ADAPT Identifies an ESCRT Complex Composition That Discriminates VCaP From LNCaP Prostate Cancer Cell Exosomes

Libraries of single-stranded oligodeoxynucleotides (ssODNs) can be enriched for sequences that specifically bind molecules on naïve complex biological samples like cells or tissues. Depending on the enrichment strategy, the ssODNs can identify molecules specifically associated with a defined biological condition, for example a pathological phenotype, and thus are potentially useful for biomarker discovery. We performed ADAPT, a variant of SELEX, on exosomes secreted by VCaP prostate cancer cells. A library of ∼1011 ssODNs was enriched for those that bind to VCaP exosomes and discriminate them from exosomes derived from LNCaP prostate cancer cells. Next-generation sequencing (NGS) identified the best discriminating ssODNs, nine of which were resynthesized and their discriminatory ability confirmed by qPCR. Affinity purification with one of the sequences (Sequence 7) combined with LC-MS/MS identified its molecular target complex, whereof most proteins are part of or associated with the multiprotein ESCRT complex participating in exosome biogenesis. Within this complex, YBX1 was identified as the directly-bound target protein. ADAPT thus is able to differentiate exosomes from cancer cell subtypes from the same lineage. The composition of ESCRT complexes in exosomes from VCaP versus LNCaP cells might constitute a discriminatory element between these prostate cancer subtypes

Partial “targeted” embolisation of brain arteriovenous malformations

The treatment of pial arteriovenous brain malformations is controversial. Little is yet known about their natural history, their pathomechanisms and the efficacy and risks of respective proposed treatments. It is known that only complete occlusion of the AVM can exclude future risk of haemorrhage and that the rates of curative embolisation of AVMs with an acceptable periprocedural risk are around 20 to 50%. As outlined in the present article, however, partial, targeted embolisation also plays a role. In acutely ruptured AVMs where the source of bleeding can be identified, targeted embolisation of this compartment may be able to secure the AVM prior to definitive treatment. In unruptured symptomatic AVMs targeted treatment may be employed if a defined pathomechanism can be identified that is related to the clinical symptoms and that can be cured with an acceptable risk via an endovascular approach depending on the individual AVM angioarchitecture. This review article gives examples of pathomechanisms and angioarchitectures that are amenable to this kind of treatment strategy

Molecular Biomechanics: The Molecular Basis of How Forces Regulate Cellular Function

Recent advances have led to the emergence of molecular biomechanics as an essential element of modern biology. These efforts focus on theoretical and experimental studies of the mechanics of proteins and nucleic acids, and the understanding of the molecular mechanisms of stress transmission, mechanosensing and mechanotransduction in living cells. In particular, single-molecule biomechanics studies of proteins and DNA, and mechanochemical coupling in biomolecular motors have demonstrated the critical importance of molecular mechanics as a new frontier in bioengineering and life sciences. To stimulate a more systematic study of the basic issues in molecular biomechanics, and attract a broader range of researchers to enter this emerging field, here we discuss its significance and relevance, describe the important issues to be addressed and the most critical questions to be answered, summarize both experimental and theoretical/computational challenges, and identify some short-term and long-term goals for the field. The needs to train young researchers in molecular biomechanics with a broader knowledge base, and to bridge and integrate molecular, subcellular and cellular level studies of biomechanics are articulated.National Institutes of Health (U.S.) (grant UO1HL80711-05 to GB)National Institutes of Health (U.S.) (grant R01GM076689-01)National Institutes of Health (U.S.) (grant R01AR033236-26)National Institutes of Health (U.S.) (grant R01GM087677-01A1)National Institutes of Health (U.S.) (grant R01AI44902)National Institutes of Health (U.S.) (grant R01AI38282)National Science Foundation (U.S.) (grant CMMI-0645054)National Science Foundation (U.S.) (grant CBET-0829205)National Science Foundation (U.S.) (grant CAREER-0955291

Titanium aneurysm clips: Part III--Clinical application in 16 patients with subarachnoid hemorrhage

This report describes the first clinical use of newly developed titanium clips in the treatment of 16 patients with subarachnoid hemorrhage. There were no immediate or delayed complications related to the titanium clips. Thirteen patients had good outcomes, and one patient had moderate disabilities (mean follow-up, 5.4 mo). Two patients with Hunt and Hess Grade IV hemorrhages died postoperatively. The average cross-sectional areas of clip artifact on postoperative magnetic resonance imaging studies was 0.96, 1.36, and 1.05 cm2 on T1-, T2-, and intermediate-weighted images, respectively. In comparison, a matched control group with cobalt alloy clips had average cross-sectional areas of 3.13, 3.70, and 2.81 cm2 on T1-, T2-, and intermediate-weighted images, respectively. The average artifact volumes on gradient echo magnetic resonance images for titanium and cobalt alloy clips were 1.8 and 10.1 cm3, respectively. In addition, the gap on magnetic resonance imaging angiograms from clip artifacts was 0.9 cm with titanium and 2.6 cm with cobalt alloy clips. In conclusion, titanium aneurysm clips seem to be safe and effective and seem to reduce clip artifacts on magnetic resonance imaging threefold, compared with commercially available cobalt alloy clips. Because of this important advantage over conventional clips, titanium clips should be considered for routine use in aneurysm surgery

Novel Heuristics of Functional Neural Networks: Implications for Future Strategies in Functional Neurosurgery

A hypothesis is proposed that (a) the skeletomotor basal ganglia-thalamocortical loop functions as a model of the behavior of the body and the environment, and that (b) dopaminergic neurons of the substantia nigra pars compacta comprise the substrates of an error distribution system projecting to the striatum. This error signal initiates the learning process in the basal ganglia - learning starts with increasing intensity of the error signal and is complete when the signal is minimized. Parkinson€™s disease (PD) may be considered as a disruption of learning processes in the basal ganglia that results from progressive degeneration of the substrate that is the error distribution system for this functional motor loop. Numerous clinical and experimental observations obtained from functional procedures for PD that show identical clinical effects in alleviating parkinsonian symptoms, e.g. thermocoagulative lesions and chronic stimulation, can be explained through the use of this conceptual theory of basal ganglia function. Because any controlling neural network must possess a model of the behavior of its controlled object, the heuristics outlined in this theory are broadly applicable for explaining the function of the nervous system, as well as being useful for planning surgical procedures and future strategies in functional neurosurgery