Technological Breakthroughs, Energy, and Efficiency at the Beginning of the First Industrial Revolution: Spillovers from the Modernization of Science

The take-off of the First Industrial Revolution in England around the mid-eighteenth century, which shifted manufacturing to the factory system, was due to the emergence of the new entrepreneurial class with highly skilled and culturally informed technicians who fully assimilated the values of capitalism and transferred them to their fundamental innovations. One could apply the Gramscian concept of “hegemony” to describe the spread of new literary and philosophical societies in which entrepreneurs, technicians, and intellectuals met to discuss solutions to newly emerging problems. Inventions that increased labor productivity flourished, and in the field of energy production, where water wheels and steam engines already existed, decisive advances were to streamline their use in capitalist production, which prevented future developments because science was still tied to old approaches. The contributions of John Smeaton to the development of water wheels, and of James Watt to the steam engine are analyzed here in detail, emphasizing how both led to the completion of Newtonian mechanics and the birth of thermodynamic science. The concept of efficiency that inspired their research was destined to inform all of modernity.In those same years in France, the regime of absolutism prevented the nascent bourgeoise from establishing their hegemony. Through the Enlightenment movement, they sublimated their planning by studying and systematizing the achievements of British “practical mechanics” in a rational sense. In particular, Lazare Carnot, trained in the school of military genius, generalized the criteria that Smeaton had established for water wheels to all mechanical machines, introducing the first formalizations of energy concepts. Lazare’s son, Sadi Carnot, inspired by the same criteria, formulated the first theory of “fire machines” in 1824, opening up the modern field of thermodynamics, which introjected from its inception the criterion of efficiency

Scientific Developments Connected with the Second Industrial Revolution: A. Baracca, S. Ruffo, and A. Russo, Scienza e Industria 1848–1915, 41 years later

The pioneering work, Scienza e Industria 1848–1915: Gli sviluppi scientifici connessi alla seconda rivoluzione industriale (Science and Industry 1848–1915: Scientific developments related to the second industrial revolution) by Angelo Baracca, Stefano Ruffo, and Arturo Russo is reproduced in this preprint. Published in Italian by Laterza in 1979, it is an unjustly forgotten treasure of a highly fertile and innovative period of the history of science. The introduction to the preprint describes the historical circumstances in which this book and the approach it proposes emerged. It covers a wide range of subjects, from the different ways in which the Second Industrial Revolution unfolded in Great Britain and in continental Europe to the upheaval in modern science, in particular in chemistry in the latter half of the nineteenth century and in physics at the beginning of the twentieth century. Although each of these themes has meanwhile become the subject of detailed historical investigations, the survey and overall picture that Scienza e Industria provides is still intriguing: it connects the new knowledge economy of the Second Industrial Revolution with the conceptual revolutions in modern physics by pointing to the mediatory role of chemistry

The Mixed Vector Current Correlator <0|T(V^3_\mu V^8_\nu )|0> To Two Loops in Chiral Perturbation Theory

The isospin-breaking correlator of the product of flavor octet vector currents, $V^3_\mu$ and $V^8_\nu$, $\Pi^{38}_{\mu\nu}(q^2)$ is computed to next-to-next- to-leading (two-loop) order in Chiral Perturbation Theory. Large corrections to both the magnitude and $q^2$-dependence of the one-loop result are found, and the reasons for the slow convergence of the chiral series for the correlator given. The two-loop expression involves a single ${\cal O}(q^6)$ counterterm, present also in the two-loop expressions for $\Pi^{33}_{\mu\nu}(q^2)$ and $\Pi^{88}_{\mu\nu}(q^2)$, which counterterm contributes a constant to the scalar correlator $\Pi^{38}(q^2)$. The feasibility of extracting the value of this counterterm from other sources is discussed. Analysis of the slope of the correlator with respect to $q^2$ using QCD sum rules is shown to suggest that, even to two-loop order, the chiral series for the correlator may not yet be well-converged.Comment: 32 pages, uses REVTEX and epsfig.sty with 7 uuencoded figures. Entire manuscript available as a ps file at http://www.physics.adelaide.edu.au/theory/home.html Also available via anonymous ftp at ftp://adelphi.adelaide.edu.au/pub/theory/ADP-95-27.T181.p

Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities.

The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) > 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.We thank T. Jacks (Kras^LSL-G12D), A. Berns (p53^Fx) and the NIH Mouse repository for mice. We also thank Sam Kleeman and Patricia Ogger for assistance with redox cell profiling and cell viability assays, respectively. We are very thankful to CRUK CI BRU staff for support with in vivo work and all the members of the Martins lab for critical comments and advice. This work was supported by the Medical Research Council.This is the author accepted manuscript. The final version is available at http://www.nature.com/nature/journal/v531/n7592/full/nature16967.html

The Pro-Oncogenic Protein IF1 Promotes Proliferation of Anoxic Cancer Cells during Re-Oxygenation

Cancer cells overexpress IF1, the endogenous protein that inhibits the hydrolytic activity of ATP synthase when mitochondrial membrane potential (Delta mu(+)(H)) falls, as in ischemia. Other roles have been ascribed to IF1, but the associated molecular mechanisms are still under debate. We investigated the ability of IF1 to promote survival and proliferation in osteosarcoma and colon carcinoma cells exposed to conditions mimicking ischemia and reperfusion, as occurs in vivo, particularly in solid tumors. IF1-silenced and parental cells were exposed to the FCCP uncoupler to collapse Delta mu(+)(H) and the bioenergetics of cell models were validated. All the uncoupled cells preserved mitochondrial mass, but the implemented mechanisms differed in IF1-expressing and IF1-silenced cells. Indeed, the membrane potential collapse and the energy charge preservation allowed an increase in both mitophagy and mitochondrial biogenesis in IF1-expressing cells only. Interestingly, the presence of IF1 also conferred a proliferative advantage to cells highly dependent on oxidative phosphorylation when the uncoupler was washed out, mimicking cell re-oxygenation. Overall, our results indicate that IF1, by allowing energy preservation and promoting mitochondrial renewal, can favor proliferation of anoxic cells and tumor growth. Therefore, hindering the action of IF1 may be promising for the therapy of tumors that rely on oxidative phosphorylation for energy production

Pilomatricoma: Clinical, Dermoscopic Findings and Management in 55 Pediatric Patients and Concise Review of the Literature with Special Emphasis on Dermoscopy

Introduction: Pilomatricoma is a benign adnexal dermal or subcutaneous tumor derived from immature hair matrix cells. Objectives: The aim of our study is to evaluate clinical and dermoscopic features of pilomatricomas, with a specific focus on pediatric lesions, and to provide a concise review of the existing literature. Methods: A single-center retrospective study was undertaken on 55 patients with a histopathological diagnosis of pilomatricoma referred to the Dermatology Unit, University of Bologna, Bologna, Italy, between 2005 and 2023. Pilomatricomas were retrospectively evaluated relying on clinical and dermoscopic images. A PubMed search was conducted. All the relevant research up to July 31, 2023, was reviewed. We classified the cases as "typical" or "atypical" based on whether they were suspected of being pilomatricomas or not. Results: A total of 55 children with pilomatricomas were observed and studied. Two patients presented with 2 pilomatricomas, leading to the identification of 58 pilomatricomas. 'Typical' pilomatricomas were observed in 79% of cases as nodular and pigmented lesions with one or more colors, ranging from blue-gray to red to yellow/white, evident on clinical examination and even better on dermoscopy. In 21% of cases, pilomatricomas presented in an 'atypical' form, which did not allow for a well-founded suspicion, placing them in differential diagnosis with other lesions and therefore requiring histological examination. Conclusions: According to our case series and systematic review of the literature, clinical appearance and dermoscopy may be sufficient to diagnose or suspect pilomatricoma in around 80% of cases, while histological examination is necessary to confirm the diagnosis in the remaining 20% of cases

Efficient mitochondrial biogenesis drives incomplete penetrance in Leber's hereditary optic neuropathy

Leber's hereditary optic neuropathy is a maternally inherited blinding disease caused as a result of homoplasmic point mutations in complex I subunit genes of mitochondrial DNA. It is characterized by incomplete penetrance, as only some mutation carriers become affected. Thus, the mitochondrial DNA mutation is necessary but not sufficient to cause optic neuropathy. Environmental triggers and genetic modifying factors have been considered to explain its variable penetrance. We measured the mitochondrial DNA copy number and mitochondrial mass indicators in blood cells from affected and carrier individuals, screening three large pedigrees and 39 independently collected smaller families with Leber's hereditary optic neuropathy, as well as muscle biopsies and cells isolated by laser capturing from post-mortem specimens of retina and optic nerves, the latter being the disease targets. We show that unaffected mutation carriers have a significantly higher mitochondrial DNA copy number and mitochondrial mass compared with their affected relatives and control individuals. Comparative studies of fibroblasts from affected, carriers and controls, under different paradigms of metabolic demand, show that carriers display the highest capacity for activating mitochondrial biogenesis. Therefore we postulate that the increased mitochondrial biogenesis in carriers may overcome some of the pathogenic effect of mitochondrial DNA mutations. Screening of a few selected genetic variants in candidate genes involved in mitochondrial biogenesis failed to reveal any significant association. Our study provides a valuable mechanism to explain variability of penetrance in Leber's hereditary optic neuropathy and clues for high throughput genetic screening to identify the nuclear modifying gene(s), opening an avenue to develop predictive genetic tests on disease risk and therapeutic strategies.TelethonAssociazione Serena Talarico per i giovani nel mondo and Fondazione Giuseppe Tomasello O.N.L.U.S.Mitocon OnlusResearch to Prevent BlindnessInternational Foundation for Optic Nerve Diseases (IFOND)Struggling Within Leber'sPoincenot FamilyEierman FoundationNational Eye InstituteUniv Rome, Dept Radiol Oncol & Pathol, Rome, ItalyUniv Bologna, Dept Biomed & NeuroMotor Sci DIBINEM, Bologna, ItalyUniv Bari, Dept Biosci Biotechnol & Biopharmaceut, Bari, ItalyBellaria Hosp, IRCCS Ist Sci Neurol Bologna, I-40139 Bologna, ItalyUSC, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA USAUSC, Keck Sch Med, Dept Neurosurg, Los Angeles, CA USAUniv Trieste, Dept Reprod Sci Dev & Publ Hlth, Trieste, ItalyUniv Trieste, IRCCS Burlo Garofolo Children Hosp, Trieste, ItalyNewcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, EnglandFdn Ist Neurol Carlo Besta IRCCS, Unit Mol Neurogenet, Milan, ItalyMRC Mitochondrial Biol Unit, Cambridge, EnglandFed Univ São Paulo UNIFESP, Dept Ophthalmol, São Paulo, BrazilUniv São Paulo, Inst Psychol, Dept Expt Psychol, São Paulo, BrazilStudio Oculist dAzeglio, Bologna, ItalyOsped San Giovanni Evangelista, Tivoli, ItalyAzienda Osped San Camillo Forlanini, Rome, ItalyUniv Rome, Dipartimento Metodi & Modelli Econ Finanza & Terr, Rome, ItalyUniv Rome, Dept Mol Med, Rome, ItalyFed Univ São Paulo UNIFESP, Dept Ophthalmol, São Paulo, BrazilTelethon: GGP06233Telethon: GGP11182Telethon: GPP10005National Eye Institute: EY03040Web of Scienc

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

Background/Aims: Dietary polyphenols from green tea have been shown to possess cardio-protective activities in different experimental models of heart diseases and age-related ventricular dysfunction. The present study was aimed at evaluating whether long term in vivo administration of green tea extracts (GTE), can exert positive effects on the normal heart, with focus on the underlying mechanisms. Methods: The study population consisted of 20 male adult Wistar rats. Ten animals were given 40 mL/day tap water solution of GTE (concentration 0.3%) for 4 weeks (GTE group). The same volume of water was administered to the 10 remaining control rats (CTRL). Then, in vivo and ex vivo measurements of cardiac function were performed in the same animal, at the organ (hemodynamics) and cellular (cardiomyocyte mechanical properties and intracellular calcium dynamics) levels. On cardiomyocytes and myocardial tissue samples collected from the same in vivo studied animals, we evaluated: (1) the intracellular content of ATP, (2) the endogenous mitochondrial respiration, (3) the expression levels of the Sarcoplasmic Reticulum Ca2+-dependent ATPase 2a (SERCA2), the Phospholamban (PLB) and the phosphorylated form of PLB, the L-type Ca2+ channel, the Na+-Ca2+ exchanger, and the ryanodine receptor 2. Results: GTE cardiomyocytes exhibited a hyperdynamic contractility compared with CTRL (the rate of shortening and re-lengthening, the fraction of shortening, the amplitude of calcium transient, and the rate of cytosolic calcium removal were significantly increased). A faster isovolumic relaxation was also observed at the organ level. Consistent with functional data, we measured a significant increase in the intracellular ATP content supported by enhanced endogenous mitochondrial respiration in GTE cardiomyocytes, as well as higher values of the ratios phosphorylated-PLB/PLB and SERCA2/PLB. Conclusions: Long-term in vivo administration of GTE improves cell mechanical properties and intracellular calcium dynamics in normal cardiomyocytes, by increasing energy availability and removing the inhibitory effect of PLB on SERCA2