Cytotoxic T lymphocytes derived from patients with chronic hepatitis C virus infection kill bystander cells via Fas-FasL interaction

The role of Fas-mediated lysis of hepatocytes in hepatitis C virus (HCV)-induced injury is frequently discussed. We therefore analyzed the effect of the number of HCV antigen-expressing cells, the mode of antigen presentation, and the number of cytotoxic T lymphocytes in a coculture system mimicking cellular components of the liver. Here, we show that endogenously processed HCV proteins are capable of inducing bystander killing. We further demonstrate that 0.8 to 1.5% of cells presenting HCV antigens suffice to induce lysis of 10 to 29% of bystander cells, suggesting that the mechanism may be operative at low fractions of infected versus uninfected hepatocytes in vivo. Our data underscore the role of the Fas pathway in HCV-related liver injury and support the exploration of Fas-based treatment strategies for patients with chronic hepatitis C virus infection.     

Diversity,taxonomy, and evolution of archaeal viruses of the class Caudoviricetes

The archaeal tailed viruses (arTV), evolutionarily related to tailed double-stranded DNA (dsDNA) bacteriophages of the class Caudoviricetes, represent the most common isolates infecting halophilic archaea. Only a handful of these viruses have been genomically characterized, limiting our appreciation of their ecological impacts and evolution. Here, we present 37 new genomes of haloarchaeal tailed virus isolates, more than doubling the current number of sequenced arTVs. Analysis of all 63 available complete genomes of arTVs, which we propose to classify into 14 new families and 3 orders, suggests ancient divergence of archaeal and bacterial tailed viruses and points to an extensive sharing of genes involved in DNA metabolism and counterdefense mechanisms, illuminating common strategies of virus–host interactions with tailed bacteriophages. Coupling of the comparative genomics with the host range analysis on a broad panel of haloarchaeal species uncovered 4 distinct groups of viral tail fiber adhesins controlling the host range expansion. The survey of metagenomes using viral hallmark genes suggests that the global architecture of the arTV community is shaped through recurrent transfers between different biomes, including hypersaline, marine, and anoxic environments.

Comparative genomics and host range analysis reveals the remarkable diversity and evolution of tailed archaeal viruses of the order Caudoviricetes, which together with their bacterial relatives arguably represent the most abundant and widespread virus group on our planet.     

Density effects on the clearance rate of the zebra mussel <Emphasis Type="Italic">Dreissena polymorpha</Emphasis>: flume study results

Zebra mussel filtration rates and regulating factors have been addressed earlier in a number of studies. Still, only a few of them have taken into consideration the refiltration phenomenon, and therefore the direct extrapolation of experimental results may only give the potential filtering capacity, and hence, over- or underestimate the actual amount of seston being removed by zebra mussels in an ecosystem. The current experimental study aimed to gain insight into the refiltration effect on the clearance rate of the zebra mussels at relatively high seston concentrations, and its potential role in controlling the filtration efficiency of the zebra mussel population. The experiment was conducted in a laboratory flume following the Latin squares design with one fixed (mussel density) and three random factors (initial total particulate matter (TPM) concentration, flume “wall effect” and distance from the flume inflow area) considered. The results showed the significant effects of mussel density and the TPM concentration on the effective clearance rate (ECR) of zebra mussels. The higher ECR values were obtained at denser mussel clumps and lower TPM concentrations. The flume “wall effect” had no significant effect on the ECR, whereas the distance from the flume inflow area appeared to have a significant impact. A positive relationship between ECR and the zebra mussel density was most evident in the proximity of the TPM source. Based on the results, we assume that at high TPM concentration, refiltration may assert itself by the elevated net clearance rate of mussels within dense clumps compared to that of mussels at relatively low individual densities. This should be taken into consideration while modelling and assessing the role of the zebra mussel in energy flow and redistribution of organic matter in an ecosystem.     

Voltage-dependent anion-selective channel 1 (VDAC1)--a mitochondrial protein, rediscovered as a novel enzyme in the plasma membrane

The eukaryotic porin or voltage-dependent anion-selective channel (VDAC1) is a pore-forming protein discovered twenty five years ago in the mitochondrial outer membrane. Its gene in eukaryotes is known, but its tertiary structure has never been solved. Structure predictions highlight the presence of several amphipathic beta-strands possibly organised in a beta-barrel. VDAC1 has recently been described as being a NADH:ferricyanide reductase in the plasma membrane. There it affects the regulation of cell growth and death. Physiological cell death (apoptosis) has become a major research focus of biomedical research. Regulation of the enzyme will have impacts on cancer and autoimmune diseases (insufficient apoptosis) as well as neurodegenerative diseases (excessive apoptosis). VDAC1 in the plasma membrane establishes a novel level of apoptosis regulation putatively via its redox activity.     

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt‐based anti‐cancer drugs

Although platinum‐based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume‐regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8‐dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug‐induced apoptosis independently from drug uptake, possibly by impairing VRAC‐dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D‐containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.     

Structure–Activity Relationships of Strychnine Analogs at Glycine Receptors

Nine strychnine derivatives including neostrychnine, strychnidine, isostrychnine, 21,22‐dihydro‐21‐hydroxy‐22‐oxo‐strychnine, and several hydrogenated analogs were synthesized, and their antagonistic activities at human α1 and α1β glycine receptors were evaluated. Isostrychnine has shown the best pharmacological profile exhibiting an IC₅₀ value of 1.6 μM at α1 glycine receptors and 3.7‐fold preference towards the α1 subtype. SAR Analysis indicates that the lactam moiety and the C(21)?C(22) bond in strychnine are essential structural features for its high antagonistic potency at glycine receptors     

Bioconversion of β-myrcene to perillene by Pleurotus ostreatus

Submerged cultures of Pleurotus ostreatus, when supplemented with β-myrcene, produced perillene, a rare furanoid monoterpene with a unique flowery citrus-like flavour. The major volatile products of the conversion were identified from which a substantiated conversion pathway has been derived. The isomeric epoxides 1,2- and 3,10-epoxymyrcene were found among the first enzymatic oxidation products. An unusual opening of both oxirane rings to the E/Z isomers of α-acaridiol was thought to be key to the fungal formation of perillene. Further oxidation of α-(Z)-acaridiol via the corresponding hydroxyaldehydes and lactols resulted in perillene formation. A new natural compound, 3-(4-methyl-3-pentenyl)-2,5-dihydrofuran-2-ol (α,α-acarilactol), was among the transformation products.     

Changes in the fine-scale genetic structure of Finland through the 20th century

Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20^th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results.