A Patient-Specific in silico Model of Inflammation and Healing Tested in Acute Vocal Fold Injury

The development of personalized medicine is a primary objective of the medical community and increasingly also of funding and registration agencies. Modeling is generally perceived as a key enabling tool to target this goal. Agent-Based Models (ABMs) have previously been used to simulate inflammation at various scales up to the whole-organism level. We extended this approach to the case of a novel, patient-specific ABM that we generated for vocal fold inflammation, with the ultimate goal of identifying individually optimized treatments. ABM simulations reproduced trajectories of inflammatory mediators in laryngeal secretions of individuals subjected to experimental phonotrauma up to 4 hrs post-injury, and predicted the levels of inflammatory mediators 24 hrs post-injury. Subject-specific simulations also predicted different outcomes from behavioral treatment regimens to which subjects had not been exposed. We propose that this translational application of computational modeling could be used to design patient-specific therapies for the larynx, and will serve as a paradigm for future extension to other clinical domains

PLK1 facilitates chromosome biorientation by suppressing centromere disintegration driven by BLM-mediated unwinding and spindle pulling

Centromeres provide a pivotal function for faithful chromosome segregation. They serve as a foundation for the assembly of the kinetochore complex and spindle connection, which is essential for chromosome biorientation. Cells lacking Polo-like kinase 1 (PLK1) activity suffer severe chromosome alignment defects, which is believed primarily due to unstable kinetochore-microtubule attachment. Here, we reveal a previously undescribed mechanism named ‘centromere disintegration’ that drives chromosome misalignment in PLK1-inactivated cells. We find that PLK1 inhibition does not necessarily compromise metaphase establishment, but instead its maintenance. We demonstrate that this is caused by unlawful unwinding of DNA by BLM helicase at a specific centromere domain underneath kinetochores. Under bipolar spindle pulling, the distorted centromeres are promptly decompacted into DNA threadlike molecules, leading to centromere rupture and whole-chromosome arm splitting. Consequently, chromosome alignment collapses. Our study unveils an unexpected role of PLK1 as a chromosome guardian to maintain centromere integrity for chromosome biorientation

International money markets: eurocurrencies

Eurocurrencies are international markets for short-term wholesale bank deposits and loans. They emerged in Western Europe in the late 1950s and rapidly reached a global scale. A Eurocurrency is a form of bank money: an unsecured short-term bank debt denominated in a currency (for instance, US dollars) but issued by banks operating offshore, in a geographical location or a legal space situated outside of the jurisdiction of the national authorities presiding over that currency (for instance, the Federal Reserve). In Eurocurrency markets, banks intermediate mainly between foreign residents. They borrow funds by "accepting" foreign currency deposits and lend foreign currency-denominated funds by "placing" deposits with other banks, by granting short-term loans or investing in other liquid assets. Historically, Eurodollars accounted for the largest share of Eurocurrencies, although other international currencies (Deutsche Marks, Japanese yens, and especially Euros since 1999) played an important role. Eurocurrency markets were a manifestation of financial integration and interdependence in a globalizing economy and performed critical functions in the distribution and creation of international liquidity. At the same time, their fast growth was a recurrent source of concerns for central bankers and policymakers due to their implications for macroeconomic policies and financial stability. This chapter analyzes different aspects of the historical development of Eurocurrency markets and their role in the international monetary and financial system. The first part discusses theoretical interpretations, presents estimates of markets' size, describes their structure, and explains the determinants of their growth. The second part analyzes the spread between Eurodollar rates and other US money market rates, the role of arbitrage, the evolution of risk factors, and the causes of historical episodes of stress and contagion in the interbank market. The last part discusses political economy issues, such as the role of governments and market forces in the emergence of Eurodollars in the 1950s and the failed attempts to impose multilateral controls on Eurocurrency markets in the 1970s

A protease-based biosensor for the detection of schistosome cercariae

Parasitic diseases affect millions of people worldwide, causing debilitating illnesses and death. Rapid and cost-effective approaches to detect parasites are needed, especially in resource-limited settings. A common signature of parasitic diseases is the release of specific proteases by the parasites at multiple stages during their life cycles. To this end, we engineered several modular Escherichia coli and Bacillus subtilis whole-cell-based biosensors which incorporate an interchangeable protease recognition motif into their designs. Herein, we describe how several of our engineered biosensors have been applied to detect the presence and activity of elastase, an enzyme released by the cercarial larvae stage of Schistosoma mansoni. Collectively, S. mansoni and several other schistosomes are responsible for the infection of an estimated 200 million people worldwide. Since our biosensors are maintained in lyophilised cells, they could be applied for the detection of S. mansoni and other parasites in settings without reliable cold chain access

Family Relationship, Water Contact and Occurrence of Buruli Ulcer in Benin

Mycobacterium ulcerans disease (Buruli ulcer) is the most widespread mycobacterial disease in the world after leprosy and tuberculosis. How M. ulcerans is introduced into the skin of humans remains unclear, but it appears that individuals living in the same environment may have different susceptibilities. This case control study aims to determine whether frequent contacts with natural water sources, family relationship or the practice of consanguineous marriages are associated with the occurrence of Buruli ulcer (BU). The study involved 416 participants, of which 104 BU-confirmed cases and 312 age, gender and village of residence matched controls (persons who had no signs or symptoms of active or inactive BU). The results confirmed that contact with natural water sources is a risk factor. Furthermore, it suggests that a combination of genetic factors may constitute risk factors for the development of BU, possibly by influencing the type of immune response in the individual, and, consequently, the development of BU infection per se and its different clinical forms. These findings may be of major therapeutic interest

The calcareous brown alga Padina pavonica in southern Britain: population change and tenacity over 300 years

Understanding long-term persistence and variability in species populations can help to predict future survival, growth and distribution; however, sustained observations are exceedingly rare. We examine and interpret a remarkable record of the calcareous brown alga Padina pavonica (Phaeophyceae) at its northern limit on the south coast of England (50°N, 1–3°W) from 1680 to 2014, which is probably the longest compilation and review of any marine algal species. Over this period, which extends from the middle of the Little Ice Age to the present, there has been considerable variability in temperature and storminess. We identified a significant number of site extinctions in the second half of the nineteenth century, which coincided with cooler conditions and stormier weather. To interpret thesechanges, we measured recruitment, growth and production of tetraspores at sheltered and exposed sites in 2012–2014, years which had low and high spring temperatures. Potential spore production was greater at the sheltered site due to a longer growing period and survival of larger fronds. Delayed growth in the cooler spring resulted in smaller fronds and lower potential production of tetraspores by early summer. Yet in the warmer year, rapid initial growth caused higher sensitivity to damage and dislodgement by summer storms, which also limited potential spore production. Antagonistic responses to multiple stressors and disturbances make future predictions of survival and distribution difficult. Fronds of Padina pavonica are sensitive to both temperature and physical disturbances, yet vegetative perennation appears to have enabled population persistence and explained the longevity of remaining populations

Predicting the onset of anxiety syndromes at 12 months in primary care attendees. The PredictA-Spain study

Background: There are no risk algorithms for the onset of anxiety syndromes at 12 months in primary care. We aimed to develop and validate internally a risk algorithm to predict the onset of anxiety syndromes at 12 months. Methods: A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multilevel logistic regression and inverse probability weighting to build the risk algorithm. Our main outcome was generalized anxiety, panic and other non-specific anxiety syndromes as measured by the Primary Care Evaluation of Mental Disorders, Patient Health Questionnaire (PRIME-MD-PHQ). We recruited 3,564 adult primary care attendees without anxiety syndromes from 174 family physicians and 32 health centers in 6 Spanish provinces. Results: The cumulative 12-month incidence of anxiety syndromes was 12.2%. The predictA-Spain risk algorithm included the following predictors of anxiety syndromes: province; sex (female); younger age; taking medicines for anxiety, depression or stress; worse physical and mental quality of life (SF-12); dissatisfaction with paid and unpaid work; perception of financial strain; and the interactions sex*age, sex*perception of financial strain, and age*dissatisfaction with paid work. The C-index was 0.80 (95% confidence interval = 0.78–0.83) and the Hedges' g = 1.17 (95% confidence interval = 1.04–1.29). The Copas shrinkage factor was 0.98 and calibration plots showed an accurate goodness of fit. Conclusions: The predictA-Spain risk algorithm is valid to predict anxiety syndromes at 12 months. Although external validation is required, the predictA-Spain is available for use as a predictive tool in the prevention of anxiety syndromes in primary care.This study was supported by the Spanish Ministry of Health (grant FIS references: PI041980, PI041771, PI042450 and PI06/1442) and the Andalusian Council of Health (grant references: 05/403 and 06/278); as well as the Spanish Network of Primary Care Research ‘redIAPP’ (RD06/0018), the ‘Aragón group’ (RD06/0018/0020), the ‘Baleares group’ (RD07/0018/0033), and the ‘SAMSERAP group’ (RD06/0018/0039)

Seasonal and Regional Dynamics of M. ulcerans Transmission in Environmental Context: Deciphering the Role of Water Bugs as Hosts and Vectors

Buruli ulcer, caused by Mycobacterium ulcerans, is a devastating skin disease. Most cases of Buruli ulcer occur in poor rural communities. As a result, treatment is frequently sought too late and about 25% of those infected—particularly children—become permanently disabled. Outbreaks of Buruli ulcer have always been associated with swampy areas. However, the route(s) of bacillus transmission is (are) still unclear. This Mycobacterium species resides in water where it colonizes many ecological niches such as aquatic plants, herbivorous animals and predatory/carnivorous insects. For several years the role of water bugs as hosts and vectors of M. ulcerans was suspected and was demonstrated under laboratory conditions. The aim of this work was to further assess the role of water bugs as hosts and vectors of M. ulcerans in environmental context. This work identifies several water bug families as hosts of M. ulcerans in Buruli ulcer endemic area. The detection of bacilli in saliva of human biting insects provides further evidence for their role in M. ulcerans transmission. Interestingly, three of these insects are good flyers, and as such could participate in M. ulcerans dissemination