N-Methylated Analogs of hIAPP Fragments 18–22, 23–27, 33–37 Inhibit Aggregation of the Amyloidogenic Core of the Hormone

Amylin (hIAPP) aggregation leads to the formation of insoluble deposits and is one of the factors in the development of type II diabetes. The aim of this research was to find N-methylated analogs of the aggregating amylin fragments 18–22, 23–27, and 33–37, which would not themselves be susceptible to aggregation and would inhibit the aggregation of the amyloidogenic cores of the hormone. None of the analogs of fragment 18–22 containing one or two N-methylated amino acid residues showed any tendency to aggregate. Only the peptide H−F(N−Me)GA(N−Me) IL−OH ( 6 ) derived from the 23–27 hIAPP hot spot did not form fibrous structures. All analogs of the 33–37 amylin fragment were characterized by the ability to form aggregates, despite the presence of N-methylated amino acids in their structures. N-Methylated peptides 1 – 5 demonstrated inhibitory properties against the aggregation of fragment 18–22. Aggregation of the amyloidogenic core of 23–27 was significantly inhibited by N-methylated peptides 1 – 3 derived from the (18–22) H−HSSNN−OH fragment and by the H−F(N-Me)GA(N−Me)IL−OH ( 6 ) fragment derived from the 23–27 amylin hot spot. Fragment (33–37) H−GSNTY−NH₂ was found to be inhibited in the presence of N-methylated peptides 1 – 3 derived from the 18–22 fragment and by the double methylated peptide H−F(N−Me)GA(N−Me)IL−OH ( 6 ). Research on the possibility of using N-methylated analogs of amyloidogenic amylin cores as inhibitors of hormone aggregation is ongoing, with a focus on finding the minimum concentration of N-methylated peptides capable of inhibiting the aggregation of hIAPP hot spots.     

Calculation of the Three-Dimensional Structures of Two Antigenic Sequences, Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro and Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro–Pro–Pro, of the Circumsporozoite Protein From a Malaria-Causing Plasmodium

Using the chain build-up procedure based on the program ECEPP, we have computed the lowest energy structures for two terminally blocked subsequences from the antigenic circumsporozoite protein of Plasmodium berghei, that is known to cause malaria in animals. The full antigenic sequence is an octapeptide proline-rich tandem repeat, (Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp)₂. We computed the structures for the first octapeptide plus one Pro from the second octapeptide, terminally blocked CH₃CO–Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro–NHCH₃ as well as the first octpeptide with an additional three Pro residues from the adjoining unit, i.e., CH₃CO–Pro–Pro–Pro–Pro–Asn–Pro–Asn–Asp–Pro–Pro–Pro–NHCH₃. We find that the first sequence adopts a number of different low energy structures, the most probable of which has a probability of occurrence of 56 %. Addition of two more Pro residues results in the adoption a single, unique lowest energy structure that has a probability of occurrence of over 95 % without solvation effects and 86 % when solvation effects are included in the calculations. We predict that this structure may be the one recognized as a major antigenic determinant.     

Forget Evil: Autonomy,the Physician–Patient Relationship,and the Duty to Refer

Aulisio and Arora argue that the moral significance of value imposition explains the moral distinction between traditional conscientious objection and non-traditional conscientious objection. The former objects to directly performing actions, whereas the latter objects to indirectly assisting actions on the grounds that indirectly assisting makes the actor morally complicit. Examples of non-traditional conscientious objection include objections to the duty to refer. Typically, we expect physicians who object to a practice to refer, but the non-traditional conscientious objector physician refuses to refer. Aulisio and Arora argue that physicians have a duty to refer because refusing to do so violates the patient’s values. While we agree with Aulisio and Arora’s conclusions, we argue value imposition cannot adequately explain the moral difference between traditional conscientious objection and non-traditional conscientious objection. Treating autonomy as the freedom to live in accordance with one’s values, as Aulisio and Arora do, is a departure from traditional liberal conceptions of autonomy and consequently fails to explain the moral difference between the two kinds of objection. We outline how a traditional liberal understanding of autonomy would help in this regard, and we make two additional arguments—one that maintains that non-traditional conscientious objection undermines society’s autonomy, and another that maintains that it undermines the physician-patient relationship—to establish why physicians have a duty to refer.     

Metazooplankton dynamics in the Salton Sea, California, 1997–1999

The dynamics of metazooplankton populations were studied over 3 years at the saline (43 g l^–1) Salton Sea, California's largest lake. Total abundance was highest in summer following late winter/early spring phytoplankton blooms. At this time, metazooplankton consisted mostly of the copepod, Apocyclops dengizicus, and the rotifer, Brachionus rotundiformis. In August or September, severe crashes in the metazooplankton populations occurred each year in mid-lake due to strong wind events which increased mixing and caused low oxygen and high sulfide concentrations throughout the water column. Larvae of the polychaete worm, Neanthes succinea and the barnacle, Balanus amphitrite were present mostly in late winter and spring. Their scarcity in summer is due in part to persistent anoxic bottom conditions that decrease adult populations and in part to predation by tilapia, an omnivorous fish that has become abundant in the lake since the 1960s. Two Synchaeta species, rotifers not previously reported from the Sea, were abundant in winter and spring and predation on these may have permitted the copepod to persist at low levels through the winter. There were two major changes in metazooplankton dynamics since 1954–1956 in addition to the appearance of the two synchaetid rotifers in the fauna. First, there are now much lower densities of barnacle and polychaete larvae in the fall, probably due to the invasion of the zooplanktivorous fish, tilapia. Second the precipitous crashes now seen in metazooplankton densities, especially the copepod, in late summer-early fall did not occur in the 1950s possibly because fall overturn events did not result in such high sulfide levels.     

Life in the Universe Paris,November 19–21, 1979

A conference on Life in the Universe, organized by the Council of Europe, and held in Paris, November 19 to 21, 1979, brought together more than 100 scientists from different fields. The aim of this conference was to promote scientific cooperation in Europe, in conjunction with other countries, in fields related to the problem of Life in the Universe. Our knowledge concerning this problem was reviewed in three different sessions. The first session was devoted to the question of planetary evolution; the second session was devoted to the question of the origin and evolution of life, and the third session was devoted to the problem of evolution of intelligence and the search for extraterrestrial intelligence. The Drake formula was the keynote of the conference. Each session tried to estimate some of the parameters of this formula, in order to examine the question: how many extraterrestrial civilizations with a level of technology at least equal to ours may be present in the universe? Even if no definite answer is given to this question, this meeting pointed out the need for more research.     

Unravelling the past 1,000 years of history of human–climate–landscape interactions at the Lindu plain,Sulawesi, Indonesia

The Lindu plain, located in the northern mountainous region of the Lore Lindu National Park in Sulawesi, Indonesia, provides many ecosystem services for the population inhabiting the area and harbours a unique biodiversity. Palynological, charcoal and diatom analyses of a lake sediment core from Lake Lindu (Danau Lindu) reveal that during the last 1,000 years the Lindu plain has been modified by human activities. Evidence of frequent burning and possible shifting cultivation from an earlier phase from ca. ad 1000 to 1200 might be related to the metal age population which erected the megaliths in the province of Central Sulawesi. From ca. ad 1200–1700 there followed 500 years of wetter climate conditions, corresponding to the southward movement of the Intertropical Convergence Zone. At the same time, decreases of macro-charcoal concentrations and pioneer vegetation indicators show that the use of the landscape of Lindu plain had become more permanent. Following a phase of forest recovery from ca. ad 1730 to 1910, the most recent part of the Lake Lindu record shows a trend towards deforestation that started in the late 20th century, lasting until now. The lake level started to fall at the beginning of the 20th century, as shown by the increase of sedimentation rate and supported by low pollen concentration and palaeomagnetic data. Such a change was unprecedented for the last 1,000 years covered by the record, and it has no link to the climate variability as reconstructed for the last hundred years. If deforestation increases and a larger amount of water is channelled away from the lake for irrigation purposes, the lake level will continue to fall. This suggests that there is a need for better management of the forests surrounding the plain and of the irrigation systems in the area open for cultivation.     

Peptide, Peptidomimetic, and Small-molecule Antagonists of the p53–HDM2 Protein–Protein Interaction

Modulation of intracellular protein–protein interactions has been – and remains – a challenging goal for the discovery and development of small-molecule therapeutic agents. Progress in the pharmacological targeting and understanding at the molecular level of one such interaction that is relevant to cancer drug research, viz. that between the tumour suppressor protein p53 and its negative regulator HDM2, is reviewed here. The first X-ray crystal structure of a complex between a small peptide from the trans-activation domain of p53 and the N-terminal domain of HDM2 was reported almost 10 years ago. The nature of this interaction, which involves just three residue side chains in the p53 peptide ligand and a compact hydrophobic binding pocket in the HDM2 receptor, together with the attractive concept of reactivating the anti-proliferative functions of p53 in tumour cells, has spurned a great deal of effort aimed at finding drug-like antagonists of this interaction. A variety of approaches, including both structure-guided peptidomimetic and de novo design, as well as high through-put screening campaigns, have provided a wealth of leads that might be turned into actual drugs. There is still some way to go as far as optimisation and preclinical development of such leads is concerned, but it is clear already now that antagonists of the p53–HDM2 protein–protein interaction have a good chance of ultimately being successful in providing a new anti-cancer therapy modality, both in monotherapy and to potentiate the effectiveness of existing chemotherapies.     

Species–area relationships in the Hantam-Tanqua-Roggeveld,Succulent Karoo,South Africa

The Hantam-Tanqua-Roggeveld subregion is part of the Succulent Karoo hotspot of biodiversity which stretches along the southwestern side of South Africa and Namibia. Forty Whittaker plots were surveyed in the spring of 2005, in eight vegetation associations, to gather diversity data for the Hantam, Tanqua Karoo and Roggeveld areas. Seven plot sizes were used to construct species–area curves using three different models namely: the untransformed linear function, the power function and the exponential function. In general, the power and exponential functions produced a more significant fit to the data than the untransformed linear function. Linear regressions using environmental parameters indicated that altitude, mean annual precipitation and mean annual temperature were significant predictors of species richness at the 1, 10, 100 and 1000 m² scales. To illustrate the variation in species–area curves and species richness across the landscape, a transect through the study area is discussed. The transect stretches eastwards from the Tanqua Karoo across the escarpment into the Roggeveld and crosses five different vegetation associations. Differences between associations were found in species richness in the 1000 m² plots. Each association also produced species–area curves with their own characteristics. Slope values for the samples within an association did not differ significantly, although the intercept value often did. Comparisons between associations along the transect revealed significant differences in the slope value between the associations, except for the Dicerothamnus rhinocerotis Mountain Renosterveld which did not differ significantly from the associations bordering it on either side.     

Anticoagulant, Fibrinolytic, and Antithrombotic Effects of the Heparin–Insulin Complex

Formation of heparin–insulin complex at the 1 : 10 molar ratio of the components has been demonstrated by spectral methods. The derived complex had anticoagulant, antithrombotic, and fibrinolytic properties of nonenzymatic nature in vitro. Intravenous injection of the complex in the animals (rats) increased anticoagulant and fibrinolytic background and at the same time decreased the plasma coagulation factors fibrinogen and factor XIIIa in the bloodstream. We propose the heparin–insulin complex as a promising antithrombotic drug.     

Reconstituting the kinetochore–microtubule interface: what, why, and how

The kinetochore is the proteinaceous complex that governs the movement of duplicated chromosomes by interacting with spindle microtubules during mitosis and meiosis. Faithful chromosome segregation requires that kinetochores form robust load-bearing attachments to the tips of dynamic spindle microtubules, correct microtubule attachment errors, and delay the onset of anaphase until all chromosomes have made proper attachments. To understand how this macromolecular machine operates to segregate duplicated chromosomes with exquisite accuracy, it is critical to reconstitute and study kinetochore–microtubule interactions in vitro using defined components. Here, we review the current status of reconstitution as well as recent progress in understanding the microtubule-binding functions of kinetochores in vivo.     

Proceedings of the XVIII Congress of the International Primatological Society Adelaide,Australia, January 7–12, 2001

International Journal of Primatology -     

Variability of the start of the growing season in Fennoscandia, 1982–2002

Fennoscandia is characterized by a large degree of climatic diversity. Vegetation phenology may respond differently to climate change according to the climatic gradients within the region. To map the annual and spatial variability of the start of the growing season (SOS) in Fennoscandia, the twice-monthly GIMMS-NDVI satellite dataset was used. The data set has an 8 × 8 km² spatial resolution and covers the period from 1982 to 2002. The mapping was done by applying pixel-specific threshold values to the NDVI data. These threshold values were determined form surface phenology data on birch (Betula sp.). Then, we produced NDVI based maps of SOS for each of the 21 years. Finally, the time differences between the SOS and the last day of snow cover, as well as dates of passing different temperatures, were analyzed for 21 meteorological stations. The analyses showed that 1985 was the most extreme year in terms of late SOS. In terms of early SOS, the year 1990 was by far the most extreme. Locally, the SOS has an average range of 1 month between the earliest and latest recorded SOS, with a trend towards a bigger range in the oceanic parts. The results indicate that a 1°C increase in spring temperatures in general corresponds to an advancement of 5–6 days in SOS. However, there is a clear trend according to the degree of oceanity, with a 1°C increase in the most oceanic parts corresponding roughly to 7–9 days earlier SOS, compared to less than 5 days earlier in the continental parts.     

Thermal, mixing, and oxygen regimes of the Salton Sea, California, 1997–1999

The Salton Sea is a shallow (mean depth = 8 m; maximum depth = 15 m), saline (41–45 g l^–1), intermittently mixing, 57 km long, 980 km² lake located in the arid southwestern United States. The Sea is a wind driven system, with predominant winds paralleling the long axis of the lake, being strongest in spring and weakest in summer and fall. The Sea mixed daily or nearly daily between September and January. During this cooling period, moderate to high levels of dissolved oxygen (3–11 mg l^–1) were found throughout the water column. Mean water column temperature ranged from a minimum of 13–14 °C in early January to a maximum of 30–34 °C in July–September. During most of this warming period, the Sea was thermally stratified but subject to periodic wind driven mixing events. Winds were stronger in spring 1998 than in 1997 or 1999, causing more rapid heating of the lake that year and also delaying onset of anoxic conditions in bottom waters. During summer months, mid-lake surface waters were sometimes supersatured with oxygen, and bottom waters were hypoxic or anoxic with sulfide concentrations > 5 mg l^–1. Oxic conditions (> 1 mg O₂ l^–1) often extended a few meters deeper nearshore than they did well offshore as a consequence of greater mixing nearshore. Mixing events in late summer deoxygenated the entire water column for a period of days. Consumption of oxygen by sulfide oxidation likely was the principal mechanism for these deoxygenation events. Sulfide concentrations in surface waters were 0.5–1 mg l^–1 approximately 3 days after one mixing event in mid-August 1999. These mixing events were associated with population crashes of phytoplankters and zooplankters and with large fish kills. In the southern basin, freshwater inflows tended to move out over the surface of the Sea mixing with saline lake water as a function of wind conditions. Salinity gradients often contributed more to water column stability than did thermal gradients in the southeasternmost portion of the lake.     

Chlorophyll a fluorescence induction: a personal perspective of the thermal phase, the J–I–P rise

The fast (up to 1?s) chlorophyll (Chl) a fluorescence induction (FI) curve, measured under saturating continuous light, has a photochemical phase, the O-J rise, related mainly to the reduction of Q(A), the primary electron acceptor plastoquinone of Photosystem II (PSII); here, the fluorescence rise depends strongly on the number of photons absorbed. This is followed by a thermal phase, the J-I-P rise, which disappears at subfreezing temperatures. According to the mainstream interpretation of the fast FI, the variable fluorescence originates from PSII antenna, and the oxidized Q(A) is the most important quencher influencing the O-J-I-P curve. As the reaction centers of PSII are gradually closed by the photochemical reduction of Q(A), Chl fluorescence, F, rises from the O level (the minimal level) to the P level (the peak); yet, the relationship between F and [Q(A) (-)] is not linear, due to the presence of other quenchers and modifiers. Several alternative theories have been proposed, which give different interpretations of the O-J-I-P transient. The main idea in these alternative theories is that in saturating light, Q(A) is almost completely reduced already at the end of the photochemical phase O-J, but the fluorescence yield is lower than its maximum value due to the presence of either a second quencher besides Q(A), or there is an another process quenching the fluorescence; in the second quencher hypothesis, this quencher is consumed (or the process of quenching the fluorescence is reversed) during the thermal phase J-I-P. In this review, we discuss these theories. Based on our critical examination, that includes pros and cons of each theory, as well mathematical modeling, we conclude that the mainstream interpretation of the O-J-I-P transient is the most credible one, as none of the alternative ideas provide adequate explanation or experimental proof for the almost complete reduction of Q(A) at the end of the O-J phase, and for the origin of the fluorescence rise during the thermal phase. However, we suggest that some of the factors influencing the fluorescence yield that have been proposed in these newer theories, as e.g., the membrane potential ΔΨ, as suggested by Vredenberg and his associates, can potentially contribute to modulate the O-J-I-P transient in parallel with the reduction of Q(A), through changes at the PSII antenna and/or at the reaction center, or, possibly, through the control of the oxidation-reduction of the PQ-pool, including proton transfer into the lumen, as suggested by Rubin and his associates. We present in this review our personal perspective mainly on our understanding of the thermal phase, the J-I-P rise during Chl a FI in plants and algae.     

Does geographic range affect the attractant–aggregation–attachment pheromone of the tropical bont tick, Amblyomma variegatum?

The tropical bont tick, Amblyomma variegatum, transmits heartwater in sub-Saharan Africa and in the Caribbean. This species has a broad geographic distribution, ranging from Madagascar and other islands in the Indian Ocean through most of sub-Saharan Africa, to several islands in the eastern Caribbean Sea. Blood fed male A. variegatum secrete an attraction–aggregation–attachment (AAA) pheromone which, combined with CO₂, excites host finding and formation of feeding clusters of these ticks. However, it is not known whether the composition of the pheromone varies throughout A. variegatums geographic range. Extracts of fed male ticks were examined for phenols and volatile organic acids by gas chromatography and mass spectrometry to determine whether differences occur in the pheromone components of populations of this species across the geographic range (Guadeloupe, Zimbabwe, Zambia and Rwanda). No significant difference in the chemical composition of the pheromone in relation to geographic range was found. No significant differences in rates of attachment in response to native versus foreign extracts were found in on-host attachment tests comparing ticks from two countries, Guadeloupe (Caribbean) and Zimbabwe (African). This finding was confirmed in more detailed studies with ticks from Guadeloupe and four African countries (Kenya, Rwanda, Zambia and Zimbabwe). On-host attachment assays from these countries did not detect consistent differences in response to extracts from different locations.In an olfactometer bioassay, females were not consistently more attracted to extracts from their native locality than from any of the foreign localities.We conclude that despite the widespread distribution of A. variegatum over both hemispheres, no significant differences in pheromone composition or biological responses to male tick pheromone secretions occur.