Analysis of proposed criteria for human response to vibration

The development of criteria for human vibration response is reviewed, including the evolution of the ISO standard 2631. The document is analyzed to show why its application to vehicle ride evaluation is strongly opposed. Alternative vertical horizontal limits for comfort are recommended in the ground vehicle ride frequency range above 1 Hz. These values are derived by correlating the absorbed power findings of Pradko and Lee with other established criteria. Special emphasis is placed on working limits in the frequency range of 1 to 10 Hz since this is the most significant area in ground vehicle ride evaluation

Venture Capital Booms and Startup Financing

We review the growing literature on the relationship between venture capital booms and startup financing, focusing on three broad areas: First, we discuss the drivers of large inflows into the venture capital asset class, particularly in recent years -- which are related to but also distinct from macroeconomic business cycles and stock market fluctuations. Second, we review the emerging literature on the real effects of venture capital financing booms. A particular focus of this work is to highlight the potential impact that booms (and busts) can have on the types of firms that VCs choose to fund and terms at which they are funded, independent of investment opportunities -- thereby shaping the trajectory of innovation being conducted by startups. Third, an important insight from recent research is that booms in venture capital financing are not just a temporal phenomenon but can also be seen in terms of the concentration of VC investment in certain industries and geographies. We also review the role of government policy, exploring the degree to which it can explain the concentration of VC funding in the US over the past forty years in just two broad areas – information and communication technologies (ICT) and biotechnology. We conclude by highlighting promising areas of further research

Statistical mechanics of clonal expansion in lymphocyte networks modelled with slow and fast variables

We study the Langevin dynamics of the adaptive immune system, modelled by a lymphocyte network in which the B cells are interacting with the T cells and antigen. We assume that B clones and T clones are evolving in different thermal noise environments and on different timescales. We derive stationary distributions and use statistical mechanics to study clonal expansion of B clones in this model when the B and T clone sizes are assumed to be the slow and fast variables respectively and vice versa. We derive distributions of B clone sizes and use general properties of ferromagnetic systems to predict characteristics of these distributions, such as the average B cell concentration, in some regimes where T cells can be modelled as binary variables. This analysis is independent of network topologies and its results are qualitatively consistent with experimental observations. In order to obtain full distributions we assume that the network topologies are random and locally equivalent to trees. The latter allows us to employ the Bethe-Peierls approach and to develop a theoretical framework which can be used to predict the distributions of B clone sizes. As an example we use this theory to compute distributions for the models of immune system defined on random regular networks.Comment: A more recent version (accepted for publication in Journal of Physics A: Mathematical and Theoretical) with improved figures, references, et

Parallel processing in immune networks

In this work we adopt a statistical mechanics approach to investigate basic, systemic features exhibited by adaptive immune systems. The lymphocyte network made by B-cells and T-cells is modeled by a bipartite spin-glass, where, following biological prescriptions, links connecting B-cells and T-cells are sparse. Interestingly, the dilution performed on links is shown to make the system able to orchestrate parallel strategies to fight several pathogens at the same time; this multitasking capability constitutes a remarkable, key property of immune systems as multiple antigens are always present within the host. We also define the stochastic process ruling the temporal evolution of lymphocyte activity, and show its relaxation toward an equilibrium measure allowing statistical mechanics investigations. Analytical results are compared with Monte Carlo simulations and signal-to-noise outcomes showing overall excellent agreement. Finally, within our model, a rationale for the experimentally well-evidenced correlation between lymphocytosis and autoimmunity is achieved; this sheds further light on the systemic features exhibited by immune networks.Comment: 21 pages, 9 figures; to appear in Phys. Rev.

Divergent selection on locally adapted major histocompatibility complex immune genes experimentally proven in the field

Although crucial for the understanding of adaptive evolution, genetically resolved examples of local adaptation are rare. To maximize survival and reproduction in their local environment, hosts should resist their local parasites and pathogens. The major histocompatibility complex (MHC) with its key function in parasite resistance represents an ideal candidate to investigate parasite-mediated local adaptation. Using replicated field mesocosms, stocked with second-generation lab-bred three-spined stickleback hybrids of a lake and a river population, we show local adaptation of MHC genotypes to population-specific parasites, independently of the genetic background. Increased allele divergence of lake MHC genotypes allows lake fish to fight the broad range of lake parasites, whereas more specific river genotypes confer selective advantages against the less diverse river parasites. Hybrids with local MHC genotype gained more body weight and thus higher fitness than those with foreign MHC in either habitat, suggesting the evolutionary significance of locally adapted MHC genotypes

Osteosarcoma

Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases

Detection of circulating tumour DNA is associated with inferior outcomes in Ewing sarcoma and osteosarcoma: a report from the Children's Oncology Group.

BackgroundNew prognostic markers are needed to identify patients with Ewing sarcoma (EWS) and osteosarcoma unlikely to benefit from standard therapy. We describe the incidence and association with outcome of circulating tumour DNA (ctDNA) using next-generation sequencing (NGS) assays.MethodsA NGS hybrid capture assay and an ultra-low-pass whole-genome sequencing assay were used to detect ctDNA in banked plasma from patients with EWS and osteosarcoma, respectively. Patients were coded as positive or negative for ctDNA and tested for association with clinical features and outcome.ResultsThe analytic cohort included 94 patients with EWS (82% from initial diagnosis) and 72 patients with primary localised osteosarcoma (100% from initial diagnosis). ctDNA was detectable in 53% and 57% of newly diagnosed patients with EWS and osteosarcoma, respectively. Among patients with newly diagnosed localised EWS, detectable ctDNA was associated with inferior 3-year event-free survival (48.6% vs. 82.1%; p = 0.006) and overall survival (79.8% vs. 92.6%; p = 0.01). In both EWS and osteosarcoma, risk of event and death increased with ctDNA levels.ConclusionsNGS assays agnostic of primary tumour sequencing results detect ctDNA in half of the plasma samples from patients with newly diagnosed EWS and osteosarcoma. Detectable ctDNA is associated with inferior outcomes

Specific immune priming in the invasive ctenophore Mnemiopsis leidyi

Specific immune priming enables an induced immune response upon repeated pathogen encounter. As a functional analogue to vertebrate immune memory, such adaptive plasticity has been described, for instance, in insects and crustaceans. However, towards the base of the metazoan tree our knowledge about the existence of specific immune priming becomes scattered. Here, we exposed the invasive ctenophore Mnemiopsis leidyi repeatedly to two different bacterial epitopes (Gram-positive or -negative) and measured gene expression. Ctenophores experienced either the same bacterial epitope twice (homologous treatments) or different bacterial epitopes (heterologous treatments). Our results demonstrate that immune gene expression depends on earlier bacterial exposure. We detected significantly different expression upon heterologous compared with homologous bacterial treatment at three immune activator and effector genes. This is the first experimental evidence for specific immune priming in Ctenophora and generally in non-bilaterian animals, hereby adding to our growing notion of plasticity in innate immune systems across all animal phyla