Project description:Although systemic inflammatory response syndrome (SIRS) is a known complication of severe influenza pneumonia, it has been reported very rarely in patients with minimal parenchymal lung disease. We here report a case of severe SIRS, anasarca, and marked vascular phenomena with minimal or no pneumonitis. This case highlights that viruses, including influenza, may cause vascular dysregulation causing SIRS, even without substantial visceral organ involvement.
Project description:A major challenge for a molecular understanding of membrane trafficking has been the elucidation of high-resolution structures of large, multisubunit tethering complexes that spatially and temporally control intracellular membrane fusion. Exocyst is a large hetero-octameric protein complex proposed to tether secretory vesicles at the plasma membrane to provide quality control of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-mediated membrane fusion. Breakthroughs in methodologies, including sample preparation, biochemical characterization, fluorescence microscopy, and single-particle cryoelectron microscopy, are providing critical insights into the structure and function of the exocyst. These studies now pose more questions than answers for understanding fundamental functional mechanisms, and they open wide the door for future studies to elucidate interactions with protein and membrane partners, potential conformational changes, and molecular insights into tethering reactions.
Project description:RNA interference involves endonucleolytic cleavage of mRNAs at a site determined by complementary siRNAs. Initial cleavage leads to rapid degradation of the message, resulting in a corresponding reduction in the level of the encoded protein. Despite intensive study, the identity of the endonucleolytic activity (designated slicer) has remained obscure. Now, a combination of structural and biochemical analyses provide compelling evidence that human Argonaute2 (Ago2), a protein already known to be a key player in the RNAi pathway, is in fact the missing endonuclease.
Project description:This exploratory synthesis investigation was undertaken to determine the viability of replacing a single carbon vertex with another p-block element in a highly strained tetrahedrane molecule. Phosphorus was selected for this purpose because the stable molecular form of elemental phosphorus is tetrahedral. Our synthetic strategy was to generate an unsaturated phosphorus center bonded to a substituted cyclopropenyl group, a situation that could lead to closure to provide the desired phosphatetrahedrane framework. This was accomplished by dehydrofluorination of the in situ generated fluorophosphine H(F)P(C t Bu)3. Tri-tert-butyl phosphatetrahedrane, P(C t Bu)3, was then isolated in 19% yield as a low-melting, volatile, colorless solid and characterized spectroscopically and by a single-crystal x-ray diffraction study, confirming the tetrahedral nature of the molecule's PC3 core. The molecule exhibits unexpected thermal stability.
Project description:The chromothripsis hypothesis suggests an extraordinary one-step catastrophic genomic event allowing a chromosome to 'shatter into many pieces' and reassemble into a functioning chromosome. Recent efforts have aimed to detect chromothripsis by looking for a genomic signature, characterized by a large number of breakpoints (50-250), but a limited number of oscillating copy number states (2-3) confined to a few chromosomes. The chromothripsis phenomenon has become widely reported in different cancers, but using inconsistent and sometimes relaxed criteria for determining rearrangements occur simultaneously rather than progressively. We revisit the original simulation approach and show that the signature is not clearly exceptional, and can be explained using only progressive rearrangements. For example, 3.9% of progressively simulated chromosomes with 50-55 breakpoints were dominated by two or three copy number states. In addition, by adjusting the parameters of the simulation, the proposed footprint appears more frequently. Lastly, we provide an algorithm to find a sequence of progressive rearrangements that explains all observed breakpoints from a proposed chromothripsis chromosome. Thus, the proposed signature cannot be considered a sufficient proof for this extraordinary hypothesis. Great caution should be exercised when labeling complex rearrangements as chromothripsis from genome hybridization and sequencing experiments.
Project description:Memory is the brain faculty to store and remember information. It is a sequential process in which four different phases can be distinguished: encoding or learning, consolidation, storage and reactivation. Since the discovery of the first Drosophila gene essential for memory formation in 1976, our knowledge of its mechanisms has progressed greatly. The current view considers the existence of engrams, ensembles of neuronal populations whose activity is temporally coordinated and represents the minimal correlate of experience in brain circuits. In order to form and maintain the engram, protein synthesis and, probably, specific transcriptional program(s) is required. The immediate early gene response during learning process has been extensively studied. However, a detailed description of the transcriptional response for later memory phases was technically challenging. Recent advances in transcriptomics have allowed us to tackle this biological problem. This review summarizes recent findings in this field, and discusses whether or not it is possible to identify a transcriptional trace for memory.
Project description:Systemic inflammatory response syndrome (SIRS) is a common complication after cardiovascular surgery that in severe cases can lead to multiple organ dysfunction syndrome and even death. We therefore set out to identify reliable early biomarkers for SIRS in a prospective small patient study for timely intervention. 21 Patients scheduled for planned cardiovascular surgery were recruited in the study, monitored for signs of SIRS and blood samples were taken to investigate biomarkers at pre-assigned time points: day of admission, start of surgery, end of surgery, days 1, 2, 3, 5 and 8 post surgery. Stored plasma and cryopreserved blood samples were analyzed for cytokine expression (IL1β, IL2, IL6, IL8, IL10, TNFα, IFNγ), other pro-inflammatory markers (sCD163, sTREM-1, ESM-1) and response to endotoxin. Acute phase proteins CRP, PCT and pro-inflammatory cytokines IL6 and IL8 were significantly increased (p<0.001) at the end of surgery in all patients but could not distinguish between groups. Normalization of samples revealed significant increases in IL1β changes (p<0.05) and decreased responses to endotoxin (p<0.01) in the SIRS group at the end of surgery. Soluble TREM-1 plasma concentrations were significantly increased in patients with SIRS (p<0.01). This small scale patient study could show that common sepsis markers PCT, CRP, IL6 and TNFα had low predictive value for early diagnosis of SIRS after cardiovascular surgery. A combination of normalized IL1β plasma levels, responses to endotoxin and soluble TREM-1 plasma concentrations at the end of surgery are predictive markers of SIRS development in this small scale study and could act as an indicator for starting early therapeutic interventions.
Project description:Articular cartilage was predicted to be one of the first tissues to successfully be regenerated, but this proved incorrect. In contrast, bone (but also vasculature and cardiac tissues) has seen numerous successful reparative approaches, despite consisting of multiple cell and tissue types and, thus, possessing more complex design requirements. Here, we use bone-regeneration successes to highlight cartilage-regeneration challenges: such as selecting appropriate cell sources and scaffolds, creating biomechanically suitable tissues, and integrating to native tissue. We also discuss technologies that can address the hurdles of engineering a tissue possessing mechanical properties that are unmatched in human-made materials and functioning in environments unfavorable to neotissue growth.
Project description:Physical entanglement, and particularly knots arise spontaneously in equilibrated polymers that are sufficiently long and densely packed. Biopolymers are no exceptions: knots have long been known to occur in proteins as well as in encapsidated viral DNA. The rapidly growing number of RNA structures has recently made it possible to investigate the incidence of physical knots in this type of biomolecule, too. Strikingly, no knots have been found to date in the known RNA structures. In this Point of View Article we discuss the absence of knots in currently available RNAs and consider the reasons why knots in RNA have not yet been found, despite the expectation that they should exist in Nature. We conclude by singling out a number of RNA sequences that, based on the properties of their predicted secondary structures, are good candidates for knotted RNAs.