Structure–activity relationship studies of manzamine A: Amidation of positions 6 and 8 of the β-carboline moiety

Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure–activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. Most of the amides showed potent activity against Mycobacterium intracellulare. The antimicrobial activity profile for position 8 series was similar to that for antimalarial activity profile, in which linear, slightly short alkyl groups adjacent to the amide carbonyl showed improved activity. Two amides 14 and 21, which showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of 14 and 21 at the dose of 30 mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity.     

Basic versus applied research: Julius Sachs (1832–1897) and the experimental physiology of plants

The German biologist Julius Sachs was the first to introduce controlled, accurate, quantitative experimentation into the botanical sciences, and is regarded as the founder of modern plant physiology. His seminal monograph Experimental-Physiologie der Pflanzen (Experimental Physiology of Plants) was published 150 y ago (1865), when Sachs was employed as a lecturer at the Agricultural Academy in Poppelsdorf/Bonn (now part of the University). This book marks the beginning of a new era of basic and applied plant science. In this contribution, I summarize the achievements of Sachs and outline his lasting legacy. In addition, I show that Sachs was one of the first biologists who integrated bacteria, which he considered to be descendants of fungi, into the botanical sciences and discussed their interaction with land plants (degradation of wood etc.). This “plant-microbe-view” of green organisms was extended and elaborated by the laboratory botanist Wilhelm Pfeffer (1845–1920), so that the term “Sachs-Pfeffer-Principle of Experimental Plant Research” appears to be appropriate to characterize this novel way of performing scientific studies on green, photoautotrophic organisms (embryophytes, algae, cyanobacteria).     

Toxic events in the Northwest Pacific coastline of Mexico during 1992–1995: origin and impact

Previously considered as toxin-free, the Baja California Peninsula has witnessed several toxic algal blooms during the past three years. Apparently these ‘red-tide’ phenomena's outbreaks are not linked to any human related activity. This may just reflect better detection and training. Such events may be periodical and natural rather than induced. The most common types of marine toxins have been detected along the coast of the Peninsula and neighboring waters by mouse bioassay and chromatographic techniques. These are: Tetrodotoxin (TTX), Amnesic Shellfish Poison (ASP), Paralytic Shellfish Poisons (PSP), Diarrhetic Shellfish Poisons (DSP) and even Ciguatera (CFP), which are related to the presence of organisms of Prorocentrum sp. and Alexandrium sp. groups, and the diatom Pseudonitzschia sp. among others. There are also some indications about different kinds of TTX in the puffer fish of the region, and reasons to believe that we are facing a quite different pattern in toxic components, since PSP toxic potency (defined as the number of mouse units per gram(MU/g)of shellfish meat) is very high in spite of low dinoflagellates cell density registered. The ecological and social impact of the above has been considerable, with mass deaths of shellfish, seagulls, dolphins and turtles, and even some human casualties. The locally registered toxicity records: PSP found in one single fanshell reaches to 23 000 MU/100 g of tissue as determined by the mouse bioassay and, on a different event, two persons killed after ingesting puffer fish fillet. The largest reservoir of commercial marine organisms in Mexico is precisely the Northwest coast of the country and important plans for building large harbors and develop aquaculture areas are in progress. Therefore, a monitoring program is essential for an adequate management of such resources. Considering the large extension of the Peninsula (about1600 km)and, at this time, the lack of efficient communication means and scarce population, the implementation of such monitoring programs presents a big challenge. This revised version was published online in August 2006 with corrections to the Cover Date.     

At the border of ecological change: status and nest sites of the Lithuanian Black Stork Ciconia nigra population 2000–2006 versus 1976–1992

Recent trends in the European Black Stork Ciconia nigra population are geographically distinct: range expansion and adaptation to human activity dominate in western and central Europe, while declines—probably induced by landscape change—are reported in the east. We studied the large Lithuanian Black Stork population in the transition zone to explore whether, and how, the detrimental influences of recent Baltic landscape changes are balanced by the West European tendency of behavioural adaptation to human activity. Based on monitoring in sample plots, the current population was estimated at 650–950 pairs, indicating a significant decrease (possibly over 20%) during the last two decades. In comparison to the Latvian and Estonian populations, however, this decline is smaller, and the reproductive success remains at a high level [66% breeding success and 2.99 ± 0.97 (SD) fledglings per successful attempt, 2000–2006]; this north–south gradient suggests a climate-mediated impact of habitat degradation in the Baltic countries. The storks are also nesting closer to forest edges and in younger stands than 15–30 years ago, which has probably reduced the nest-tree limitation, as indicated by an increased use of large oaks. Thus, habitat degradation and adaptation seem to be taking place simultaneously in the Lithuanian Black Stork population, as was expected from its geographical location. In general, our study supports the view that, whenever possible, species conservation strategies and the use of indicator species should be geographically explicit.     

Gender-Dependent Frequency–Spatial Organization of the Brain Cortex Activity during Convergent and Divergent Thinking: I. Analysis of the EEG Power

The frequency–spatial organization of the brain cortex activity of men and women was studied during convergent (CTh) and divergent (DTh) thinking by means of EEG power mapping in a broad frequency band. Right-handed 17- to 23-year-old students (36 men and 30 women) participated in the study. Mental arithmetic was used as a model of CTh. Functional changes in the EEG patterns in the ₁ and ₁ frequency bands were distinct in CTh: the activation of the frontal cortical regions with a predominant involvement of right-hemispheric mechanisms of sustained attention was characteristic of the men, whereas, in the women, desynchronization of the ₁ rhythm was shifted to the caudal part of the cortex with a stronger left-hemispheric control over the calculating operations. This difference may be indicative of the involvement of different attention mechanisms and, consequently, the predominant use of the verbal or visuospatial strategies of CTh in men and women. Regardless of the gender, DTh was accompanied by an increase in the EEG power in the ₂ band. The successful performance of a divergent task was determined by different frequency components of the brain activation in men and women. In men, successful performance was associated with a substantial increase in the power of the ₂ rhythm and weak EEG desynchronization in the ₁ band; in women, successful performance was characterized by a lower increase in the amplitude of the ₂ oscillations as compared to noncreative persons and stronger EEG desynchronization in the ₁ band. The reciprocal changes in the power of the ₁ and ₂ rhythms in men and women during successful DTh may reflect the difference in interactions between cortical and subcortical structures in the regulation of voluntary, involuntary, and differential attention.     

Elastic behavior of a red blood cell with the membrane’s nonuniform natural state: equilibrium shape,motion transition under shear flow,and elongation during tank-treading motion

Direct numerical simulations of the mechanics of a single red blood cell (RBC) were performed by considering the nonuniform natural state of the elastic membrane. A RBC was modeled as an incompressible viscous fluid encapsulated by an elastic membrane. The in-plane shear and area dilatation deformations of the membrane were modeled by Skalak constitutive equation, while out-of-plane bending deformation was formulated by the spring model. The natural state of the membrane with respect to in-plane shear deformation was modeled as a sphere ( \(\alpha =0\) ), biconcave disk shape ( \(\alpha =1\) ) and their intermediate shapes ( \(0<\alpha <1\) ) with the nonuniformity parameter \(\alpha \) , while the natural state with respect to out-of-plane bending deformation was modeled as a flat plane. According to the numerical simulations, at an experimentally measured in-plane shear modulus of \(2.5\times 10^{-6}\,\hbox {N}/\hbox {m}\) and an out-of-plane bending rigidity of \(2.0\times 10^{-19}\,\hbox {N}\cdot \hbox {m}\) of the cell membrane, the following results were obtained. (i) The RBC shape at equilibrium was biconcave discoid for \(\alpha >0.22\) and cupped otherwise; (ii) the experimentally measured fluid shear stress at the transition between tumbling and tank-treading motions under shear flow was reproduced for \(0.05<\alpha <0.34\) ; (iii) the elongation deformation of the RBC during tank-treading motion from the simulation was consistent with that from in vitro experiments, irrespective of the \(\alpha \) value. Based on our RBC modeling, the three phenomena (i), (ii), and (iii) were mechanically consistent for \(0.22<\alpha <0.34\) . The condition \(0.05<\alpha <0.22\) precludes a biconcave discoid shape at equilibrium (i); however, it gives appropriate fluid shear stress at the motion transition under shear flow (ii), suggesting that a combined effect of \(\alpha \) and the natural state with respect to out-of-plane bending deformation is necessary for understanding details of the RBC mechanics at equilibrium. Our numerical results demonstrate that moderate nonuniformity in a membrane’s natural state with respect to in-plane shear deformation plays a key role in RBC mechanics.     

Bone remodelling around the tibia due to total ankle replacement: effects of implant material and implant–bone interfacial conditions

Abstract

One of the major causes of implant loosening is due to excessive bone resorption surrounding the implant due to bone remodelling. The objective of the study is to investigate the effects of implant material and implant–bone interface conditions on bone remodelling around tibia bone due to total ankle replacement. Finite element models of intact and implanted ankles were developed using CT scan data sets. Bone remodelling algorithm was used in combination with FE analysis to predict the bone density changes around the ankle joint. Dorsiflexion, neutral, and plantar flexion positions were considered, along with muscle force and ligaments. Implant–bone interfacial conditions were assumed as debonded and bonded to represent non-osseointegration and fully osseointegration at the porous coated surface of the implant. To investigate the effect of implant material, three finite element models having different material combinations of the implant were developed. For model 1, tibial and talar components were made of Co–Cr–Mo, and meniscal bearing was made of UHMWPE. For model 2, tibial and talar components were made of ceramic and meniscal bearing was made of UHMWPE. For model 3, tibial and talar components were made of ceramic and meniscal bearing was made of CFR-PEEK. Changes in implant material showed no significant changes in bone density due to bone remodelling. Therefore, ceramic appears to be a viable alternative to metal and CFR-PEEK can be used in place of UHMWPE. This study also indicates that proper bonding between implant and bone is essential for long-term survival of the prosthetic components.     

Dynamic changes in the distribution and time course of blood–brain barrier-permeative nitroxides in the mouse head with EPR imaging: visualization of blood flow in a mouse model of ischemia

Electron paramagnetic resonance (EPR) imaging using nitroxides as redox-sensitive probes is a powerful, noninvasive method that can be used under various physiological conditions to visualize changes in redox status that result from oxidative damage. Two blood–brain barrier-permeative nitroxides, 3-hydroxymethyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (HMP) and 3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine-1-yloxy (MCP), have been widely used as redox-sensitive probes in the brains of small animals, but their in vivo distribution and properties have not yet been analyzed in detail. In this study, a custom-made continuous-wave three-dimensional (3D) EPR imager was used to obtain 3D EPR images of mouse heads using MCP or HMP. This EPR imager made it possible to take 3D EPR images reconstructed from data from 181 projections acquired every 60 s. Using this improved EPR imager and magnetic resonance imaging, the distribution and reduction time courses of HMP and MCP were examined in mouse heads. EPR images of living mice revealed that HMP and MCP have different distributions and different time courses for entering the brain. Based on the pharmacokinetics of the reduction reactions of HMP and MCP in the mouse head, the half-lives of HMP and MCP were clearly and accurately mapped pixel by pixel. An ischemic mouse model was prepared, and the half-life of MCP was mapped in the mouse head. Compared to the half-life in control mice, the half-life of MCP in the ischemic model mouse brain was significantly increased, suggesting a shift in the redox balance. This in vivo EPR imaging method using BBB-permeative MCP is a useful noninvasive method for assessing changes in the redox status in mouse brains under oxidative stress.     

Changes in Meningococcal Strains in the Era of a Serogroup C Vaccination Campaign: Trends and Evolution in Belgium during the Period 1997–2012

Background

Invasive meningococcal disease (IMD) is a major cause of bacterial meningitides and septicaemia. This study shows the results of the laboratory-based surveillance of IMD in Belgium over the period 1997–2012.

Methods

The results are based on microbiological and molecular laboratory surveillance of 2997 clinical isolates of N. meningitides received by the Belgian Meningococcal Reference Centre (BMRC) over the period 1997–2012.

Results

Serogroup B has always been a major cause of meningococcal disease in Belgium, with P3.4 as most frequent serotype till 2008, while an increase in non-serotypable strains has been observed in the last few years. Clonal complexes cc-41/44 and cc-269 are most frequently observed in serogroup B strains. In the late nineties, the incidence of serogroup C disease increased considerably and peaked in 2001, mainly associated with phenotypes C:2a:P1.5,2, C:2a:P1.5 and C:2a:P1.2 (ST-11/ET-37 clonal complex). The introduction of the meningococcal C conjugate vaccine has been followed by an 88% significant decrease in serogroup C disease from 2001 to 2004 nationally, yet sharper in Flanders (92%) compared to Wallonia (77%). Since 2008 a difference in incidence of serogroup C was observed in Flanders (0–0.1/100,000) versus Wallonia (0.1–0.3/100,000).

Conclusion

This study showed the change in epidemiology and strain population over a 16 years period spanning an exhaustive vaccination campaign and highlights the influence of regional vaccination policies with different cohorts sizes on short and long-term IMD incidences.     

The upper Shemshak Formation (Toarcian–Aalenian) of the Eastern Alborz (Iran): Biota and palaeoenvironments during a transgressive–regressive cycle

The siliciclastic, up to 4,000 m thick Upper Triassic–Bajocian Shemshak Formation is widespread across the Iran Plate, especially in the Alborz Mountains of northern Iran. In contrast to its lower, generally non-marine part, the upper part is marine. Based on the Tazareh section of the eastern Alborz, an integrated analysis of this marine interval is presented. The 1,700 m thick marine sedimentary succession records a gradual deepening from inner to mid and outer shelf environments from the Middle Toarcian to early Late Aalenian. During the Late Aalenian–Early Bajocian, the trend was reversed and infilling of the basin by a large delta system occurred. This general facies development reflects a nearly symmetrical transgressive–regressive (T–R) megacycle, terminated by the inter-regional mid-Cimmerian tectonic event. A renewed transgression in the early Late Bajocian initiated a subsequent sedimentary megacycle. The bioturbated mid and outer shelf sediments contain a low to moderately diverse benthic fauna dominated by deep burrowing bivalves, often preserved in the growth position. A hierarchy of four orders of sedimentary cycles can be recognized (parasequences, parasequence sets, unconformity-bounded third-order depositional sequences, and the 13 ma long second-order T–R megacycle). A regional correlation with the Jajarm area (200 km to the east) shows a very similar temporal facies pattern of the upper Shemshak Formation. The eastern Alborz T–R cycle is completely out-of-phase with other (eustatic) sea-level curves, suggesting regional tectonic control. Rough estimates of subsidence rates give an average value of 126 m/ma. However, much higher values for the Aalenian (230 m/ma), particularly the Late Aalenian (700 m/ma), indicate a distinct increase in subsidence rate towards the Early Bajocian mid-Cimmerian tectonic event. These high subsidence rates suggest that the sediments of the Shemshak Formation of the eastern Alborz formed in a (young) rift basin.     

Trends in the Attack Rates,Incidence, and Mortality of Stroke during 1986–2012: Data of Kaunas (Lithuania) Stroke Registry

BackgroundThere is a lack of reliable epidemiological data on longitudinal trends in stroke attack rates, incidence, and mortality in the countries of the Baltic region.AimsThe aim of the present study was to explore the longitudinal trends of stroke in middle-aged urban population of Lithuania during the period of 1986 through 2012.MethodsAll stroke events in the studied population were ascertained and validated according to the standardized criteria outlined by the WHO MONICA Project. The study included all patients in Kaunas (Lithuania) city aged 25 to 64 years who experienced a stroke between 1986 and 2012. Estimates of time-trends of the annual percentage change in stroke attack rates, incidence of stroke, and mortality from this condition were made by applying the Joinpoint regression analysis.ResultsDuring the study period, 9,992 stroke events were registered. The overall proportion of recurrent events was 25.7%. Overall, 18.9% of the events (20.0% in men, and 17.4% in women) were fatal within 28 days. During the period of 1986 to 2012, a flat trend in the incidence of stroke was observed among both male and female middle-aged inhabitants of Kaunas city, while attack rates were increasing due to the increase in recurrent strokes. Both mortality and 28-day case fatality of stroke declined significantly over the study period in both sexes.ConclusionsAn increase both in the incidence and recurrence of stroke among middle-aged men residing in Kaunas city and in the recurrence of stroke among women denotes the inefficiency of measures applied both for primary and secondary prevention of stroke in Lithuania. The revision of current prevention strategies and the introduction of new ones are of paramount importance in order to fight the epidemic of stroke.     

Biogeochemical changes at the sediment–water interface during redox transitions in an acidic reservoir: exchange of protons,acidity and electron donors and acceptors

Redox transitions induced by seasonal changes in water column O₂ concentration can have important effects on solutes exchange across the sediment–water interface in systems polluted with acid mine drainage (AMD), thus influencing natural attenuation and bioremediation processes. The effect of such transitions was studied in a mesocosm experiment with water and sediment cores from an acidic reservoir (El Sancho, SW Spain). Rates of aerobic organic matter mineralization and oxidation of reduced inorganic compounds increased under oxic conditions (OX). Anaerobic process, like Fe(III) and sulfate reduction, also increased due to higher O₂ availability and penetration depth in the sediment, resulting in higher regeneration rates of their corresponding anaerobic e^? acceptors. The contribution of the different processes to oxygen uptake changed considerably over time. pH decreased due to the precipitation of schwertmannite and the release of H⁺ from the sediment, favouring the dissolution of Al-hydroxides and hydroxysulfates at the sediment surface. The increase in dissolved Al was the main contributor to water column acidity during OX. Changes in organic matter degradation rates and co-precipitation and dissolution of dissolved organic carbon and nitrogen with redox-sensitive Fe(III) compounds affected considerably C and N cycling at the sediment–water interface during redox transitions. The release of NO₂^? and NO₃^? during the hypoxic period could be attributed to ammonium oxidation coupled to ferric iron reduction (Feammox). Considering the multiple effects of redox transitions at the sediment–water interface is critical for the successful outcome of natural attenuation and bioremediation of AMD impacted aquatic environments.     

Synthesis and structure–activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo[1.5-a]pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe

A structure–activity relationship of the 3- and 6-positions of the pyrazolo[1,5-a]pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3. The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency. From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows >300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.     

Metal trabecular bone reconstruction system better improves clinical efficacy and biomechanical repair of osteonecrosis of the femoral head than free vascularized fibular graft: A case–control study

In this study, we aim to compare and analyze the biomechanical repair and clinical efficacy of osteonecrosis of the femoral head (ONFH) with the use of metal trabecular bone reconstruction system and free vascularized fibular graft. The study enrolled 66 adult patients from medical records of nontraumatic ARCO 2A–3B stage ONFH. A simple ONFH model without surgical treatment was established in 13 cases, 29 cases were treated with metal trabecular bone reconstruction system, and 24 cases were treated with free vascularized fibular graft. Computer-recognized and extracted femur outlines were imported, and three-dimensional reconstructions were performed. The stress concentration and stress peak value were analyzed, and the Harris score, visual analog scale pain score, and operation status of the above patients were compared. Finally, quality of life assessment was performed using SF-36 scale. Metal trabecular bone reconstruction system provided less operation time, blood loss, and the total length of postoperative hospital stay than free vascularized fibular graft. Metal trabecular bone reconstruction system promoted bone reconstruction, increased bone mineral density and Harris score. The total clinical effective rate of young patients (20–40 years) was higher than that of older patients (41–60 years). Metal trabecular bone reconstruction system provided higher physical component summary, mental component summary, and role/social component summary than free vascularized fibular graft. This study demonstrates that both metal trabecular bone reconstruction system and free vascularized fibular graft can prevent or delay the progression of ONFH, while metal trabecular bone reconstruction system is a better choice because of better short-term clinical efficacy.