Is Charge Scaling Really Mandatory when Developing Fixed-Charge Atomistic Force Fields for Deep Eutectic Solvents?

In recent years, molecular dynamic simulations on choline chloride based deep eutectic solvents (DES) have flourished. Most of these studies point to the fact that in order to accurately reproduce dynamical properties of the latter using a fixed-charge atomistic force field (FF) one has to resort to charge scaling. In this work, we propose an alternative to charge scaling and show that the sole refinement of the Lennard-Jones parameters of the oxygen and hydrogen of the hydroxyl function in the GAFF v2.11 FF enables an accurate description of static, dynamical, and structural properties of two commonly used DES, namely, ethaline (1:2 mixture of choline chloride and ethylene glycol) and glyceline (1:2 mixture of choline chloride and glycerol). Various computed physicochemical properties for both mixtures with our modified version of the GAFF v2.11 FF are found in good agreement with experimental data. Most importantly, however, is the fact that self-diffusion coefficients for the various components of both ethaline and glyceline are found within a maximum deviation of 33% from experimental values, which is at least as good if not better than current scaled-charge FF. Finally, computed radial distribution functions match with those reported in the literature.

TERRESTRIAL EFFECTS OF NEARBY SUPERNOVAE IN THE EARLY PLEISTOCENE.

Recent results have strongly confirmed that multiple supernovae happened at distances of ∼100 pc, consisting of two main events: one at 1.7-3.2 million years ago, and the other at 6.5-8.7 million years ago. These events are said to be responsible for excavating the Local Bubble in the interstellar medium and depositing 60Fe on Earth and the Moon. Other events are indicated by effects in the local cosmic ray (CR) spectrum. Given this updated and refined picture, we ask whether such supernovae are expected to have had substantial effects on the terrestrial atmosphere and biota. In a first look at the most probable cases, combining photon and CR effects, we find that a supernova at 100 pc can have only a small effect on terrestrial organisms from visible light and that chemical changes such as ozone depletion are weak. However, tropospheric ionization right down to the ground, due to the penetration of ⩾TeV CRs, will increase by nearly an order of magnitude for thousands of years, and irradiation by muons on the ground and in the upper ocean will increase twentyfold, which will approximately triple the overall radiation load on terrestrial organisms. Such irradiation has been linked to possible changes in climate and increased cancer and mutation rates. This may be related to a minor mass extinction around the Pliocene-Pleistocene boundary, and further research on the effects is needed.

Linear and nonlinear measures predict swimming in the leech

Stimulation of a trigger interneuron of an isolated nerve cord preparation of the medicinal leech, Hirudo medicinalis, sometimes leads to swimming; sometimes it does not. We investigate signals transmitted in the ventral cord of the leech after stimulation and seek quantitative measures that would make it possible to distinguish signals that predict swimming from those that do not. We find that a number of linear as well as nonlinear measures provide statistically significant distinctions between the two kinds of signals. The linear measures are the time dependence of (i) the standard deviation and (ii) the autocorrelation function at a small time delay. The nonlinear measures are (i) a measure of nonlinear predictability and (ii) the time dependence of a measure of the size of the embedded signal trajectory. Calculations using surrogate data suggest that the differences between the two classes of signals are dynamical as well as statistical.

Development and validation of a reversed-phase liquid chromatographic method for analysis of aspirin and warfarin in a combination tablet formulation.

A stability-indicating liquid chromatographic method for the simultaneous analysis of aspirin and warfarin in warfarin sodium/aspirin combination (DuP 647) tablets has been developed and validated. This paper presents linearity, accuracy, precision, robustness, recovery, limits of detection and quantitation, and cross-validation data. The method has been shown to be specific and stability-indicating, and to give results comparable to existing methods for the individual components. Solution stability has been optimized for routine analysis.

Transgenic rats carrying the mouse renin gene--morphological characterization of a low-renin hypertension model.

Transgenic rats [TGR; strain name TGR(mRen2)27] harboring the mouse Ren-2 renin gene have been recently generated as a model for the study of primary hypertension that offers the advantage of a clearly-defined genetic alteration. Expression of the mouse Ren-2 gene causes severe hypertension (200 to 260 mm Hg) which is responsive to converting enzyme inhibitors. Compared to control transgene-negative littermates, plasma renin and angiotensin II values are lowered in TGR, whereas plasma prorenin values are strongly elevated. The adrenal gland in TGR shows marked overexpression of mouse renin messenger RNA; in situ hybridization using a 35S-labelled mouse-renin RNA probe reveals that enhanced renin expression is mainly localized to cells of the zona glomerulosa and outer zona fasciculata. Immunohistochemically, renin protein in the TGR adrenal gland is stored in larger quantities than in controls. Adrenal transgene expression probably accounts for most of the elevated plasma prorenin level in TGR, since bilateral adrenalectomy (ADX) causes a significant decrease in prorenin level (318 +/- 79 ng angiotensin I/ml/hr before ADX to 70 +/- 43 ng 4 days after ADX, P less than 0.0005). In the kidney, renin synthesis is almost completely suppressed in TGR. In situ hybridization demonstrates that few juxtaglomerular afferent arterioles express renin. Immunohistochemically, the TGR kidney shows significantly reduced renin and angiotensin II immunoreactivity at the afferent arteriole. Ultrastructural analysis of the afferent arteriolar wall frequently shows the complete absence of renin secretory granules since the granular cells are mostly converted into smooth muscle cells. Beginning at an age of approximately four to six months, TGR develop hypertension-related alterations and pathological lesions in various tissues. In the kidney, the wall thickness of arterioles and arteries is strongly increased, and glomerular lesions including different stages of sclerosis are observed. The thoracic aorta displays a considerable increase in tunica media thickness due to both myocyte hypertrophy and interstitial fibrosis. Coronary arteries and arterioles of the heart are thickened and perivascular fibrosis is observed. The data show that TGR(mRen2)27 transgenic rats display all typical characteristics of hypertensive pathology, making them an interesting model for therapeutic interventions. The fact that these changes occur in animals with a single gene difference to normotensive rats makes them a particularly suitable model for studies on gene-related hypertensive processes.

[Autoradiographic analysis of proliferative processes in the arterial terminal vascular system in experimental hypertension]. / Autoradiographische Analyse proliferativer Prozesse an der arteriellen terminalen Strombahn bei experimenteller Hypertonie.

The participation of various vascular wall cells in the proliferation process and their distribution in the arterial terminal vascular bed were investigated by 3H-thymidine autoradiography in rats during an acute angiotensin hypertension. The results show that both the proliferative pattern and the distribution of labeled cells have distinct differences according to the functional importance and the histologic structure of the vessels. A common feature of all vascular parts is the enhancement of the proliferation of smooth muscle cells. In particular, the proliferation is increased in the arterioles, suggesting a structural adaptation to the raised vascular tonus. The strongly altered endothelium of peripheral vessels show a retarded reparative cell proliferation. This implies a considerable risk factor for the development of an arteriosclerosis in the circulatory periphery.

[Functional and structural vascular reactions following intermittent administration of angiotensin in spontaneously hypertensive rats]. / Funktionelle und strukturelle Gefässreaktionen nach intermittierender Angiotensin-Applikation bei spontan-hypertonen Ratten.

In order to find out whether after repeated intermittent treatment with angiotensin-II (A-II) the hypertrophically and hyperplastically altered vascular walls show the same adaptation as with normotensive rats (NR), investigations were performed on 44 male 16-week-old spontaneously hypertensive rats (SHR) (Okamoto-Aoki). In three repeated series daily doses of 0.15 mg depot A-II, the lowest blood pressure effective dose attended by vascular and organic reactions, were applied for 5 days. We found that the functional reactivity of the arterial vascular system in SHR was retained after repeated intermittent administration of A-II despite the hypertrophically hyperplastic processes. This was equally true for the structural reactivity as shown by the occurrence of equal vascular alterations following each new injection series as those which appeared after the first administration of A-II. Thereafter, no structural adaptation of the arterial vascular system occurred in the SHR. The extensive A-II induced vascular alterations did not lead in SHR to additional sustained increase in blood pressure. On discontinuation of A-II treatment the A-II-induced vascular alterations reconverted within a month, even after repeated intermittent A-II treatment, despite the existence of high blood pressure. They are thus reversible. A similar remission is observed also with the A-II-induced myocardial alterations. It thus becomes obvious that, with maintained reactivity of the vascular walls against A-II and with an existing hypertension, R-A-S stimulating factors obviously are able to induce structural alterations at the arterial vessels.

[Functional and structural reactivity of the arterial vascular system to angiotensin II in spontaneously hypertensive rats]. / Untersuchungen zum funktionellen und strukturellen Reaktionsvermögen des arteriellen Gefässsystems spontan-hypertoner Ratten auf Angiotensin II.

In 55 spontaneously hypertensive rats (SHR) (Okamoto/Aoki) and 63 normotensive Wistar rats (NR) receiving Angiotensin-II, hypertrophically-hyperplastically altered vessels of SHR were tested for their functional and structural reactivity and compared with the behaviour of the arterial vascular system at essential hypertension of man. After 5 days of treatment with 0.15 and 0.02 mg depot-Angiotensin II (A-II) SHR showed an increase in systolic and, with 0.15 mg A-II, even in diastolic blood pressure and bradycardia. At either A-II dosage, plasmatic vasculoses were found at the arterioles and small arteries both in SHR and similarly treated NR, though in higher frequency and in a larger quantity in SHR, as it was the case also with myocardial alterations. Although in the arterial vessels in SHR there developed already primary hypertrophically-hyperplastic wall alterations, A-II application led to functional and structural reactions. Consequently, an additional vasoconstrictor stimulus does not lead in SHR to a process comparable with essential hypertension in man, but merely to reversible, acute vasculopathies.

[Functional and structural behavior of the cardiovascular system of normotonic and spontaneously hypertensive rats following chemical sympathectomy and angiotensin administration]. / Zum funktionellen und strukturellen Verhalten des Herz-Kreislauf-systems normotoner und spontan-hypertoner Ratten nach chemischer Sympathektomie und Angiotensin-Applikation.

The non-cleared influences of the sympathetic nervous system [sN] on structural reactions of SHR and on the direct cardiac effects of AII and the structural vascular behavior were investigated. In 67 spontaneously hypertensive rats (Okamoto-Aoki) and 55 normotonic Wistar rats (NR) the blood pressure behaviour, the structural vascular and organ reactions and the noradrenaline (NA) content of the myocardium were examined with an intact sympathetic nervous system as well as after its almost complete elimination by chemical sympathectomy with 6-hydroxy-dopamine (6-OH-DA). Moreover, the functional and structural responsiveness of the arterial vessels of sympathectomized animals to angiotensin II administrations was investigated. 6-OH-DA in the dosage applied, induces during its time of action in NR a smaller, in SHR a larger decrease of blood pressure and, presumably induced by intense NA-depletion of the myocardium, myocardial alterations. Despite extensive AII-induced alterations of the already early hypertrophically-hyperplastically changed vascular wall, the structural and functional responsiveness of the arterial vascular system was maintained even after sympathectomy, and the sensitivity of the SHR to AII remained. For maintaining hypertension, the cooperation of structural and functional influences is necessary, as is indicated by the reduction of blood pressure in sympathectomized SHR and its regular return to the daily initial values of normotonic animals under additional AII administration. Besides the vascular alterations contributing to the exacerbation of the hypertension, here the sNS is of essential importance. For obtaining a total pressure effect of AII the sNS obviously has not necessarily to be intact, though its activity state can influence the responsiveness of the arterial vascular system to AII. The reduction of the sympathicotonus by sympathectomy seems to have a protective effect on the development of AII-induced structural vascular alterations; in contrast to the myocardium in SHR, in which it induces an exacerbation and an increase in the AII-induced myocardial alteration. These findings obtained from rats are supposed to be important also for the essential hypertension in man. By maintaining the functional responsiveness of the arterial vascular system, antihypertensives which react with the different parts of the sNS cab become effective while structural alterations of the vascular wall can be influenced, too. The possibility of the simultaneous development of myocardial alterations should be taken into special consideration.

Pathomorphological reactions of myocardium and intramural vessels of rats in the course of hypertension induced by depot angiotensin. Autoradiographic, light and electron microscopic investigations.

Autoradiographic, light and electron microscopic investigations on the effect of depot angiotensin on the hearts of rats suggested that the myocardium and the intramural vessels reacted with an activation of the mesenchymal and DNA metabolism already 3 hrs, after the injection of depot angiotensin. The reactions in the capillaries and small arterioles were dominating. Degenerative alterations could be found in the cardiac muscle cells only 9 hrs. after injection and culminated in infarction-like necroses and intensive mesenchymal proliferation after the 4th A II injection. Despite further daily applications of A II the degenerative and necrotic myocardial alterations will extensively diminish until the 14th day of experiment, while the mesenchymal activation and the enhanced DNA synthesis in the vessels remained unchanged. Thus an initial stage with the development of disseminated muscle fibre necroses and infarction-like alterations and a stage of compensatory adaptation may be distinguished in the heart after depot angiotensin injections.

[Pathomorphological reactions and noradrenalin content of the heart after administration of depot angiotensin in trained and untrained rats]. / Pathomorphologische Reaktionen und Noradrenalingehalt des Herzens nach Applikation von Depot-Angiotensin bei trainierten und untrainierten Ratten.

A 14-days' training of rats designed to adapt the animals to the procedure of blood-pressure measurement caused in the myocardium a decrease, in serum an increase in noradrenaline ( NA) content. The latter remained unchanged following 3 days of treatment with 2.5 mg depot angiotensin II (AII) but decreased by more than one-half in the myocardium of untreated animals, and increased in serum. Despite the considerable difference in myocardial NA content and blood-pressure behaviour, both trained and untrained rats showed the same morphological reactions following administration of A II. These myocardial alterations which largely correspond to the so-called epinephrine myocarditis should not therefore be due solely to NA action; rather, the involvement of A II should be considered also.

[Angiotensin-induced hypertension in pigs]. / Untersuchungen an Schweinen mit Angiotensin-bedingter Blutdruckerhöhung

In pigs receiving up to 14 days daily injections of depot angiotensin, repeated daily bloody measurements of the blood pressure at the carotid artery proved unsuitable because of ensueing septic processes, in contrast to the unbloody measurement at the caudal artery. The depot angiotensin, despite the use of preparations with varying content of angiotensin-II and carrier solution, caused immediately after the injections a very strong maximal rise in systolic and diastolic blood pressure that occurred also with longer periods of the experiment; this rise gradually diminished in the course of the day but remained mostly in the hypertonic range and showed daily initial values above normal. The pig proved to be much more sensitive to angiotensin than the rat, for instance. Despite the proved vasoconstricting action of angiotensin, light-microscopic alterations at the vessels, kidneys, and the myocardium could not be observed. Part of the arterioles showed an increased wall thickness in animals killed on the 8th and 15th day of the experiment. The differences in the pathomorphological and blood pressure behaviour from the rat are discussed. The first experimental results qualify the pig as an experimental animal for comparative hypertension studies.

[Studies on the blood pressure effects of various high doses of angiotensin II in depot form in rats under defined conditions]. / Untersuchungen zur Blutdruckwirksamkeit verschieden hoher Dosen Angiotensin II in Depotform bei Ratten unter definierten Umweltbedingungen

Daily s.c. injections of 0.02--10.0 mg angiotensin in depot form for 14 days caused in rats, under defined conditions, pronounced dose-dependent effects, with an unusual tolerance to the drug being observed. The behaviour of the systolic and diastolic blood pressure and heart rate allowed to define 4 dose ranges. In the lowest dose range of 0.02 mg angiotensin-II a lasting borderline hypertension with only straight-line changes of diastolic blood pressure and bradycardia were observed. The doses of 0.15--1.25 mg angiotensin-II caused a continual blood pressure rise and led, between day 4 and 6 of the experiment, to a pronounced lasting resistance high-pressure without appreciable changes in heart rate. The strongest resistance high-pressure, which occurred as early as on day 3, with pronounced tachycardia was achieved with a dose of 2.5 mg angiotensin-II. Higher doses produced pronounced tachycardia but no significant effects on blood pressure. The varying dose-dependent effects of depot angiotensin are discussed, and the possibility is pointed out to study by the angiotensin-II hypertension model various mechanisms of a long-time hypertensive dysregulation.

Ultrastructural investigation of peripheral arterial vessels in the cortex of rats with experimental hypertension.

The peripheral arterial blood vessels in the cerebrum of 36 experimental animals and 9 controls were studied by electron microscopy. In 5 rats of these renal hypertension was produced (the animals were sacrificed 3 to 15 days following the second operation). 24 animals were treated with depot angiotensin (0.02 to 2.5 mg/daily) for 3 hr up to 40 days, and 7 rats were neurotized for 1 to 41/2 months. The alterations of the cerebral vessels were distinctly different within these 3 models already in the early reactions. Thus, even in the first 14 days of the experiment with renal and angiotensinogenic hypertension alterations were observed that did never occur in the neurotized rats. There were always observed disturbances in permeability of the cerebral vessels, but they were never followed by such heavy wall insudations as usually noticed in the splanchnic vessels. The less frequent occurrence of hemorrhages and malacic processes in the rat brain is ascribed aside from the physiological properties of the brain supply, to genetic factors and the absence of arteriosclerotic burden to the vascular wall in the non-dietetically pretreated experimental animals.