Recently I read that scientists have compared the vibrational frequency of a chemical bond of methane in a distant galaxy with that of methane here on Earth, and they now know that in the past 7 billion years, a particular nuclear force has remained unchanged to within at least 1 part in 10 billion. That experimental result failed to ease my mind regarding the world’s stability, but it does illustrate the deep understanding we now have of our universe. Einstein’s theory—surely one of humanity’s grandest intellectual achievements—did open up new vistas that revealed the origin and evolution of our universe.Just over 100 years ago, Albert Einstein published his general theory of relativity—10 years after his annus mirabilis when he, arguably, laid the foundations of quantum physics. In its broadest terms, the theory established the intimate connection between space, time, and matter. That inseparable relationship had no practical consequences under normal conditions, and Newton’s well-established laws of motion needed to be modified only under very extreme ones—say, at speeds approaching the speed of light. So Einstein was astonished by the enormous fuss four years later, when an astronomical observation—the deflection of light by the Sun’s gravity—confirmed his theory.Einstein maintained that unlike Copernicus’s theory, which demoted our planet from its central role in the solar system, his theory did not affect anyone’s philosophy or worldview. Indeed, in 1915, when his eight-page paper “On the general theory of relativity” appeared in the Proceedings of the Royal Prussian Academy of Sciences, few people paid attention to it, and among physicists, there were more than a few skeptics.Surprisingly for that time, Einstein presented his new theory to the general public even before it was quite finished, first in a newspaper article and soon after that in a popular lecture in Berlin’s Treptow Observatory in June 1915. In fact, he gave nonspecialist lectures on relativity on many other occasions and also wrote a hugely successful book about it. Explaining your work to lay audiences is an excellent way to clarify your own ideas, but Einstein also saw it as a scientist’s responsibility to society.11. J. Eisinger, Einstein at Home, Prometheus Books (2016); Einstein on the Road, Prometheus Books (2011). That paper was one of seven articles he published in 1915. Another was entitled “My opinion on the war,” in which he defended his pacifist position even as nationalistic fervor swept Germany. That Einstein was able to complete his theory under the prevailing circumstances is evidence of his extraordinary power of concentration.World War I was in its second year, Berlin was experiencing a severe food shortage, and Einstein’s personal life was in a shambles. His marriage to Mileva Marić had broken up the year before, and she had returned to Zürich with their two sons. Since then Einstein had been engaged in a bitter exchange of letters with her, even while he anxiously tried to retain a close relationship with his sons, who were 5 and 11 at the time. He had moved to an apartment not far from that of his cousin and good friend Elsa Löwenthal. A divorce agreement with Mileva became official in February 1919, and he married Elsa in June.In November of that year, at a well-publicized meeting of the Royal Society in London, Arthur Eddington announced that his astronomical expeditions had measured the deflection of starlight by the Sun’s gravitational field and that the result confirmed the general theory of relativity. Einstein became a worldwide celebrity overnight, and his life was changed irrevocably.REFERENCESSection:ChooseTop of pageREFERENCES <<1. J. Eisinger, Einstein at Home, Prometheus Books (2016); Google ScholarEinstein on the Road, Prometheus Books (2011). Google Scholar© 2016 American Institute of Physics.

Introduction During the past several years, numerous reports have appeared in the popular media claiming that Beethoven suffered from lead disease. That claim was based on the analysis of hairs from Beethoven's head, hairs that several of his admirers had collected as mementos of the great man shortly after his death. In at least one instance is the provenance of such hairs is well established and documented.1 The initial repon stated that Beethoven's hair contained high levels of lead, but scant quantitative information was provided at that time or subsequendy; nor have the results of these hair analyses appeared in the professional literature to date.2 The colossal publicity that Beethoven's purported lead-poisoning received in the press and other media seems out of proportion to the sparse evidence on which these reports were based, evidence which, until recently, has received little scrutiny.3 Last year Dr. Christian Reiter reported the results of a different type of analysis of Beethoven's hair and his study has renewed speculation, not only regarding Beethoven's lead disease, but also regarding the cause of his death.4 Dr. Reiter did not determine the lead content of Beethoven's hair, as had been attempted earlier but measured the distribution of lead (Pb) along an individual hair. He interpreted this longitudinal Pb concentration profile as a temporal record of lead exposure during the last three months of Beethoven's life. Dr. Reiter relates the dates of five peaks of the Pb profile to the dates of five medical interventions that might have exposed Beethoven to lead and concludes that Dr. Andreas Wawruch, his physician, had inadvertently lead-poisoned him and was responsible for his death. Before reviewing Dr. Reiters experiment and analysis, some general comments regarding the use of hair as an indicator of lead exposure are in order. Ever since the dangers of ingesting lead became widely recognized, physicians and public health authorities have searched for reliable diagnostic indicaron (biomarkers) of the severity of a person's lead exposure. Today the most widely used indicator is the level of lead in blood (blood-Pb), although others are also used, including the levels of metabolites induced by lead exposure and the level of lead stored in bone (bone-Pb), which can be measured non-invasiveh/.5 At first sight, the lead content of hair (hair-Pb) might represent a more convenient, less intrusive, and cheaper alternative to these methods, and consequently many investigatore have studied and tested die effectiveness of hair-Pb as a biomarker.6 Most recently, a panel of experts, convened by the U.S. Center for Disease Control examined the reliability of this approach and concluded that hair-Pb is an ineffective biomarker.7 Among the reasons given were the great variability among hair specimens from the same head, the inconsistency of assays performed by different laboratories, and the impossibility of distinguishing between endogenous and externally adherent lead.8 Hair-Pb was consequently not recommended as an indicator and there exist no established protocols that relate hair-Pb levels to blood-Pb levels or to other indicators, or indeed, the symptoms of lead disease. Dr. Reiter's Experiment and Data Analysis In this section I will briefly describe the novel experimental method used by Dr. Reiter to obtain the Pb profile of an individual hair, before examining critically the assumptions underlying his data analysis and conclusion. Dr. Reiter obtained several hairs from Dr. Alfredo Guevara, Nogales, Arizona, who owns a portion of a well-authenticated lock of Beethoven's hair. A narrow laser beam at right angles to a 4 cm. long hair was used to vaporize the hair along its length, and the lead concentration in the resultant vapor was determined by means of a mass spectrometer. The data allowed Dr. Reiter to obtain the Pb concentration profile of the hair along its length. …

In the past several years a number of inadequately substantiated reports appeared in the popular media, asserting that lead (Pb) found in Beethoven's hair indicated that he was a victim of Pb poisoning and suggesting that lead played a role in his deafness and illnesses. This article reviews critically a recent report of the longitudinal distribution of Pb along individual hairs belonging to Beethoven by Dr Reiter 1 Reiter, C. Beethovens Todesursachen und seine Locken. Wiener Beethoven-Gesellschaft Mitteilungsblatt XXXVIII (Jan. 2007): 1–6, The German text is available at http://www.sjsu.edu/depts/beethoven/hair/Reiter.html. An English translation has recently appeared in the Beethoven Journal 22(1):2–5 [Google Scholar], who interprets the Pb concentration profile of an individual hair in terms of several hypothetical occurrences which might have exposed Beethoven to lead during the last few months of his life and concludes that the resulting Pb poisoning caused his death. This hypothesis is, however, in need of substantiation by additional data since it is at variance with the known kinetics of Pb in blood and because the Pb content of hair is recognized as a problematical and unreliable biomarker of lead absorption, in part, because it is not possible to exclude exogenous Pb contamination in the specimen. In view of Beethoven's extraordinarily well-documented medical history and autopsy report, briefly summarized here, and in the absence of persuasive evidence that Beethoven suffered from lead disease, it is concluded that lead did not contribute significantly to his deafness, illnesses, or death.

THE colica Pictonum or colic of Poitou, under these and many other names, was a frequent, widespread, and deadly disease from Roman times until the eighteenth century. Its unique pathognomonic, notably a severe colic succeeded by paralysis and other central nervous system dysfunction, makes it possible to identify the disease with certainty as chronic lead disease, usually caused by the ingestion of lead-adulterated wines. The custom of sweetening and preserving sour wines with lead-containing additives is traced to the Romans. They had made the empirical discovery that sapa, a syrup prepared by concentrating must in a lead vessel, kept wine from spoiling and that it had, moreover, an agreeable flavour. Reports of outbreaks of the colica Pictonum appear in the medical literature from Roman times, but the correct aetiology of the disease was not discovered until the seventeenth century following a series of outbreaks in Southern Germany which were related to unfavourable climatic and political conditions. The connexion between the disease and prevailing methods for "correcting" wines was drawn in 1696 by Eberhard Gockel, then the city physician of Ulm. This achievement can be traced to his familiarity with Samuel Stockhausen's work on plumbism among miners and potters, as well as to the favourable epidemiological situation presented by Gockel's monastic patients. From the literary evidence assembled here and from experimental determinations of the lead content of sapa and similar concentrates, it is possible to estimate the lead levels and toxicity of wines from various eras. The levels range up to 80 mg/l and make it apparent that many wines were sufficiently toxic to account for the incidence and severity of the colica Pictonum. Explanations for the disastrous persistence of the colic of Poitou are discussed, as are the similarities between Gockel's approach and the methods of modern environmental medicine.

Lipid analogues and glycosylphosphati-dylinositol (GPI)-anchored proteins incorporated in glass-supported phospholipid bilayers (SBL) were coupled to small (30 nm diameter) fluorescent beads whose motion in the liquid phase was tracked by intensified fluorescence video microscopy. Streptavidin (St), covalently attached to the carboxyl modified surface of the polystyrene bead, bound either the biotinylated membrane component, or a biotinylated monoclonal antibody (mAb) directed against a specific membrane constituent. The positions of the beads tethered to randomly diffusing membrane molecules were recorded at 0.2 sec intervals for about l min. The mean square displacement (ϱ) of the beads was found to be a linear function of diffusion time t, and the diffusion coefficient, D, was derived from the relation, ϱ(t) = 4Dt. The values of D for biotinylated phosphatidylethanolamine (Bi-PE) dispersed in an egg lecithin: cholesterol (80:20%) bilayer obtained by this methodology range from 0.05 to 0.6 μm2/sec with an average of 〈D〉 = 0.26 μm2/sec, similar to the value of 〈D〉 = 0.24 μm2/sec for fluorescein-conjugated phosphati-dylethanolamine (Fl-PE) linked to St-coupled beads by the anti-fluorescein mAb 4-4-20 or its Fab fragment. These values of D are comparable to those reported for Fl-PE linked to 30 nm gold particles but are several times lower than that of Fl-PE in the same planar bilayer as measured by fluorescence photobleaching recovery, D = 1.3 μm2sec. The mobilities of two GPI-anchored proteins in similar SBL were also determined by use of the appropriate biotinylated mAb and were found to be 〈D〉 = 0.25 and 0.56 μm2/sec for the decay accelerating factor (DAF, CD55) and the human FcγRIIIB (CD16) receptors, respectively. The methodology described here is suitable for tracking any accessible membrane component.

Using quantitative fluorescence microscopy of red cells loaded non-disruptively with 1-2.5 mmol/l cells of fura-2, we examined the distribution of the incorporated free chelator among and within individual cells. Cytoplasmic hemoglobin quenched the effective fluorescence yield of fura-2 by a factor of about 100. All red cells were found to fluoresce upon excitation at 380 nm, and the fluorescence intensities they emitted at 510 nm were approximately +/- 20% about the mean intensity, indicating a fairly uniform distribution of incorporated chelator among the cells. Red cells loaded with these high levels of fura-2 retained their biconcave shape, and a comparison between their transmission images at 415 nm and their fura-2 fluorescence images suggests that the concentration of fura-2 was also uniform throughout the cytosol. These results validate assumptions made in earlier experiments with non-fluorescent incorporated Ca2+ chelators, and demonstrate the feasibility of fura-2 and Ca2+ imaging of intact red cells, despite considerable quenching of probe fluorescence by hemoglobin.

The quantitation of the non-heme porphyrin content of circulating erythrocytes is an important tool in the screening, diagnosis, and management of lead disease, iron deficiency anemia, and certain porphyrias. Useful information about these pathological conditions may be obtained from the distribution of the non-heme porphyrin content of individual red blood cells. An image-based cytometry system was developed and used to determine the cellular distributions of zinc protoporphyrin (ZPP) in the erythrocytes of normal and lead-exposed human subjects. The fluorescence cytometry system described here lends itself to a wide range of statistical studies of cell populations, in which extrinsic fluorescent probes or antibodies may be used instead of porphyrin. Image-based cytometry appears to offer a number of important advantages over the more conventional flow cytometry systems, including greater sensitivity, applicability to a wider range of cellular parameters, and the ability to retain images of each cell used in the survey for subsequent examination. Pairs of absorption and fluorescence images of many fields of dispersed immobilized red cells were acquired by means of a program which controls the microscope stage, focussing, shutters, filter wheels, and a cooled, slow-scan CCD camera. The observed marked differences in the ZPP distributions of erythrocytes from donors with chronic and acute lead exposure are discussed in terms of the metabolism of internalized lead.

Erythrocytes of patients suffering from erythropoietic protoporphyria (EPP) contain high levels of unchelated protoporphyrin IX (PP) molecules when they enter circulation, and the leakage of PP that leaks from the circulating cells is responsible for the patients' cutaneous photosensitivity. The level of PP in EPP blood has long been used as an indicator of the severity of the disease and is useful in its management. The present study investigates what additional information may be obtained by determining the distribution of the PP content of individual EPP red cells. Absorption and fluorescence images of fields of the dispersed and immobilized red cells from nine patients with EPP were acquired under computer control by use of an inverted fluorescence microscope equipped with a cooled slow-scan charge-coupled device camera. The distribution functions of the fluorescence emitted by individual red blood cells (IRBC) were derived by a suitable image analysis program and were converted to the distributions of the cellular PP content by relating the average value of the distributions (Iav) to the PP level of packed cells, as determined by an extraction assay. The IRBC distributions show that a small percentage of the red cells is responsible for most of the PP fluorescence, and the distributions of IRBC/Iav for the nine patients with EPP were found to be very similar. This is consistent with the leakage rate during circulation being approximately proportional to the cells' PP content.

The effect of spatially varying diffusivity and solubility on the efficiency of intramembrane transport is investigated by obtaining solutions to the generalized lateral diffusion equation in which both the diffusion coefficient, D(r), and the partition coefficient, K(r), are functions of position. The mean-time-to-capture by a sink, tc, of particles diffusing in a plane is obtained analytically for the case of a sink surrounded by gradients in D(r) and K(r) with radially symmetrical geometry. It is shown that for particles originating at random locations, tc is shortened dramatically, if in an annular region around the sink, D and K are significantly greater than in the remainder of the plane. Similarly, a viscous boundary layer surrounding a sink is demonstrated to represent a significant barrier for diffusing particles. To investigate more complex geometries, a finite difference numerical integration method is used and is shown to provide comparable results for tc with modest computational power. The same method is used to calculate the tc for particles originating at a source that is joined to the sink by a channel. The increase in the rate with which particles travel from a source to a sink when they are joined by a high diffusivity and/or solubility channel is illustrated by several numerical examples and by graphical representations that show the equilibrium particle density (and hence the effective particle flow) in the presence of different sink, source, and channel combinations. These results are discussed in terms of fluidity domains and other membrane heterogeneities.

The practice of doctoring wines with lead additives in order to sweeten and preserve them was widespread in Europe from Roman times on and was responsible for numerous epidemics. However, it was not until the 17th century that it was recognised that a common and frequently fatal disease, known as the colic of Poitou and by many other names, was caused by the consumption of leaded wines. The correct aetiology of the disease was discovered by Eberhard Gockel, city physician of Ulm, which city was at the time the centre of the German wine trade. The local colic outbreaks of the 1690s and Gockel's findings had resulted in serious economic losses to Ulm, and in response to this crisis Duke Eberhard Ludwig of Württemberg issued, in 1693, a strict edict against adulterating wines with lead. This law, which is here presented in facsimile and translation, is an early example of consumer protection legislation. Apart from attempting to control the distribution of litharge (lead acetate), the edict requires that witnesses report offenders to the authorities on pain of equal culpability ('whistle blowing') and prescribes the death penalty for convicted perpetrators.

The resonance energy transfer (RET) from a cylindrical assembly of donors to acceptors in a plane was investigated, and the dependence the average RET rate (kT) on the cylinder's size, shape, and proximity to the acceptor plane was determined. This geometry provides a model for the RET from a donor-containing protein to acceptors embedded in an associated phospholipid mono- or bilayer. The determination of kT for a series of acceptors at different levels in the phospholipid layer is shown to provide information on the protein's relationship to the phospholipid layer. Two models for the donor (D) and acceptor (A) distributions are employed: (a) The D's and A's are uniformly distributed in the cylinder and the plane, respectively, and analytical expressions for kT in terms of experimental parameters are derived. (b) The RET rates between all D, A pairs within the cylinder and in the plane are calculated and averaged for a large number of random D and A distributions. The average transfer rates obtained by the two approaches are in agreement and the width of the frequency distribution of kT for the latter provides an estimate of the error to be expected when, as is usually the case, the true D and A locations are unknown. This methodology is illustrated by analyzing RET from the 37 tryptophan residues of the apo-B100 protein to a series of pyrenylphosphatidylcholine acceptors inserted in the phospholipid monolayer of the human low-density lipoprotein particle, and it is concluded that significant portions of the protein penetrate the phospholipid layer.

The lateral mobility of pyrenyl phospholipid probes in dimyristoylphosphatidylcholine (DMPC) vesicles was determined from the dependence of the pyrene monomeric and excimeric fluorescence yields on the molar probe ratio. The analysis of the experimental data makes use of the milling crowd model for two-dimensional diffusivity and the computer simulated random walks of probes in an array of lipids. The fluorescence yields for 1-palmitoyl-2-(1'-pyrenedecanoyl)phosphatidylcholine (py10PC) in DMPC bilayers are well fitted by the model both below and above the fluid-gel phase transition temperature (Tc) and permit the evaluation of the probe diffusion rate (f), which is the frequency with which probes take random steps of length L, the host membrane lipid-lipid spacing. The lateral diffusion coefficient is then obtained from the relationship D = fL2/4. In passing through the fluid-gel phase transition of DMPC (Tc = 24 degrees C), the lateral mobility of py10PC determined in this way decrease only moderately, while D measured by fluorescence photobleaching recovery (FPR) experiments is lowered by two or more orders of magnitude in gel phase. This difference in gel phase diffusivities is discussed and considered to be related either to (a) the diffusion length in FPR experiments being about a micrometer or over 100 times greater than that of excimeric probes (approximately 1 nm), or (b) to nonrandomicity in the distribution of the pyrenyl probes in gel phase DMPC. At 35 degrees C, in fluid DMPC vesicles, the diffusion rate is f = 1.8 x 10(8) s-1, corresponding to D = 29 microns2 s-1, which is about three times larger than the value obtained in FPR experiments. The activation energy for lateral diffusion in fluid DMPC was determined to be 8.0 kcal/mol.

In the intramolecular excimeric membrane probe, dipyrenylphosphatidylcholine (dipyn PC), pyrene moieties are linked to the terminal carbons of the two acyl chains, each of which contains n carbons. We show here how the probe intramolecular excimer production rate, K, may be determined from the excimer/monomer intensity ratio, rl, by making use of the fluorescence titrations of the related monopyrenyl probe, pyn PC, analyzed according to the milling crowd model. rl and the rate K of dipy10 PC in four model membrane systems were measured over a wide temperature range and both parameters are shown to be sensitive functions of the lateral fluidity of the host matrix. A model for relating the intramolecular and intermolecular excimer formation rates is proposed according to which both processes are limited by the reorientational rate of the pyrene moiety. Above the fluid-gel transition temperature, Tc, the diffusion rate (f) of the monopyrenyl probe (pyn PC) is accordingly related to K by: pE approximately K/(K + 1/2f + tau -1M), where pE is the probability of excimer formation between nearest neighbor pyn PC probes, and tau M is the monomer lifetime. Values of pE derived in this way are found to be consistent with pE values derived from the milling crowd analysis of fluorescence yield titration experiments. K for dipy10 PC in DMPC multibilayers ranges from 0.21 x 10(7) s-1 at 10 degrees C in the gel phase, to 5.7 x 10(7) s-1 at 60 degrees C in the fluid phase, whereas the lateral diffusion coefficient, D, for py10 PC in the same bilayers ranged from 8 to 34 microns2 s-1, when calculated with D = fL2/4, L being the average lipid-lipid spacing of the host membrane. Above Tc and at the same reduced temperature, (T - Tc)/Tc, both f for py10 PC, and K for dipy10 PC were found to have relative magnitudes in the order: DPPC greater than DMPC greater than POPC greater than DOPC. This and the similarity of the activation energies for f and K suggest that the rotation of the the pyrene moiety is the rate-limiting step for both the lateral mobility of py10 PC and intramolecular excimer formation in dipy10 PC.