Philosophy and Science in Leibniz

This paper explores the question of Leibniz’s contribution to the rise of modern ‘science’. To be sure, it is now generally agreed that the modern category of ‘science’ did not exist in the early modern period. At the same time, this period witnessed a very important stage in the process from which modern science eventually emerged. My discussion will be aimed at uncovering the new enterprise, and the new distinctions which were taking shape in the early modern period under the banner of the old Aristotelian terminology. I will argue that Leibniz begins to theorize a distinction between physics and metaphysics that tracks our distinction between the autonomous enterprise of science in its modern meaning, and the enterprise of philosophy. I will try to show that, for Leibniz, physics proper is the study of natural phenomena in mathematical and mechanical terms without recourse for its explanations to metaphysical notions. This autonomy, however, does not imply for Leibniz that physics can say on its own all that there is to be said about the natural world. Quite the opposite. Leibniz inherits from the Aristotelian tradition the view that physics needs metaphysical roots or a metaphysical grounding. For Leibniz, what is ultimately real is reached by metaphysics, not by physics. This is, in my view, Leibniz’s chief insight: the new mathematical physics is an autonomous enterprise which offers its own kind of explanations but does not exhaust what can (and should) be said about the natural world

Primates in peril: the significance of Brazil, Madagascar, Indonesia and the Democratic Republic of the Congo for global primate conservation

Primates occur in 90 countries, but four—Brazil, Madagascar, Indonesia, and the Democratic Republic of the Congo (DRC)—harbor 65% of the world’s primate species (439) and 60% of these primates are Vulnerable, Endangered, or Critically Endangered (IUCN Red List of Threatened Species 2017-3). Considering their importance for global primate conservation, we examine the anthropogenic pressures each country is facing that place their primate populations at risk. Habitat loss and fragmentation are main threats to primates in Brazil, Madagascar and Indonesia. However, in DRC hunting for the commercial bushmeat trade is the primary threat. Encroachment on primate habitats driven by local and global market demands for food and non-food commodities hunting, illegal trade, the proliferation of invasive species, and human and domestic-animal borne infectious diseases cause habitat loss, population declines, and extirpation. Modeling agricultural expansion in the 21st century for the four countries under a worst-case-scenario, showed a primate range contraction of 78% for Brazil, 72% for Indonesia 62% for Madagascar and 32% for DRC. These pressures unfold in the context of expanding human populations with low levels of development. Weak governance across these four countries may limit effective primate conservation planning. We examine landscape and local approaches to effective primate conservation policies and assess the distribution of protected areas and primates in each country. P rimates in Brazil and Madagascar have 38% of their range inside protected areas, 17% in Indonesia and 14% in DRC, suggesting that the great majority of primate populations remain vulnerable. We list the key challenges faced by the four countries to avert primate extinctions now and in the future. In the short term, effective law enforcement to stop illegal hunting and illegal forest destruction is absolutely key. Long-term success can only be achieved by focusing local and global public awareness, actively engaging with international organizations, multinational businesses and consumer nations to reduce unsustainable demands on the environment. Finally, the four primate range states need to ensure that integrated, sustainable land-use planning for economic development includes the maintenance of biodiversity and intact, functional natural ecosystems

A Single-Stranded DNA Aptamer That Selectively Binds to Staphylococcus aureus Enterotoxin B

The bacterium Staphylococcus aureus is a common foodborne pathogen capable of secreting a cocktail of small, stable, and strain-specific, staphylococcal enterotoxins (SEs). Staphylococcal food poisoning (SFP) results when improperly handled food contaminated with SEs is consumed. Gastrointestinal symptoms of SFP include emesis, diarrhea and severe abdominal pain, which manifest within hours of ingesting contaminated food. Immuno-affinity based methods directly detect, identify, and quantify several SEs within a food or clinical sample. However, the success of these assays depends upon the availability of a monoclonal antibody, the development of which is non-trivial and costly. The current scope of the available immuno-affinity based methods is limited to the classical SEs and does not encompass all of the known or emergent SEs. In contrast to antibodies, aptamers are short nucleic acids that exhibit high affinity and specificity for their targets without the high-costs and ethical concerns of animal husbandry. Further, researchers may choose to freely distribute aptamers and develop assays without the proprietary issues that increase the per-sample cost of immuno-affinity assays. This study describes a novel aptamer, selected in vitro, with affinity to staphylococcal enterotoxin B (SEB) that may be used in lieu of antibodies in SE detection assays. The aptamer, designated APTSEB1, successfully isolates SEB from a complex mixture of SEs with extremely high discrimination. This work sets the foundation for future aptamer and assay development towards the entire family of SEs. The rapid, robust, and low-cost identification and quantification of all of the SEs in S. aureus contaminated food is essential for food safety and epidemiological efforts. An in vitro generated library of SE aptamers could potentially allow for the comprehensive and cost-effective analysis of food samples that immuno-affinity assays currently cannot provide

Supervised exercise training as an adjunctive therapy for venous leg ulcers: study protocol for a randomised controlled trial

Background: Venous leg ulcers are common, chronic wounds that are painful and reduce quality of life. Compression therapy is known to assist in the healing of venous leg ulceration. Supervised exercise training that targets an improvement in calf muscle pump function might be a useful adjunctive therapy for enhancing ulcer healing and other aspects of physical and mental health. However, the evidence of exercise for individuals with venous ulcers is sparse. Here, we describe the protocol for a study that aims to assess the feasibility of undertaking a randomised controlled trial of a supervised exercise programme in people who are receiving compression for venous ulceration. Methods/Design: This is a randomised, controlled, assessor-blinded, two-centre, feasibility trial with two parallel groups. Eighty adults who are receiving lower-limb compression for a venous leg ulcer will be randomly assigned to receive usual care (compression only) or usual care plus a 12-week supervised exercise programme. Participants in the exercise group will be invited to undertake three, 60-minute sessions of supervised exercise each week, and each session will involve a combination of treadmill walking, upright cycling and strength and flexibility exercises for the lower limbs. Participants will be assessed before randomisation and 3, 6 and 12 months after randomisation. Primary outcomes include rates of recruitment, retention and adherence. Secondary outcomes include time to ulcer healing, proportion of participants healed, percentage and absolute change in ulcer size, health-related quality of life (EQ-5D-5L and VEINES-QOL/Sym), lower-limb cutaneous microvascular function (laser Doppler flowmetry coupled with iontophoresis) and physical fitness (30-second sit-to-stand test, chair sit and reach test, 6-minute walk test and ankle range of motion). The costs associated with the exercise programme and health-care utilisation will be calculated. We will also complete interviews with a sub-sample of participants to explore their experiences of having a venous ulcer and the acceptability of the exercise intervention and study procedures. Discussion: Data from this study will be used to refine the supervised exercise programme, investigate the acceptability of the intervention and study design and determine the most appropriate outcome measures, thereby providing estimates of the factors needed to design an adequately powered trial across several centres

High Cooperativity of the SV40 Major Capsid Protein VP1 in Virus Assembly

SV40 is a small, non enveloped DNA virus with an icosahedral capsid of 45 nm. The outer shell is composed of pentamers of the major capsid protein, VP1, linked via their flexible carboxy-terminal arms. Its morphogenesis occurs by assembly of capsomers around the viral minichromosome. However the steps leading to the formation of mature virus are poorly understood. Intermediates of the assembly reaction could not be isolated from cells infected with wt SV40. Here we have used recombinant VP1 produced in insect cells for in vitro assembly studies around supercoiled heterologous plasmid DNA carrying a reporter gene. This strategy yields infective nanoparticles, affording a simple quantitative transduction assay. We show that VP1 assembles under physiological conditions into uniform nanoparticles of the same shape, size and CsCl density as the wild type virus. The stoichiometry is one DNA molecule per capsid. VP1 deleted in the C-arm, which is unable to assemble but can bind DNA, was inactive indicating genuine assembly rather than non-specific DNA-binding. The reaction requires host enzymatic activities, consistent with the participation of chaperones, as recently shown. Our results demonstrate dramatic cooperativity of VP1, with a Hill coefficient of ∼6. These findings suggest that assembly may be a concerted reaction. We propose that concerted assembly is facilitated by simultaneous binding of multiple capsomers to a single DNA molecule, as we have recently reported, thus increasing their local concentration. Emerging principles of SV40 assembly may help understanding assembly of other complex systems. In addition, the SV40-based nanoparticles described here are potential gene therapy vectors that combine efficient gene delivery with safety and flexibility

A Two-Stage Model for Lipid Modulation of the Activity of Integral Membrane Proteins

Lipid-protein interactions play an essential role in the regulation of biological function of integral membrane proteins; however, the underlying molecular mechanisms are not fully understood. Here we explore the modulation by phospholipids of the enzymatic activity of the plasma membrane calcium pump reconstituted in detergent-phospholipid mixed micelles of variable composition. The presence of increasing quantities of phospholipids in the micelles produced a cooperative increase in the ATPase activity of the enzyme. This activation effect was reversible and depended on the phospholipid/detergent ratio and not on the total lipid concentration. Enzyme activation was accompanied by a small structural change at the transmembrane domain reported by 1-aniline-8-naphtalenesulfonate fluorescence. In addition, the composition of the amphipilic environment sensed by the protein was evaluated by measuring the relative affinity of the assayed phospholipid for the transmembrane surface of the protein. The obtained results allow us to postulate a two-stage mechanistic model explaining the modulation of protein activity based on the exchange among non-structural amphiphiles at the hydrophobic transmembrane surface, and a lipid-induced conformational change. The model allowed to obtain a cooperativity coefficient reporting on the efficiency of the transduction step between lipid adsorption and catalytic site activation. This model can be easily applied to other phospholipid/detergent mixtures as well to other membrane proteins. The systematic quantitative evaluation of these systems could contribute to gain insight into the structure-activity relationships between proteins and lipids in biological membranes

Ricin Toxicokinetics and Its Sensitive Detection in Mouse Sera or Feces Using Immuno-PCR

Ricin (also called RCA-II or RCA(60)), one of the most potent toxins and documented bioweapons, is derived from castor beans of Ricinus communis. Several in vitro methods have been designed for ricin detection in complex food matrices in the event of intentional contamination. Recently, a novel Immuno-PCR (IPCR) assay was developed with a limit of detection of 10 fg/ml in a buffer matrix and about 10-1000-fold greater sensitivity than other methods in various food matrices.In order to devise a better diagnostic test for ricin, the IPCR assay was adapted for the detection of ricin in biological samples collected from mice after intoxication. The limit of detection in both mouse sera and feces was as low as 1 pg/ml. Using the mouse intravenous (iv) model for ricin intoxication, a biphasic half-life of ricin, with a rapid t(1/2)α of 4 min and a slower t(1/2)β of 86 min were observed. The molecular biodistribution time for ricin following oral ingestion was estimated using an antibody neutralization assay. Ricin was detected in the blood stream starting at approximately 6-7 h post- oral intoxication. Whole animal histopathological analysis was performed on mice treated orally or systemically with ricin. Severe lesions were observed in the pancreas, spleen and intestinal mesenteric lymph nodes, but no severe pathology in other major organs was observed.The determination of in vivo toxicokinetics and pathological effects of ricin following systemic and oral intoxication provide a better understanding of the etiology of intoxication and will help in the future design of more effective diagnostic and therapeutic methods

Towards the minimal amount of exercise for improving metabolic health: beneficial effects of reduced-exertion high-intensity interval training

High-intensity interval training (HIT) has been proposed as a time-efficient alternative to traditional cardiorespiratory exercise training, but is very fatiguing. In this study, we investigated the effects of a reduced-exertion HIT (REHIT) exercise intervention on insulin sensitivity and aerobic capacity. Twenty-nine healthy but sedentary young men and women were randomly assigned to the REHIT intervention (men, n = 7; women, n = 8) or a control group (men, n = 6; women, n = 8). Subjects assigned to the control groups maintained their normal sedentary lifestyle, whilst subjects in the training groups completed three exercise sessions per week for 6 weeks. The 10-min exercise sessions consisted of low-intensity cycling (60 W) and one (first session) or two (all other sessions) brief ‘all-out’ sprints (10 s in week 1, 15 s in weeks 2–3 and 20 s in the final 3 weeks). Aerobic capacity ( V˙O2peakV˙O2peak ) and the glucose and insulin response to a 75-g glucose load (OGTT) were determined before and 3 days after the exercise program. Despite relatively low ratings of perceived exertion (RPE 13 ± 1), insulin sensitivity significantly increased by 28% in the male training group following the REHIT intervention (P < 0.05). V˙O2peakV˙O2peak increased in the male training (+15%) and female training (+12%) groups (P < 0.01). In conclusion we show that a novel, feasible exercise intervention can improve metabolic health and aerobic capacity. REHIT may offer a genuinely time-efficient alternative to HIT and conventional cardiorespiratory exercise training for improving risk factors of T2D

Transcriptomic landscape of breast cancers through mRNA sequencing

Breast cancer is a heterogeneous disease with a poorly defined genetic landscape, which poses a major challenge in diagnosis and treatment. By massively parallel mRNA sequencing, we obtained 1.2 billion reads from 17 individual human tissues belonging to TNBC, Non-TNBC, and HER2-positive breast cancers and defined their comprehensive digital transcriptome for the first time. Surprisingly, we identified a high number of novel and unannotated transcripts, revealing the global breast cancer transcriptomic adaptations. Comparative transcriptomic analyses elucidated differentially expressed transcripts between the three breast cancer groups, identifying several new modulators of breast cancer. Our study also identified common transcriptional regulatory elements, such as highly abundant primary transcripts, including osteonectin, RACK1, calnexin, calreticulin, FTL, and B2M, and “genomic hotspots” enriched in primary transcripts between the three groups. Thus, our study opens previously unexplored niches that could enable a better understanding of the disease and the development of potential intervention strategies