The aggregation of cytochrome C may be linked to its flexibility during refolding

Large-scale expression of biopharmaceutical proteins in cellular hosts results in production of large insoluble mass aggregates. In order to generate functional product, these aggregates require further processing through refolding with denaturant, a process in itself that can result in aggregation. Using a model folding protein, cytochrome C, we show how an increase in final denaturant concentration decreases the propensity of the protein to aggregate during refolding. Using polarised fluorescence anisotropy, we show how reduced levels of aggregation can be achieved by increasing the period of time the protein remains flexible during refolding, mediated through dilution ratios. This highlights the relationship between the flexibility of a protein and its propensity to aggregate. We attribute this behaviour to the preferential urea-residue interaction, over self-association between molecules

Human Communication Dynamics in Digital Footsteps: A Study of the Agreement between Self-Reported Ties and Email Networks

Digital communication data has created opportunities to advance the knowledge of human dynamics in many areas, including national security, behavioral health, and consumerism. While digital data uniquely captures the totality of a person's communication, past research consistently shows that a subset of contacts makes up a person's “social network” of unique resource providers. To address this gap, we analyzed the correspondence between self-reported social network data and email communication data with the objective of identifying the dynamics in e-communication that correlate with a person's perception of a significant network tie. First, we examined the predictive utility of three popular methods to derive social network data from email data based on volume and reciprocity of bilateral email exchanges. Second, we observed differences in the response dynamics along self-reported ties, allowing us to introduce and test a new method that incorporates time-resolved exchange data. Using a range of robustness checks for measurement and misreporting errors in self-report and email data, we find that the methods have similar predictive utility. Although e-communication has lowered communication costs with large numbers of persons, and potentially extended our number of, and reach to contacts, our case results suggest that underlying behavioral patterns indicative of friendship or professional contacts continue to operate in a classical fashion in email interactions

Beyond word frequency: Bursts, lulls, and scaling in the temporal distributions of words

Background: Zipf's discovery that word frequency distributions obey a power law established parallels between biological and physical processes, and language, laying the groundwork for a complex systems perspective on human communication. More recent research has also identified scaling regularities in the dynamics underlying the successive occurrences of events, suggesting the possibility of similar findings for language as well. Methodology/Principal Findings: By considering frequent words in USENET discussion groups and in disparate databases where the language has different levels of formality, here we show that the distributions of distances between successive occurrences of the same word display bursty deviations from a Poisson process and are well characterized by a stretched exponential (Weibull) scaling. The extent of this deviation depends strongly on semantic type -- a measure of the logicality of each word -- and less strongly on frequency. We develop a generative model of this behavior that fully determines the dynamics of word usage. Conclusions/Significance: Recurrence patterns of words are well described by a stretched exponential distribution of recurrence times, an empirical scaling that cannot be anticipated from Zipf's law. Because the use of words provides a uniquely precise and powerful lens on human thought and activity, our findings also have implications for other overt manifestations of collective human dynamics

Gas-forming intrahepatic abscess: A possible complication of arterial infusion chemotherapy

Three cases of intrahepatic gas-forming abscesses are presented with liver metastases and indwelling hepatic artery catheters for drug infusion. This may represent a further complication of intrahepatic arterial drug infusion. Possible etiologies along with future prospects for this form of therapy are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/48150/1/261_2005_Article_BF01887516.pd

Past Arctic aliens have passed away, current ones may stay

Published version. Source at http://doi.org/10.1007/s10530-015-0937-9.Increased human activity and climate change are expected to increase the numbers and impact of alien species in the Arctic, but knowledge of alien species is poor in most Arctic regions. Through field investigations over the last 10 years, and review of alien vascular plant records for the high Arctic Archipelago Svalbard over the past 130 years, we explored long term trends in persistence and phenology. In total, 448 observations of 105 taxa have been recorded from 28 sites. Recent surveys at 18 of these sites revealed that alien species had disappeared at half of them. Investigations at a further 49 sites characterised by former human activity and/or current tourist landing sites did not reveal any alien species. Patterns of alien species distribution suggest that greater alien species richness is more likely to be aligned with ongoing human inhabitation than sites of transient use. The probability of an alien species being in a more advanced phenological stage increased with higher mean July temperatures. As higher mean July temperatures are positively correlated with more recent year, the latter finding suggests a clear warming effect on the increased reproductive potential of alien plants, and thus an increased potential for spread in Svalbard. Given that both human activity and temperatures are expected to increase in the future, there is need to respond in policy and action to reduce the potential for further alien species introduction and spread in the Arctic

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies

Clinical and molecular consequences of disease-associated de novo mutations in SATB2

Purpose: To characterize features associated with de novo mutations affecting SATB2 function in individuals ascertained on the basis of intellectual disability. Methods: Twenty previously unreported individuals with 19 different SATB2 mutations (11 loss-of-function and 8 missense variants) were studied. Fibroblasts were used to measure mutant protein production. Subcellular localization and mobility of wild-type and mutant SATB2 were assessed using fluorescently tagged protein. Results: Recurrent clinical features included neurodevelopmental impairment (19/19), absent/near absent speech (16/19), normal somatic growth (17/19), cleft palate (9/19), drooling (12/19), and dental anomalies (8/19). Six of eight missense variants clustered in the first CUT domain. Sibling recurrence due to gonadal mosaicism was seen in one family. A nonsense mutation in the last exon resulted in production of a truncated protein retaining all three DNA-binding domains. SATB2 nuclear mobility was mutation-dependent; p.Arg389Cys in CUT1 increased mobility and both p.Gly515Ser in CUT2 and p.Gln566Lys between CUT2 and HOX reduced mobility. The clinical features in individuals with missense variants were indistinguishable from those with loss of function. Conclusion: SATB2 haploinsufficiency is a common cause of syndromic intellectual disability. When mutant SATB2 protein is produced, the protein appears functionally inactive with a disrupted pattern of chromatin or matrix association

Approved by: AN INFRASTRUCTURE FOR DATABASE TAMPER DETECTION AND FORENSIC ANALYSIS

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