Tetrabenzoporphyrin and -mono-, - Cis -di- and tetrabenzotriazaporphyrin derivatives: Electrochemical and spectroscopic implications of meso CH Group replacement with nitrogen

Nonperipherally hexyl-substituted metal-free tetrabenzoporphyrin (2H-TBP, 1a) tetrabenzomonoazaporphyrin (2H-TBMAP, 2a), tetrabenzo-cis-diazaporphyrin (2H-TBDAP, 3a), tetrabenzotriazaporphyrin (2H-TBTAP, 4a), and phthalocyanine (2H-Pc, 5a), as well as their copper complexes (1b-5b), were synthesized. As the number of meso nitrogen atoms increases from zero to four, Îmax of the Q-band absorption peak becomes red-shifted by almost 100 nm, and extinction coefficients increased at least threefold. Simultaneously the blue-shifted Soret (UV) band substantially decreased in intensity. These changes were related to the relative electron-density of each macrocycle expressed as the group electronegativity sum of all meso N and CH atom groups, âχR. X-ray photoelectron spectroscopy differentiated between the three different types of macrocyclic nitrogen atoms (the Ninner, (NH)inner, and Nmeso) in the metal-free complexes. Binding energies of the Nmeso and Ninner,Cu atoms in copper chelates could not be resolved. Copper insertion lowered especially the cathodic redox potentials, while all four observed redox processes occurred at larger potentials as the number of meso nitrogens increased. Computational chemical methods using density functional theory confirmed 1b to exhibit a Cu(II) reduction prior to ring-based reductions, while for 2b, Cu(II) reduction is the first reductive step only if the nonperipheral substituents are hydrogen. When they are methyl groups, it is the second reduction process; when they are ethyl, propyl, or hexyl, it becomes the third reductive process. Spectro-electrochemical measurements showed redox processes were associated with a substantial change in intensity of at least two main absorbances (the Q and Soret bands) in the UV spectra of these compounds

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses

Tetrabenzoporphyrin and -mono‑, -<i>cis</i>-di- and Tetrabenzotriazaporphyrin Derivatives: Electrochemical and Spectroscopic Implications of meso CH Group Replacement with Nitrogen

Nonperipherally hexyl-substituted metal-free tetrabenzoporphyrin (2H-TBP, <b>1a</b>) tetrabenzomonoazaporphyrin (2H-TBMAP, <b>2a</b>), tetrabenzo-<i>cis-</i>diazaporphyrin (2H-TBDAP, <b>3a</b>), tetrabenzotriazaporphyrin (2H-TBTAP, <b>4a</b>), and phthalocyanine (2H-Pc, <b>5a</b>), as well as their copper complexes (<b>1b</b>–<b>5b</b>), were synthesized. As the number of meso nitrogen atoms increases from zero to four, λ_max of the Q-band absorption peak becomes red-shifted by almost 100 nm, and extinction coefficients increased at least threefold. Simultaneously the blue-shifted Soret (UV) band substantially decreased in intensity. These changes were related to the relative electron-density of each macrocycle expressed as the group electronegativity sum of all meso N and CH atom groups, ∑χ_R. X-ray photoelectron spectroscopy differentiated between the three different types of macrocyclic nitrogen atoms (the N_inner, (<u>N</u>H)_inner, and N_meso) in the metal-free complexes. Binding energies of the N_meso and N_inner,Cu atoms in copper chelates could not be resolved. Copper insertion lowered especially the cathodic redox potentials, while all four observed redox processes occurred at larger potentials as the number of meso nitrogens increased. Computational chemical methods using density functional theory confirmed <b>1b</b> to exhibit a Cu­(II) reduction prior to ring-based reductions, while for <b>2b</b>, Cu­(II) reduction is the first reductive step only if the nonperipheral substituents are hydrogen. When they are methyl groups, it is the second reduction process; when they are ethyl, propyl, or hexyl, it becomes the third reductive process. Spectro-electrochemical measurements showed redox processes were associated with a substantial change in intensity of at least two main absorbances (the Q and Soret bands) in the UV spectra of these compounds

Scoring system predictive of survival for patients undergoing stereotactic body radiation therapy for liver tumors

<p>Abstract</p> <p>Background</p> <p>Stereotactic body radiation therapy (SBRT) is an emerging treatment option for liver tumors. This study evaluated outcomes after SBRT to identify prognostic variables and to develop a novel scoring system predictive of survival.</p> <p>Methods</p> <p>The medical records of 52 patients with a total of 85 liver lesions treated with SBRT from 2003 to 2010 were retrospectively reviewed. Twenty-four patients had 1 lesion; 27 had 2 or more. Thirteen lesions were primary tumors; 72 were metastases. Fiducials were placed in all patients prior to SBRT. The median prescribed dose was 30 Gy (range, 16 – 50 Gy) in a median of 3 fractions (range, 1–5).</p> <p>Results</p> <p>With median follow-up of 11.3 months, median overall survival (OS) was 12.5 months, and 1 year OS was 50.8%. In 42 patients with radiographic follow up, 1 year local control was 74.8%. On univariate analysis, number of lesions (p = 0.0243) and active extralesional disease (p < 0.0001) were predictive of OS; Karnofsky Performance Status (KPS) approached statistical significance (p = 0.0606). A scoring system for predicting survival was developed by allocating 1 point for each of the three following factors: active extralesional disease, 2 or more lesions, and KPS ≤ 80%. Score was associated with OS (p < 0.0001). For scores of 0, 1, 2 and 3, median survival intervals were 34, 12.5, 7.6, and 2.8 months, respectively.</p> <p>Conclusions</p> <p>SBRT offers a safe and feasible treatment option for liver tumors. A prognostic scoring system based on the number of liver lesions, activity of extralesional disease, and KPS predicts survival following SBRT and can be used as a guide for prospective validation and ultimately for treatment decision-making.</p

Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis

We used exome sequencing to study a non-consanguineous family with two children who had anterior segment dysgenesis, sclerocornea, microphthalmia, hypotonia and developmental delays. Sanger sequencing verified two Peroxidasin (PXDN) mutations in both sibs—a maternally inherited, nonsense mutation, c.1021C>T predicting p.(Arg341*), and a paternally inherited, 23-basepair deletion causing a frameshift and premature protein truncation, c.2375_2397del23, predicting p.(Leu792Hisfs*67). We re-examined exome data from 20 other patients with structural eye defects and identified two additional PXDN mutations in a sporadic male with bilateral microphthalmia, cataracts and anterior segment dysgenesis—a maternally inherited, frameshift mutation, c.1192delT, predicting p.(Tyr398Thrfs*40) and a paternally inherited, missense substitution that was predicted to be deleterious, c.947 A>C, predicting p.(Gln316Pro). Mutations in PXDN were previously reported in three families with congenital cataracts, microcornea, sclerocornea and developmental glaucoma. The gene is expressed in corneal epithelium and is secreted into the extracellular matrix. Defective peroxidasin has been shown to impair sulfilimine bond formation in collagen IV, a constituent of the basement membrane, implying that the eye defects result because of loss of basement membrane integrity in the developing eye. Our finding of a broader phenotype than previously appreciated for PXDN mutations is typical for exome-sequencing studies, which have proven to be highly effective for mutation detection in patients with atypical presentations. We conclude that PXDN sequencing should be considered in microphthalmia with anterior segment dysgenesis

Seasonal variations in cardiovascular disease

Cardiovascular disease (CVD) follows a seasonal pattern in many populations. Broadly defined winter peaks and clusters of all subtypes of CVD after 'cold snaps' are consistently described, with corollary peaks linked to heat waves. Individuals living in milder climates might be more vulnerable to seasonality. Although seasonal variation in CVD is largely driven by predictable changes in weather conditions, a complex interaction between ambient environmental conditions and the individual is evident. Behavioural and physiological responses to seasonal change modulate susceptibility to cardiovascular seasonality. The heterogeneity in environmental conditions and population dynamics across the globe means that a definitive study of this complex phenomenon is unlikely. However, given the size of the problem and a range of possible targets to reduce seasonal provocation of CVD in vulnerable individuals, scope exists for both greater recognition of the problem and application of multifaceted interventions to attenuate its effects. In this Review, we identify the physiological and environmental factors that contribute to seasonality in nearly all forms of CVD, highlight findings from large-scale population studies of this phenomenon across the globe, and describe the potential strategies that might attenuate peaks in cardiovascular events during cold and hot periods of the year.Simon Stewart, Ashley K. Keates, Adele Redfern and John J. V. McMurra

Seasonal variations in cardiovascular disease

Cardiovascular disease (CVD) follows a seasonal pattern in many populations. Broadly defined winter peaks and clusters of all subtypes of CVD after 'cold snaps' are consistently described, with corollary peaks linked to heat waves. Individuals living in milder climates might be more vulnerable to seasonality. Although seasonal variation in CVD is largely driven by predictable changes in weather conditions, a complex interaction between ambient environmental conditions and the individual is evident. Behavioural and physiological responses to seasonal change modulate susceptibility to cardiovascular seasonality. The heterogeneity in environmental conditions and population dynamics across the globe means that a definitive study of this complex phenomenon is unlikely. However, given the size of the problem and a range of possible targets to reduce seasonal provocation of CVD in vulnerable individuals, scope exists for both greater recognition of the problem and application of multifaceted interventions to attenuate its effects. In this Review, we identify the physiological and environmental factors that contribute to seasonality in nearly all forms of CVD, highlight findings from large-scale population studies of this phenomenon across the globe, and describe the potential strategies that might attenuate peaks in cardiovascular events during cold and hot periods of the year