Theory and practice of modal identification

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Reverse transcriptases can clamp together nucleic acids strands with two complementary bases at their 3′-termini for initiating DNA synthesis

We present evidence that the reverse transcriptase (RT) of human immunodeficiency virus type-1 stabilizes in vitro very short (2-nt) duplexes of 3′-overhangs of the primer strand that are annealed to complementary dinucleotides tails of DNA or RNA template strands, provided that these sequences contain at least one C or G. This RT-induced strand ‘clamping’ activity promotes RT-directed DNA synthesis. This function is achieved only when the functional template strand is adjacent to a second DNA or RNA segment, annealed upstream to most of the primer (without gaps). The combined clamp/polymerase activity is typical to RTs, as it was found in different RTs from diverse retroviral groups, whereas cellular DNA-polymerases (devoid of 3′→5′ exonucleolytic activity) showed no clamp activity. The clamp-associated DNA-binding activity is markedly stabilized by dGTP, even when dGTP is not incorporated into the nascent DNA strand. The hereby-described function can help RTs in bridging over nicks in the copied RNA or DNA templates, encountered during reverse transcription. Moreover, the template-independent blunt-end synthesis of RTs can allow strand transfers onto compatible acceptor strands while synthesizing DNA. These RT properties can shed light on potentially-new roles of RTs in the reverse-transcription process and define new targets for anti-retroviral drugs

Halogen, Chalcogen, and Pnicogen Bonding Involving Hypervalent Atoms

The additional substituents arising from hypervalency present a number of complicating issues for the formation of noncovalent bonds. The XF5 molecule (X=Cl, Br, I) was allowed to form a halogen bond with NH3 as base. Hypervalent chalcogen bonding is examined by way of YF4 and YF6 (Y=S, Se, Te), and ZF5 (Z=P, As, Sb) is used to model pnicogen bonding. Pnicogen bonds are particularly strong, with interaction energies approaching 50 kcal/mol, and also involve wholesale rearrangement from trigonal bipyramidal in the monomer to square pyramidal in the complex, subject to a large deformation energy. YF4 chalcogen bonding is also strong, and like pnicogen bonding, is enhanced by a heavier central atom. XF5 halogen bond energies are roughly 9 kcal/mol, and display a unique sensitivity to the identity of the X atom. The crowded octahedral structure of YF6 permits only very weak interactions. As the F atoms of SeF6 are replaced progressively by H, a chalcogen bond appears in combination with SeH··N and NH··F H-bonds. The strongest such chalcogen bond appears in SeF3H3··NH3, with a binding energy of 7 kcal/mol, wherein the base is located in the H3 face of the Lewis acid. Results are discussed in the context of the way in which the positions and intensities of σ-holes are influenced by the locations of substituents and lone electron pairs

Lithium reduces apoptosis and autophagy after neonatal hypoxia–ischemia

Lithium is used in the treatment of bipolar mood disorder. Reportedly, lithium can be neuroprotective in models of adult brain ischemia. The purpose of this study was to evaluate the effects of lithium in a model of neonatal hypoxic–ischemic brain injury. Nine-day-old male rats were subjected to unilateral hypoxia–ischemia (HI) and 2 mmol/kg lithium chloride was injected i.p. immediately after the insult. Additional lithium injections, 1 mmol/kg, were administered at 24-h intervals. Pups were killed 6, 24 or 72 h after HI. Lithium reduced the infarct volume from 24.7±2.9 to 13.8±3.3 mm3 (44.1%) and total tissue loss (degeneration + lack of growth) from 67.4±4.4 to 38.4±5.9 mm3 (43.1%) compared with vehicle at 72 h after HI. Injury was reduced in the cortex, hippocampus, thalamus and striatum. Lithium reduced the ischemia-induced dephosphorylation of glycogen synthase kinase-3β and extracellular signal-regulated kinase, the activation of calpain and caspase-3, the mitochondrial release of cytochrome c and apoptosis-inducing factor, as well as autophagy. We conclude that lithium could mitigate the brain injury after HI by inhibiting neuronal apoptosis. The lithium doses used were in the same range as those used in bipolar patients, suggesting that lithium might be safely used for the avoidance of neonatal brain injury

Switch Chemistry at Cryogenic Conditions: Quantum Tunnelling under Electric Fields

While the influence of intramolecular electric fields is a known feature in enzymes, the use of oriented external electric fields (EEF) to enhance or inhibit molecular reactivity is a promising topic still in its infancy. Herein we will explore computationally the effects that EEF can provoke in simple molecules close to the absolute zero, where quantum tunnelling (QT) is the sole mechanistic option. We studied three exemplary systems, each one with different reactivity features and known QT kinetics: bond-shifting in pentalene, Cope rearrangement in semibullvalene, and cycloreversion of diazabicyclohexadiene. The kinetics of these cases depdend both on the field strength and its direction, usually giving subtle but remarkable changes. However, for the cycloreversion, which suffers large changes on the dipole through the reaction, we also observed striking results. Between the effects caused by the EEF on the QT we observed an inversion of the Arrhenius equation, deactivation of the molecular fluxionality, and stabilization or instantaneous decomposition of the system. All these effects may well be achieved, literally, at the flick of a switch.<br /

How to Twist, Split and Warp a σ‑Hole with Hypervalent Halogens

Halogen bonds (XB) are no longer newcomers in the chemistry family. However, XB in hypervalent halogens has not been thoroughly studied. We provide a molecular orbital explanation of the shape and strength of XBs in hypervalent halogens and other species, focusing on the charge transfer and electrostatic aspects of these bonds. Our results show that σ-holes (and subsequently the XBs associated with them) can be easily divided and bent by the influence of equatorial substituents. The inductive effect of both the equatorial and axial groups can affect these distortions, but also the angle between the equatorial ligands has a large influence on the shape of the σ-holes and the molecular orbitals acting as electron acceptor. Although the observation of these warped XB can be hindered by other noncovalent interactions, they may be ubiquitous in crystal structures of hypervalent species, where multiple XB can appear as secondary interactions on each halogen. We propose what can be considered the archetypal hypervalent halogen donor (a pincer type iodosodilactone) and a Lewis dot structure that includes the σ-holes

Central Sensitization and Psychological State Distinguishing Complex Regional Pain Syndrome from Other Chronic Limb Pain Conditions: A Cluster Analysis Model

Complex regional pain syndrome (CRPS) taxonomy has been updated with reported subtypes and is defined as primary pain alongside other chronic limb pain (CLP) conditions. We aimed at identifying CRPS clinical phenotypes that distinguish CRPS from other CLP conditions. Cluster analysis was carried out to classify 61 chronic CRPS and 31 CLP patients based on evoked pain (intensity of hyperalgesia and dynamic allodynia, allodynia area, and after-sensation) and psychological (depression, kinesiophobia, mental distress, and depersonalization) measures. Pro-inflammatory cytokine IL-6 and TNF-α serum levels were measured. Three cluster groups were created: ‘CRPS’ (78.7% CRPS; 6.5% CLP); ‘CLP’ (64.5% CLP; 4.9% CRPS), and ‘Mixed’ (16.4% CRPS; 29% CLP). The groups differed in all measures, predominantly in allodynia and hyperalgesia (p 0.58). ‘CRPS’ demonstrated higher psychological and evoked pain measures vs. ‘CLP’. ‘Mixed’ exhibited similarities to ‘CRPS’ in psychological profile and to ‘CLP’ in evoked pain measures. The serum level of TNF-αwas higher in the ‘CRPS’ vs. ‘CLP’ (p < 0.001) groups. In conclusion, pain hypersensitivity reflecting nociplastic pain mechanisms and psychological state measures created different clinical phenotypes of CRPS and possible CRPS subtypes, which distinguishes them from other CLP conditions, with the pro-inflammatory TNF-α cytokine as an additional potential biomarker