kinetics revealed that copolymers do not change the rate of crystal growth, but may retard nucleation leading to a more spherulitic morphology. The dynamic storage modulus slightly increased in the glassy region with the small addition amounts of MAPP, while mechanical dampening systematically decreased with MAPP addition. An analysis of the viscoelastic behavior did not reveal any real differences in molecular coupling around the β‐transition of PP with the addition of the MAPP copolymer. At low addition levels, MAPP does not appear to have a significant impact on the viscoelastic properties of the polymer blend. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Melt‐stable poly(1,4‐dioxan‐2‐one) (co)polymers by ring‐opening polymerization via continuous reactive extrusion

Bulk polymerization of ?‐caprolactone (CL), 1,4‐dioxan‐2‐one (PDX), and mixtures of PDX and CL was carried out by initiation with Al(O^secBu)₃ in a co‐rotating twin‐screw extruder through a fast single‐step process. Both homopolymerizations and copolymerization of PDX and CL proceed very rapidly and reach almost complete (co)‐ monomer(s) conversion as soon as 8 mol% of CL are added in the feed. Even though poly(1,4‐dioxan‐2‐one) (PPDX) is known to thermally degrade mainly through unzipping depolymerization promoted from the hydroxyl end‐groups and yielding PDX monomer, it turns out that the thermal stability of PPDX chains is substantially improved by the copolymerization of PDX with limited amounts of CL. Interestingly, DSC analysis of the so‐obtained P(PDX‐co‐CL) copolymers has demonstrated that a CL molar fraction as high as 11 mol% does not prevent the crystallization of the resulting copolymer, which retains a melting temperature close to 95°C. This last observation has been explained by the formation of a blocky‐like copolymer structure, in which short PPDX and PCL sequences are randomly distributed. POLYM. ENG. SCI., 45:622–629, 2005. © 2005 Society of Plastics Engineers.     

Microkinetic model for the pyrolysis of methyl esters: From model compound to industrial biodiesel

A tool for the generation of decomposition schemes of large molecules has been developed. These decomposition schemes contain radicals which can be eliminated from the model equations if both the μ‐hypothesis and the pseudosteady‐state approximation are valid. The reaction rate coefficients and thermodynamic parameters have been calculated by incorporating a comprehensive group additive framework. A microkinetic model for the pyrolysis of methyl esters with a carbon number of up to 19 has been generated using this tool. It is validated by comparing calculated and experimental yields of the pyrolysis of methyl decanoate and novel rapeseed methyl ester pyrolysis data in the temperature range from 800 to 1100 K and methyl ester partial pressure range from 1 × 10^?3 to 1 × 10^?2 MPa. This modeling frame work allows to not only assess the use of methyl ester mixtures as potential feedstock for olefin production but also their effect as blend‐in or trace impurity. © 2015 American Institute of Chemical Engineers AIChE J, 61: 4309–4322, 2015