Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous ...role in the body. In this review, we discuss these two “faces” of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed iron-dependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids. We present arguments favoring the enzymatic mechanisms of ferroptotically engaged non-heme iron of 15-lipoxygenases (15-LOX) in complexes with phosphatidylethanolamine binding protein 1 (PEBP1) as a catalyst of highly selective and specific oxidation reactions of arachidonoyl- (AA) and adrenoyl-phosphatidylethanolamines (PE). We discuss possible role of iron chaperons as control mechanisms for guided iron delivery directly to their “protein clients” thus limiting non-enzymatic redox-cycling reactions. We also consider opportunities of loosely-bound iron to contribute to the production of pro-ferroptotic lipid oxidation products. Finally, we propose a two-stage iron-dependent mechanism for iron in ferroptosis by combining its catalytic role in the 15-LOX-driven production of 15-hydroperoxy-AA-PE (HOO-AA-PE) as well as possible involvement of loosely-bound iron in oxidative cleavage of HOO-AA-PE to oxidatively truncated electrophiles capable of attacking nucleophilic targets in yet to be identified proteins leading to cell demise.
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•Phospholipid peroxidation in ferroptosis.•Lipoxygenase oxidation of arachidonoyl phosphatidylethanolamine.•Guided transportation of iron to target destinations in cells.•GPX4 reduction of hydroperoxy-arachidonoyl-phosphatidylethanolamine.•ACSL4 biosynthesis of arachidonoyl phosphatidylethanolamine is required for.
is one of the most clinically important nosocomial pathogens. The World Health Organisation refers it to its «critical priority» category to develop new strategies for effective therapy. This ...microorganism is capable of producing structurally diverse capsular polysaccharides (CPSs), which serve as primary receptors for
bacteriophages carrying polysaccharide-depolymerasing enzymes. In this study, eight novel bacterial viruses that specifically infect
strains belonging to K2/K93, K32, K37, K44, K48, K87, K89 and K116 capsular types were isolated and characterized. The overall genomic architecture demonstrated that these viruses are representatives of the
genus of the family
The linear double-stranded DNA phage genomes of 41,105-42,402 bp share high nucleotide sequence identity, except for genes encoding structural depolymerases or tailspikes which determine the host specificity. Deletion mutants lacking N-terminal domains of tailspike proteins were cloned, expressed and purified. The structurally defined CPSs of the phage bacterial hosts were cleaved with the specific recombinant depolymerases, and the resultant oligosaccharides that corresponded to monomers or/and dimers of the CPS repeats (K-units) were isolated. Structures of the derived oligosaccharides were established by nuclear magnetic resonance spectroscopy and high-resolution electrospray ionization mass spectrometry. The data obtained showed that all depolymerases studied were glycosidases that cleave specifically the
CPSs by the hydrolytic mechanism, in most cases, by the linkage between the K-units.
, a nonfermentative, Gram-negative, aerobic bacterium, is one of the most significant nosocomial pathogens. The pathogenicity of
is based on the cooperative action of many factors, one of them being the production of capsular polysaccharides (CPSs) that surround bacterial cells with a thick protective layer. Polymorphism of the chromosomal capsule loci is responsible for the observed high structural diversity of the CPSs. In this study, we describe eight novel lytic phages which have different tailspike depolymerases (TSDs) determining the interaction of the viruses with corresponding
capsular types (K-types). Moreover, we elucidate the structures of oligosaccharide products obtained by cleavage of the CPSs by the recombinant depolymerases. We believe that as the TSDs determine phage specificity, the diversity of their structures should be taken into consideration as selection criteria for inclusion of certain phage candidate to the cocktail designed to control
with different K-types.
To evaluate the effect of pre-biopsy magnetic resonance imaging (MRI) on cancer diagnostic times, and to report MRI-directed pathology outcomes.
In total, 1483 patients were referred with prostate ...cancer suspicion during a 30-month period. Upfront MRI was performed in 745 patients: 332 MRIs in the 15 months prior to dedicated scanning slots (group 1), and 413 in the 15 months post-introduction (group 2). A further 88 patients had initial MRI following clinical assessment. Biopsy via the transrectal (TR) or transperineal (TP) approach was performed, with MRI/ultrasound fusion for MRI targets. Clinically significant cancer (csPCa) was defined as Gleason ≥3+4. Negative MRIs were defined as Likert 1–2. Per-case clinical decisions were taken to biopsy or not.
44.4% of patients avoided biopsy. 484/833 (58.1%) MRIs were negative; 37.4% of these patients had biopsy with a negative predictive value (NPV) of 92.8% for Gleason ≥3+4 and 98.3% for ≥4+3. Overall prostate cancer prevalence was 34.3% (24.6% csPCa). In 323 MRI-positive cases, any cancer was present in 78.9% (csPCa 60.4%). Of the 1483 patients, 1232 (83.1%) completed all diagnostic tests within 28 days. Upfront MRI patients met this standard in 621/833 (74.5%), improving from 66.9% to 81.1% with reserved slots (group 2) with a reduced diagnostic time from median 25.5 to 20.9 days. Biopsy scheduling delayed the pathway in 69.7%, with MRI responsible in 22.3%, reducing to 10.3% in group 2. TP biopsies met the 28-day standard in significantly less cases (29.7%), compared to TR (67.4%, p<0.0001).
Reserved MRI slots reduces time-to-diagnosis, and upfront MRI safely avoids biopsy in a significant proportion of men, whilst maintaining expected csPCa detection rates.
•Overall biopsy avoidance rate in the upfront MRI cohort was 44% in a 3 year period.•Use of reserved MRI slots reduced diagnostic time from median 25.5 to 20.9 days.•NPV in men with negative MR undergoing biopsy for high clinical risk was high at 92%.•Cancer detection matched literature reported rates for clinically significant cancer.
Orthorhombic lithium cuprate LiCu
2
O
2
was exposed to high temperature and pressure of 950°C and 4.5 GPa. X-ray diffraction studies indicate that the treated samples of LiCu
2
O
2
had tetragonal ...symmetry, in contrast to the orthorhombic one of the phase synthesized at atmospheric pressure. Temperature dependences of dielectric permittivity ε and tangent of dielectric loss tanδ, as well as DC (direct current), resistivity, ρ were investigated in the temperature range 77–296 K. No anomalous changes of the studied parameters inherent in the phase transitions were detected in this temperature range. The ρ(
T
) dependences were common to semiconductors. These dependences were linearized in the Mott coordinates logρ–1/
T
0.25
. It indicated the variable length hopping mechanism of conduction between the next nearest neighbors in the studied samples.
Phosphorylthioformic acid morpholides can be successfully used as a precursor in the synthesis of complexes of phosphoryl-substituted thiohydrazides with hydrazine and morpholine. The reaction of ...sterically hindered phosphorylthioformic acid morpholides with hydrazine hydrate proceeds chemoselectively with the formation of hydrazono(morpholino)methylphosphodiamides.
Nanostructured near-IR antireflective layer was produced on a GaAs slab surface by direct femtosecond laser fabrication of a surface diffraction grating. The single nanostructured layer on the GaAs ...slab reduces its total reflection at the wavelength λ ≈ 2.5 μm by 42 %, in agreement with the second-order approximation of the effective medium theory, with negligible increase of its absorbance.
Reactions of various phosphorylthioformic acid morpholides with hydrazine afford phosphorylthioformhydrazides. The latter react under mild conditions with
N, N
′-carbonyldiimidazole to form novel ...5-phosphoryl-1,3,4(3
H
)-thiadiazol-2-ones.
The method and algorithm for determining total ozone column amounts (TOC) based on spectroscopic measurements of outgoing thermal radiation by IKFS-2 spectrometer (on-board ″Meteor-M No. 2″ ...satellite) are described. The algorithm is based on the artifi cial neural network method and satellite measurements of TOC using ozone monitoring instrumentation (OMI). Comparison of the results of TOC measurements by IKFS-2 spectrometer and by ground-based instruments (Dobson, Brewer, and M-124 ozonometers) are given. It is shown that systematic discrepancy between the results of satellite and ground-based measurements in most cases does not exceed 1%, and RMSD values are within 3.0–4.5%. The empirical assessment of random measurement errors in the determination of TOC demonstrates that Dobson and Brewer TOC measurement random total errors are ~1% (in direct solar radiation measurements mode), and OMI and IKFS-2 satellite measurements give 2.8 and 3.6% random errors, respectively.
The ion channel TRPV1, which is one of the most important integrators of pain and inflammatory stimuli, is considered a promising therapeutic target in the treatment of pain conditions. In this work, ...we performed a comparative study of the analgesic effect in the “hot plate” test of recombinant analogues of Kunitz-type peptides from the sea anemone
Heteractis crispa
venom: APHC1—modulator of TRPV1 and HCRG21—a full blocker of TRPV1. As a result of biological tests, it was shown that the full blocker HCRG21, despite the higher value of 50% effective concentration of TRPV1 inhibition, had an equal analgesic ability with the APHC1 upon intramuscular administration and retained it for 13 h of observation. The analgesic effect of APHC1 at a dose of 0.1 mg/kg when administered intramuscularly developed very quickly in 5 min but lasted 3 h. The differences in the pharmacodynamic profile of the peptides are in good agreement with different mechanisms of binding to TRPV1.
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