Inhibition of TGF-beta2 with AP 12009 in recurrent malignant gliomas: from preclinical to phase I/II studies

Transforming growth factor-beta2 (TGF-beta2) is known to suppress the immune response to cancer cells and plays a pivotal role in tumor progression by regulating key mechanisms including proliferation, metastasis, and angiogenesis. For targeted protein suppression the TGF-beta2-specific antisense oligodeoxynucleotide AP 12009 was developed. In vitro experiments have been performed to prove specificity and efficacy of the TGF-beta2 inhibitor AP 12009 employing patient-derived malignant glioma cells as well as peripheral blood mononuclear cells (PBMCs) from patients. Clinically, the antisense compound AP 12009 was assessed in three Phase I/II-studies for the treatment of patients with recurrent or refractory malignant (high-grade) glioma WHO grade III or IV. Although the study was not primarily designed as an efficacy evaluation, prolonged survival compared to literature data and response data were observed, which are very rarely seen in this tumor indication. Two patients experienced long-lasting complete tumor remissions. These results implicate targeted TGF-beta2-suppression using AP 12009 as a promising novel approach for malignant gliomas and other highly aggressive, TGF-beta-2-overexpressing tumors.     

In situ proteolysis for protein crystallization and structure determination

We tested the general applicability of in situ proteolysis to form protein crystals suitable for structure determination by adding a protease (chymotrypsin or trypsin) digestion step to crystallization trials of 55 bacterial and 14 human proteins that had proven recalcitrant to our best efforts at crystallization or structure determination. This is a work in progress; so far we determined structures of 9 bacterial proteins and the human aminoimidazole ribonucleotide synthetase (AIRS) domain.     

Discovery of a natural thiamine adenine nucleotide

Several important cofactors are adenine nucleotides with a vitamin as the catalytic moiety. Here, we report the discovery of the first adenine nucleotide containing vitamin B1: adenosine thiamine triphosphate (AThTP, 1), or thiaminylated ATP. We discovered AThTP in Escherichia coli and found that it accumulates specifically in response to carbon starvation, thereby acting as a signal rather than a cofactor. We detected smaller amounts in yeast and in plant and animal tissues.     

The invasive crayfish Faxonius immunis causes the collapse of macroinvertebrate communities in Central European ponds

Aquatic Ecology - The invasive crayfish Faxonius immunis is regarded as a threat to amphibians and macroinvertebrates in the Upper Rhine Valley, Germany, eradicating macrophytes and establishing...     

Nutrient recycling by insect and fish communities in high-elevation tropical streams

Hydrobiologia - High- to mid-elevation streams are often oligotrophic, but harbor diverse groups of aquatic animals that can satisfy a substantial proportion of nutrient demand. Therefore, we...     

Preface: Blasts from the past and back to the future

The invasion of dreissenid mussels into inland waters of the Northern Hemisphere has received considerable attention and, both zebra mussels and quagga mussels continue to spread westward. Despite studies aimed at understanding the biology of dreissenid mussels, relatively few studies have focused on water velocity and other hydrodynamic characteristics of water flow. The objective of this review was to identify, through a search of online databases, the papers that have been made available that directly have assessed the influence of hydrodynamic characteristics of water flow on dreissenid mussel biology. Using Thompson Reuters Web of Science, Google Scholar, and other resources, 46 papers were identified. These papers detailed that metrics associated with hydrodynamics of water flow, including current, wave action, velocity, flow rate, and discharge, can influence the biology of dreissenid mussels (primarily zebra mussel, which were studied far more than quagga mussel). Hydrodynamic characteristics influenced external fertilization, larval development and settlement, juvenile recruitment and attachment, and suspension feeding, growth and abundance of adults. In most cases, the impact of higher flow rates were locally negative and may present an opportunity for applications of water flow to control the spread or establishment of dreissenid mussels. Several knowledge gaps have been identified.

     

The impacts of introduced House Mice on the breeding success of nesting seabirds on Gough Island

Invasive species are the main threat to island biodiversity; seabirds are particularly vulnerable and are one of the most threatened groups of birds. Gough Island, a UNESCO World Heritage Site in the South Atlantic Ocean, is an Important Bird and Biodiversity Area, and one of the most important seabird colonies globally. Invasive House Mice Mus musculus depredate eggs and chicks of most seabird species on the island, but the extent of their impact has not been quantified. We used field data and bootstrapped normal distributions to estimate breeding success and the number of surviving chicks for 10 seabird species on Gough Island, and compared estimates with those of analogous species from predator‐free islands. We examined the effects of season and nest‐site location on the breeding success of populations on Gough Island, predicting that the breeding success of Gough birds would be lower than that of analogues, particularly among small burrow‐nesting species. We also predicted that winter‐breeding species would exhibit lower breeding success than summer‐breeding species, because mice have fewer alternative food sources in winter; and below‐ground nesters would have lower breeding success than surface nesters, as below‐ground species are smaller so their chicks are easier prey for mice. We did indeed find that seabirds on Gough Island had low breeding success compared with analogues, losing an estimated 1 739 000 (1 467 000–2 116 000) eggs/chicks annually. Seven of the 10 focal species on Gough Island had particularly high chick mortality and may have been subject to intense mouse predation. Below‐ground and winter breeders had lower breeding success than surface‐ and summer‐breeders. MacGillivray's Prion Pachyptila macgillivrayi, Atlantic Petrel Pterodroma incerta and Tristan Albatross Diomedea dabbenena are endemic or near‐endemic to Gough Island and are likely to be driven to extinction if invasive mice are not removed.     

Structural and functional properties of αβ-heterodimers of tropomyosin with myopathic mutations Q147P and K49del in the β-chain

Tropomyosin (Tpm) is an α-helical coiled-coil actin-binding protein that plays a key role in the Ca²⁺-regulated contraction of striated muscles. Two Tpm isoforms, α (Tpm 1.1) and β (Tpm 2.2), are expressed in fast skeletal muscles. These Tpm isoforms can form either αα and ββ homodimers, or αβ heterodimers. However, only αα-Tpm and αβ-Tpm dimers are usually present in most of fast skeletal muscles, because ββ-homodimers are relatively unstable and cannot exist under physiologic conditions. Nevertheless, the most of previous studies of myopathy-causing mutations in the Tpm β-chains were performed on the ββ-homodimers. In the present work, we applied different methods to investigate the effects of two myopathic mutations in the β-chain, Q147P and K49del (i.e. deletion of Lys49), on structural and functional properties of Tpm αβ-heterodimers and to compare them with the properties of ββ-homodimers carrying these mutations in both β-chains. The results show that the properties of αβ-Tpm heterodimers with these mutations in the β-chain differ significantly from the properties of ββ-homodimers with the same substitutions in both β-chains. This indicates that the αβ-heterodimer is a more appropriate model for studying the effects of myopathic mutations in the β-chain of Tpm than the ββ-homodimer which virtually does not exist in human skeletal muscles.     

New data from Oman indicate benthic high biomass productivity coupled with low taxonomic diversity in the aftermath of the Permian–Triassic Boundary mass extinction

A new Early Triassic marine fauna is described from an exotic block (olistolith) from the Ad Daffah conglomerate in eastern Oman (Batain), which provides new insights into the ecology and diversity during the early aftermath of the Permian–Triassic Boundary mass extinction. Based on conodont quantitative biochronology, we assign a middle Griesbachian age to the upper part of this boulder. It was derived from an offshore seamount and yielded both nektonic and benthic faunas, including conodonts, ammonoids, gastropods and crinoid ossicles in mass abundance. This demonstrates that despite the stratigraphically near extinction at the Permian–Triassic Boundary, Crinoidea produced enough biomass to form crinoidal limestone as early as middle Griesbachian time. Baudicrinus, previously placed in Dadocrinidae, is now placed in Holocrinidae; therefore, Dadocrinidae are absent in the Early Triassic, and Holocrinidae remains the most basal crown‐group articulates, originating during the middle Griesbachian in the Tethyan Realm. Abundant gastropods assigned to Naticopsis reached a shell size larger than 20 mm and provide another example against any generalized Lilliput effect during the Griesbachian. Whereas the benthic biomass was as high as to allow the resumption of small carbonate factories, the taxonomic diversity of the benthos remained low compared to post‐Early Triassic times. This slow benthic taxonomic recovery is here attributed to low competition within impoverished post‐extinction faunas.     

Small-angle neutron and X-ray scattering analysis of the supramolecular organization of rhodopsin in photoreceptor membrane

The supramolecular organization of the visual pigment rhodopsin in the photoreceptor membrane remains contentious. Specifically, whether this G protein-coupled receptor functions as a monomer or dimer remains unknown, as does the presence or absence of ordered packing of rhodopsin molecules in the photoreceptor membrane. Completely opposite opinions have been expressed on both issues. Herein, using small-angle neutron and X-ray scattering approaches, we performed a comparative analysis of the structural characteristics of the photoreceptor membrane samples in buffer, both in the outer segment of photoreceptor cells, and in the free photoreceptor disks. The average distance between the centers of two neighboring rhodopsin molecules was found to be ~5.8 nm in both cases. The results indicate an unusually high packing density of rhodopsin molecules in the photoreceptor membrane, but molecules appear to be randomly distributed in the membrane without any regular ordering.