Halogen bonding in hypervalent iodine and bromine derivatives: Halonium salts

Halogen bonds have been identified in a series of ionic compounds involving bromonium and iodonium cations and several different anions, some also containing hypervalent atoms. The hypervalent bromine and iodine atoms in the examined compounds are found to have positive Ï\u83-holes on the extensions of their covalent bonds, while the hypervalent atoms in the anions have negative Ï\u83-holes. The positive Ï\u83-holes on the halogens of the studied halonium salts determine the linearity of the short contacts between the halogen and neutral or anionic electron donors, as usual in halogen bonds

Efficacy of 1998 <i>vs</i> 2006 first-line antiretroviral regimens for HIV infection: an ordinary clinics retrospective investigation

Purpose: The evidence suggesting increased HAART efficacy over time comes from randomized trials or cohort studies. This retrospective multicenter survey aimed to assess the variation over time in the efficacy and tolerability of first-line HAART regimens in unselected patients treated in ordinary clinical settings. Methods: Retrospective analysis of data of all patients starting first-line HAART regimens in 1998 and 2006 at adhering centers in the Italian CISAI group. Results: For the 543 patients included, mean age was 39.1 ± 9.8y in 1998 and 41.0 ± 10.7y in 2006 (p=0.03), with a similar proportion of males. Baseline mean log10 HIV-RNA was 4.56 ± 0.97 copies/mL in 1998 vs 4.91 ± 0.96 copies/mL in 2006 (p&lt;0.001); baseline mean CD4 T-cell counts were 343 ± 314/mm3 in 1998 vs 244 ± 174/mm3 in 2006 (p&lt;0.001). The following outcomes were significantly improved at 48w in 2006: proportion with undetectable HIV-RNA (86.3% vs 58.0%; p&lt;0.001); mean increase in CD4 T-cells count (252 ± 225 vs 173 ± 246; p&lt;0.001); HAART modification (20.1% vs 29.2%; p=0.02); HAART interruption (7.3% vs 14.6%; p=0.01); proportion reporting optimal adherence (92.2% vs 82.7%, p=0.03). No differences were observed in the prevalence of grade 3-4 WHO toxicities (26.4% vs 26.6%; p=0.9). Multivariate logistic regression showed that being treated in 1998 remained an independent predictor of virological failure after several adjustments, including adherence. Conclusions: Our data from patients not included in clinical trials or cohort studies provide an additional line of evidence that the effectiveness of HAART significantly improved in 2006. Treated patients, however, were significantly older and more frequently late HIV presenters in 2006 than in 1998.</br

The isoprenoid end product N6-isopentenyladenosine reduces inflammatory response through the inhibition of the NF\uce\ubaB and STAT3 pathways in cystic fibrosis cells

N6-isopentenyladenosine (iPA) is an intermediate of the mevalonate pathway that exhibits various anti-cancer effects. However, studies on its anti-inflammatory activity are scarce and underlying molecular mechanisms are unknown. Therefore, we aimed to investigate the ability of iPA to exert anti-inflammatory effects in the human cystic fibrosis (CF) cell model of exacerbated inflammation. TNF alpha-stimulated CF cells CuFi-1 and its normal counterpart NuLi-1 were pre-treated with increasing concentrations of iPA and cell viability and proliferation were assessed by MTT and BrdU assays. The effect of iPA on IL-8 and RANTES secretion was determined by ELISA, and the activation and expression of signaling molecules and selenoproteins were studied by Western blot. To assess the direct effect of iPA on NF kappa B activity, luciferase assay was performed on TNF alpha-stimulated HEK293/T cells transfected with a NF kappa B reporter plasmid. We demonstrated for the first time that iPA prevents IL-8 and RANTES release in TNF alpha-stimulated CF cells and this effect is mediated by increasing the expression of the direct NF kappa B inhibitor I kappa B alpha and decreasing the levels of STAT3. Consistent with this, we showed that iPA inhibited TNF alpha-mediated NF kappa B activation in HEK/293T cells. Finally, we also found that iPA improved the levels of glutathione peroxidase 1 and thioredoxin reductase 1 only in CF cells suggesting its ability to maintain sufficient expression of these anti-oxidant selenoproteins. Our findings indicate that iPA can exert anti-inflammatory activity especially in the cases of excessive inflammatory response as in CF

Covid-19 And Rheumatic Autoimmune Systemic Diseases: Role of Pre-Existing Lung Involvement and Ongoing Treatments

The Covid-19 pandemic may have a deleterious impact on patients with autoimmune systemic diseases (ASD) due to their deep immune-system alterations

Genetic determinants in a critical domain of ns5a correlate with hepatocellular carcinoma in cirrhotic patients infected with hcv genotype 1b

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain‐1 interacts with cellular proteins inducing pro‐oncogenic pathways. Thus, we explore genetic variations in NS5A domain‐1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype‐1b infected DAA‐naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, p = 0.01), T122M (8.8% vs. 0.0%, p &lt; 0.001), M133I (20.6% vs. 3.9%, p &lt; 0.001), and Q181E (11.8% vs. 0.6%, p &lt; 0.001). By multivariable analysis, the presence of &gt;1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7–82.3); p &lt; 0.001). Focusing on HCC‐group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4–6.2) log IU/mL vs. 5.3 (4.4–5.6) log IU/mL, p = 0.02) and lower ALT (35 (30–71) vs. 83 (48–108) U/L, p = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell‐cycle regulation (p53, p85‐PIK3, and β‐ catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV‐mediated oncogenesis. The role of these NS5A domain‐1 mutations in triggering pro‐oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation

Isomerization of 1,6-dimethylcyclohexadienyl cations obtained in the gas phase from insertion of ortho-tolylium ions into methane at 1-3 atm pressure. Does it involve excited or thermal species?

1,6-Dimethylcyclohexadienyl cations have been conveniently produced in the gas phase, without any contamination from their isomers, by insertion of stable ortho-tolylium ions, obtained from selective F--transfer from ortho-fluorotoluene to radiolytic SiF3+, into methane. The relative extent of competing isomerization pathways occurring in the 1,6-dimethylcyclohexadienyl cation thus formed, i.e. methyl and hydrogen 1,2-shifts, has been measured as a function of the temperature (40-150 degrees C) and pressure (1-3 atm) of the bulk gas (SiF4). At any given temperature, the strong, negative pressure dependence of the relative extent of methyl versus hydrogen 1,2-transfer reveals that the latter isomerization channel involves a vibrationally excited 1,6-dimethylcyclohexadienyl intermediate. This observation is discussed in the framework of the more general problem of the specific activation mode, either electrostatic or thermal, operating in gas-phase ionic processes at different pressures

Close contacts involving germanium and tin in crystal structures: experimental evidence of tetrel bonds

Modeling indicates the presence of a region of low electronic density (a σ-hole) on group 14 elements, and this offers an explanation for the ability of these elements to act as electrophilic sites and to form attractive interactions with nucleophiles. While many papers have described theoretical investigations of interactions involving carbon and silicon, such investigations of the heavier group 14 elements are relatively scarce. The purpose of this review is to rectify, to some extent, the current lack of experimental data on interactions formed by germanium and tin with nucleophiles. A survey of crystal structures in the Cambridge Structural Database is reported. This survey reveals that close contacts between Ge or Sn and lone-pair-possessing atoms are quite common, they can be either intra- or intermolecular contacts, and they are usually oriented along the extension of the covalent bond formed by the tetrel with the most electron-withdrawing substituent. Several examples are discussed in which germanium and tin atoms bear four carbon residues or in which halogen, oxygen, sulfur, or nitrogen substituents replace one, two, or three of those carbon residues. These close contacts are assumed to be the result of attractive interactions between the involved atoms and afford experimental evidence of the ability of germanium and tin to act as electrophilic sites, namely tetrel bond (TB) donors. This ability can govern the conformations and the packing of organic derivatives in the solid state. TBs can therefore be considered a promising and robust tool for crystal engineering