So what do we really mean when we say that systems biology is holistic?

Background: An old debate has undergone a resurgence in systems biology: that of reductionism versus holism. At least 35 articles in the systems biology literature since 2003 have touched on this issue. The histories of holism and reductionism in the philosophy of biology are reviewed, and the current debate in systems biology is placed in context. Results: Inter-theoretic reductionism in the strict sense envisaged by its creators from the 1930s to the 1960s is largely impractical in biology, and was effectively abandoned by the early 1970s in favour of a more piecemeal approach using individual reductive explanations. Classical holism was a stillborn theory of the 1920s, but the term survived in several fields as a loose umbrella designation for various kinds of anti-reductionism which often differ markedly. Several of these different anti-reductionisms are on display in the holistic rhetoric of the recent systems biology literature. This debate also coincides with a time when interesting arguments are being proposed within the philosophy of biology for a new kind of reductionism. Conclusions: Engaging more deeply with these issues should sharpen our ideas concerning the philosophy of systems biology and its future best methodology. As with previous decisive moments in the history of biology, only those theories that immediately suggest relatively easy experiments will be winners

Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants

Modelling reconfigurable manufacturing systems with coloured timed Petri nets

International audienceReconfigurable manufacturing systems (RMSs) have been acknowledged as a promising means of providing manufacturing companies with the required production capacities and capabilities. This is accomplished through reconfiguring system elements over time for a diverse set of individualized products often required in small quantities and with short delivery lead times. Recognizing the importance of dynamic modeling and visualization in decision-making support in RMSs and the limitations of current research, we propose in this work to model RMSs with Petri net (PN) techniques focusing on the process of reconfiguring system elements while considering constraints and system performance. In view of the modeling challenges, including variety handling, production variation accommodation, machine selection, and constraint satisfaction, we develop a new formalism of colored timed PNs. In conjunction with colored tokens and timing in colored and timed PNs, we also define a reconfiguration mechanism to meet modeling challenges. An application case from an electronics company producing mobile phone vibration motors is presented. Also reported are system analysis and application results, which show how the proposed formalism can be used in the reconfiguration decision making process

Clonal haematopoiesis and risk of chronic liver disease

Chronic liver disease is a major public health burden worldwide. Although different aetiologies and mechanisms of liver injury exist, progression of chronic liver disease follows a common pathway of liver inflammation, injury and fibrosis. Here we examined the association between clonal haematopoiesis of indeterminate potential (CHIP) and chronic liver disease in 214,563 individuals from 4 independent cohorts with whole-exome sequencing data (Framingham Heart Study, Atherosclerosis Risk in Communities Study, UK Biobank and Mass General Brigham Biobank). CHIP was associated with an increased risk of prevalent and incident chronic liver disease (odds ratio = 2.01, 95% confidence interval (95% CI) [1.46, 2.79]; P < 0.001). Individuals with CHIP were more likely to demonstrate liver inflammation and fibrosis detectable by magnetic resonance imaging compared to those without CHIP (odds ratio = 1.74, 95% CI [1.16, 2.60]; P = 0.007). To assess potential causality, Mendelian randomization analyses showed that genetic predisposition to CHIP was associated with a greater risk of chronic liver disease (odds ratio = 2.37, 95% CI [1.57, 3.6]; P < 0.001). In a dietary model of non-alcoholic steatohepatitis, mice transplanted with Tet2-deficient haematopoietic cells demonstrated more severe liver inflammation and fibrosis. These effects were mediated by the NLRP3 inflammasome and increased levels of expression of downstream inflammatory cytokines in Tet2-deficient macrophages. In summary, clonal haematopoiesis is associated with an elevated risk of liver inflammation and chronic liver disease progression through an aberrant inflammatory response

Seasonal and annual fluxes of nutrients and organic matter from large rivers to the Arctic Ocean and surrounding seas

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Estuaries and Coasts 35 (2012): 369-382, doi:10.1007/s12237-011-9386-6.River inputs of nutrients and organic matter impact the biogeochemistry of arctic estuaries and the Arctic Ocean as a whole, yet there is considerable uncertainty about the magnitude of fluvial fluxes at the pan-arctic scale. Samples from the six largest arctic rivers, with a combined watershed area of 11.3 x 106 km2, have revealed strong seasonal variations in constituent concentrations and fluxes within rivers as well as large differences among the rivers. Specifically, we investigate fluxes of dissolved organic carbon, dissolved organic nitrogen, total dissolved phosphorus, dissolved inorganic nitrogen, nitrate, and silica. This is the first time that seasonal and annual constituent fluxes have been determined using consistent sampling and analytical methods at the pan arctic scale, and consequently provide the best available estimates for constituent flux from land to the Arctic Ocean and surrounding seas. Given the large inputs of river water to the relatively small Arctic Ocean, and the dramatic impacts that climate change is having in the Arctic, it is particularly urgent that we establish the contemporary river fluxes so that we will be able to detect future changes and evaluate the impact of the changes on the biogeochemistry of the receiving coastal and ocean systems.This work was supported by the National Science Foundation through grants OPP-0229302, OPP-0519840, OPP-0732522, and OPP-0732944. Additional support was provided by the U. S. Geological Survey (Yukon River) and the Department of Indian and Northern Affairs (Mackenzie River)

Chlamydia trachomatis Incidence and Re-Infection among Young Women – Behavioural and Microbiological Characteristics

This study aimed to estimate rates of chlamydia incidence and re-infection and to investigate the dynamics of chlamydia organism load in prevalent, incident and re-infections among young Australian women.1,116 women aged 16 to 25 years were recruited from primary care clinics in Australia. Vaginal swabs were collected at 3 to 6 month intervals for chlamydia testing. Chlamydia organism load was measured by quantitative PCR.There were 47 incident cases of chlamydia diagnosed and 1,056.34 person years of follow up with a rate of 4.4 per 100 person years (95% CI: 3.3, 5.9). Incident infection was associated with being aged 16 to 20 years [RR = 3.7 (95%CI: 1.9, 7.1)], being employed [RR = 2.4 (95%CI: 1.1, 4.9)] and having two or more new sex partners [RR = 5.5 (95%CI: 2.6, 11.7)]. Recent antibiotic use was associated with a reduced incidence [RR:0.1 (95%CI: 0.0, 0.5)]. There were 14 re-infections with a rate of 22.3 per 100 person years (95%CI: 13.2, 37.6). The median time to re-infection was 4.6 months. Organism load was higher for prevalent than incident infections (p<0.01) and for prevalent than re-infections (p<0.01).Chlamydia is common among young women and a high proportion of women are re-infected within a short period of time, highlighting the need for effective partner treatment and repeat testing. The difference in organism load between prevalent and incident infections suggests prevalent infection may be more important for ongoing transmission of chlamydia

A Tale of Four “Carp”: Invasion Potential and Ecological Niche Modeling

. We assessed the geographic potential of four Eurasian cyprinid fishes (common carp, tench, grass carp, black carp) as invaders in North America via ecological niche modeling (ENM). These “carp” represent four stages of invasion of the continent (a long-established invader with a wide distribution, a long-established invader with a limited distribution, a spreading invader whose distribution is expanding, and a newly introduced potential invader that is not yet established), and as such illustrate the progressive reduction of distributional disequilibrium over the history of species' invasions.We used ENM to estimate the potential distributional area for each species in North America using models based on native range distribution data. Environmental data layers for native and introduced ranges were imported from state, national, and international climate and environmental databases. Models were evaluated using independent validation data on native and invaded areas. We calculated omission error for the independent validation data for each species: all native range tests were highly successful (all omission values <7%); invaded-range predictions were predictive for common and grass carp (omission values 8.8 and 19.8%, respectively). Model omission was high for introduced tench populations (54.7%), but the model correctly identified some areas where the species has been successful; distributional predictions for black carp show that large portions of eastern North America are at risk.ENMs predicted potential ranges of carp species accurately even in regions where the species have not been present until recently. ENM can forecast species' potential geographic ranges with reasonable precision and within the short screening time required by proposed U.S. invasive species legislation

Inter-assessor reliability of practice based biomechanical assessment of the foot and ankle

Background There is no consensus on which protocols should be used to assess foot and lower limb biomechanics in clinical practice. The reliability of many assessments has been questioned by previous research. The aim of this investigation was to (i) identify (through consensus) what biomechanical examinations are used in clinical practice and (ii) evaluate the inter-assessor reliability of some of these examinations. Methods Part1: Using a modified Delphi technique 12 podiatrists derived consensus on the biomechanical examinations used in clinical practice. Part 2: Eleven podiatrists assessed 6 participants using a subset of the assessment protocol derived in Part 1. Examinations were compared between assessors. Results Clinicians choose to estimate rather than quantitatively measure foot position and motion. Poor inter-assessor reliability was recorded for all examinations. Intra-class correlation coefficient values (ICC) for relaxed calcaneal stance position were less than 0.23 and were less than 0.14 for neutral calcaneal stance position. For the examination of ankle joint dorsiflexion, ICC values suggest moderate reliability (less than 0.61). The results of a random effects ANOVA highlight that participant (up to 5.7°), assessor (up to 5.8°) and random (upto 5.7°) error all contribute to the total error (up to 9.5° for relaxed calcaneal stance position, up to 10.7° for the examination of ankle joint dorsiflexion). Kappa Fleiss values for categorisation of first ray position and mobility were less than 0.05 and for limb length assessment less than 0.02, indicating slight agreement. Conclusion Static biomechanical assessment of the foot, leg and lower limb is an important protocol in clinical practice, but the key examinations used to make inferences about dynamic foot function and to determine orthotic prescription are unreliable