Bystander CD4 T-cell death is inhibited by broadly neutralizing anti-HIV antibodies only at levels blocking cell-to-cell viral transmission

The progressive loss of CD4+ T cells during HIV infection of lymphoid tissues involves both the apoptotic death of activated and productively infected CD4 T cells and the pyroptotic death of large numbers of resting and abortively infected bystander CD4 T cells. HIV spreads both through cellular release of virions and cell-to-cell transmission involving the formation of virological synapses. Cell-to-cell transmission results in high-level transfer of large quantities of virions to the target cell exceeding that achieved with cell-free virions. Broadly neutralizing anti-HIV antibodies (bNAbs) binding to HIV envelope protein capably block cell-free virus spread, and when added at higher concentrations can also interdict cell-to-cell transmission. Exploiting these distinct dose–response differences, we now show that four different bNAbs block the pyroptotic death of bystander cells, but only when added at concentrations sufficient to block cell-to-cell transmission. These findings further support the conclusion that HIV killing of abortively infected bystander CD4 T cells requires cell-to-cell transfer of virions. As bNAbs attract more interest as potential therapeutics, it will be important to consider the higher concentrations of these antibodies required to block the inflammatory death of bystander CD4 T cells.     

Habitat use of the ocelot (Leopardus pardalis) in Brazilian Amazon

Amazonia forest plays a major role in providing ecosystem services for human and sanctuaries for wildlife. However, ongoing deforestation and habitat fragmentation in the Brazilian Amazon has threatened both. The ocelot is an ecologically important mesopredator and a potential conservation ambassador species, yet there are no previous studies on its habitat preference and spatial patterns in this biome. From 2010 to 2017, twelve sites were surveyed, totaling 899 camera trap stations, the largest known dataset for this species. Using occupancy modeling incorporating spatial autocorrelation, we assessed habitat use for ocelot populations across the Brazilian Amazon. Our results revealed a positive sigmoidal correlation between remote‐sensing derived metrics of forest cover, disjunct core area density, elevation, distance to roads, distance to settlements and habitat use, and that habitat use by ocelots was negatively associated with slope and distance to river/lake. These findings shed light on the regional scale habitat use of ocelots and indicate important species–habitat relationships, thus providing valuable information for conservation management and land‐use planning.     

Vacuolar membrane structures and their roles in plant–pathogen interactions

Plant Molecular Biology - Short review focussing on the role and targeting of vacuolar substructure in plant immunity and pathogenesis. Plants lack specialized immune cells, therefore each plant...     

Daily rhythms of leukocytes populations,biochemical and enzymatic blood parameters in a carnivorous freshwater catfish (Lophiosilurus alexandri)

The aim of this study was to investigate the daily rhythms of hematological, biochemical and enzymatic parameters of the blood of a nocturnal model of fish (Lophiosilurus alexandri) bred in the laboratory (F1). Thirty-six juveniles were stocked in six tanks of a recirculation aquaculture system for 20 days. The fish were exposed to a light:dark cycle of 12:12 h and were fed 1% of biomass twice a day with commercial diet. The daily rhythms of hematological, biochemical and enzymatic parameters were then measured at six sampling times “zeitgeber time = ZT” at four-hour intervals under light:dark 12:12 h (lights on = ZT0, at 8.00 a.m). No differences were observed to alkaline phosphatase, glucose, cortisol, aspartate aminotransferase, superoxide dismutase, total protein and hematocrit (p > 0.05). However, white blood cell count, Lymphocytes (LYN), Neutrophils (NEU), Eosinophil and Neutrophils to Lymphocytes ratio were significant different between sample times (p < 0.05). Also, a significant difference in alanine transaminase was observed, with a peak of production at nighttime. In contrast, glutathione peroxidase peaked at 8:00. Uric acid, magnesium and Calcium (Ca⁺⁺) showed statistically significant differences (p < 0.05). A significant difference was observed (p < 0.05), with a peak of albumin at 08:00 and triglycerides at 12:00, while cholesterol was low (p < 0.05) at 08:00 and higher from 12:00 to 04:00. Cosinor analysis revealed also rhythmicity to SOD, UA, Mg and Ca⁺⁺, ALB and CHO (p < 0.05). In conclusion, the time of day must be considered a key factor when using blood parameters as biomarkers for disease, health and welfare in the L. alexandri aquaculture.     

Bicyclic carbamates as inhibitors of papain-like cathepsin proteases

A 6-oxa-1-aza-bicyclo[3.2.1]octan-7-one system inhibits the proteolytic activity of several cysteine proteases belonging to the papain family. In vitro mechanistic studies and in silico calculations suggest that the minimal pi-overlap between the bridgehead nitrogen and the carbonyl leads to a considerable weakening of the urethane system, making it susceptible to nucleophilic attack from the active site thiol group. The resulting covalent adduct is slowly hydrolyzed, releasing the hydroxypiperidine product of the inhibitor. Synthesis and testing of a set of analogs led to variable protease subtype selectivities ranging from micromolar to nanomolar potencies.     

Enantioselective determination of metoprolol acidic metabolite in plasma and urine using liquid chromatography chiral columns: applications to pharmacokinetics

Enantioselective separations on chiral stationary phases with or without derivatization were developed and compared for the HPLC analysis of (+)-(R)- and (-)-(S)-metoprolol acidic metabolite in human plasma and urine. The enantiomers were analysed in plasma and urine without derivatization on a Chiralcel OD-R column, and in urine after derivatization using methanol in acidic medium on a Chiralcel OD-H column. The quantitation limits were 17 ng of each enantiomer/ml plasma and 0.5 microgram of each enantiomer/ml urine using both methods. The confident limits show that the methods are compatible with pharmacokinetic investigations of the enantioselective metabolism of metoprolol. The methods were employed in a metabolism study of racemic metoprolol administered to a patient phenotyped as an extensive metabolizer of debrisoquine. The enantiomeric ratio (+)-(R)/(-)-(S)-acid metabolite was 1.1 for plasma and 1.2 for urine. Clearances were 0.41 and 0.25 l/h/kg, respectively, for the (+)-(R)- and (-)-(S)-enantiomers. The correlation coefficients between the urine concentrations of the acid metabolite enantiomers obtained by the two methods were >0.99. The two methods demonstrated interchangeable application to pharmacokinetics.     

Multiparametric magnetic resonance imaging-guided salvage radiotherapy in prostate cancer

AimTo analyse the efficacy and toxicity of postprostatectomy SRT in patients with a BCR evaluated with mpMRI.BackgroundMultiparametric magnetic resonance imaging (mpMRI) has the ability to detect the site of pelvic recurrence in patients with biochemical recurrence (BCR) after radical prostatectomy (RP). However, we do not know the oncological outcomes of mpMRI-guided savage radiotherapy (SRT).ResultsLocal, lymph node, and pelvic bone recurrence was observed in 13, 4 and 2 patients, respectively. PSA levels were significantly lower in patients with negative mpMRI (0.4 ng/mL [0.4]) vs. positive mpMRI (2.2 ng/mL [4.1], p = 0.003). Median planning target volume doses in patients with visible vs. non-visible recurrences were 76 Gy vs. 70 Gy. Overall, mean follow-up was 41 months (6–81). Biochemical relapse-free survival (bRFS) at 3 years was 82.3% and 82.5%, respectively, for the negative and positive mpMRI groups (p = 0.800). Three-year rates of late grade ≥2 urinary and rectal toxicity were 14.8% and 1.9%, respectively; all but one patient recovered without sequelae.ConclusionSRT to the macroscopic recurrence identified by mpMRI is a feasible and well-tolerated option. In this study, there were no differences in bRFS between MRI-positive and MRI-negative patients, indicating effective targeting of MRI-positive lesions.     

Dehydrodieugenols from Ocotea cymbarum

The trunk wood of Ocotea cymbarum from the Amazon basin contains α-phellandrene, α-pinene, eugenol, dehydrodieugenol and its monomethyl ether, as well as the previously unknown dehydrodieugenol-B (4,5′-diallyl-2′-hydroxy-2,3′-dimethoxydiphenyl ether).     

Chromosome number variation and polyploidy in the genus Echinocereus (Cactaceae)

Analyses of meiotic and mitotic chromosomes were undertaken in 16 taxa of Echinocereus belonging to 12 species and all seven taxonomic sections (sensu Taylor). Chromosome numbers are reported for the first time for eight taxa, and previously published chromosome counts are confirmed for the remaining eight. Both diploid and polyploid counts were obtained. Eleven (69%) of the taxa surveyed were diploid (2n = 22); the five varieties of E. engelmannii were polyploid (2n = 44). Overall, chromosome counts are available for 23 of the 48 proposed species (sensu Taylor). Of these, 19 (82%) are diploid, and four (18%) are polyploid. Polyploid cytotypes are most common in the primitive sections, e.g., sections Erecti and Triglochidiatus, which suggests that polyploidy is probably a derived condition in Echinocereus. Polyploid taxa range from medium to high latitudes and elevations relative to the overall distribution of the genus. Polyploidy, hybridization, and cryptic chromosomal rearrangements are thought to be the major causes of the speciation events of the genus.