Lead‐related effects on rat fibroblasts

Lead (Pb) is an environmental toxicant that can induce structural and functional abnormalities of multiple organ systems, including the central nervous and the immune systems. The aim of this study was to evaluate the effects of extracellular Pb supplementation on the cellular content of the metal and on the proliferation and the survival of normal rat fibroblasts.We found that the concentration of Pb in the culture medium was 0.060 M and the normal Pb concentration in rat fibroblasts was 3.1 ± 0.1 ng/10⁷ cells. Then we exposed the cells to increasing concentration of Pb (as Pb acetate) from 0.078–320 M. We observed a dosedependent inhibition of cell proliferation after 48 h, which was already apparent at a concentration of 0.312 M (p = 0.122) and became statistically significant for concentration higher than 0.625 M (p = 0.0003 at 5 M). Cell proliferation was completely compromised at 320 M Pb total inhibition of cell proliferation.To investigate the mechanisms of Pbmediated inhibition of cell proliferation, we evaluated the occurrence of apoptosis in the same cells and found that cytosolic DNA fragments, hallmark of apoptotic cell death, increased significantly at Pb concentrations from 2.5–10.0 M. The occurrence of apoptosis was also confirmed by FACS analysis which showed the appearance of a subdiploid peak at Pb concentrations from 5–20 M. The distribution of cells in the cell cycle showed a dosedependent accumulation of cells in the G₀/G₁ phase mainly compensated by a decrease in the percentage of cells in the S phase. In conclusion, our results demonstrate that induction of apoptosis contributes to the Pbinduced inhibition of cell proliferation in rat fibroblasts.     

When Does Reward Maximization Lead to Matching Law?

What kind of strategies subjects follow in various behavioral circumstances has been a central issue in decision making. In particular, which behavioral strategy, maximizing or matching, is more fundamental to animal''s decision behavior has been a matter of debate. Here, we prove that any algorithm to achieve the stationary condition for maximizing the average reward should lead to matching when it ignores the dependence of the expected outcome on subject''s past choices. We may term this strategy of partial reward maximization “matching strategy”. Then, this strategy is applied to the case where the subject''s decision system updates the information for making a decision. Such information includes subject''s past actions or sensory stimuli, and the internal storage of this information is often called “state variables”. We demonstrate that the matching strategy provides an easy way to maximize reward when combined with the exploration of the state variables that correctly represent the crucial information for reward maximization. Our results reveal for the first time how a strategy to achieve matching behavior is beneficial to reward maximization, achieving a novel insight into the relationship between maximizing and matching.     

Common Infections May Lead to Alzheimer’s Disease

正Alzheimer’s disease (AD), also known as Alzheimer’s, is a chronic neurodegenerative disorder with hallmark amyloid plaques in brain tissue. The diseases commences slowly and worsens over time (Sjogren et al. 1952). Although it has been investigated for over six decades, the cause of AD     

Sorption of Cadmium and Lead by Bacteria–Ferrihydrite Composites

The sorptive behavior of bacteria—iron oxide composites was investigated in batch metal sorption assays using ferrihydrite in isolation (0.13 and 0.14 g/L ferrihydrite in cadmium and lead systems, respectively) as well as in combination with Bacillus subtilis (0.25 g/L adsorbent mixture) and Escherichia coli (0.27 g/L adsorbent mixture). A pH range from 3.0 to 6.5 was studied using total metal concentrations of 1.0 × 10 ^{? 4.0} and 3.2 × 10 ^{? 5} M with adsorbent mixtures proportioned on a 1:1 mass/volume basis. The log of the apparent surface complex formation constants (log K ^S _M ) and sorption capacity (S _max ) values were determined by fitting the experimental data to one-site Langmuir sorption isotherms. The one-site model effectively described the sorption data (r ² > 0.9), where Cd ^{2 +} exhibited somewhat lower sorption affinities (log K ^S _M = ?3 for ferrihydrite, ?1.7 for B. subtilis–ferrihydrite, and ?1.1 for E. coli–ferrihydrite) than Pb ^{2 +} (log K ^S _M = ?0.9 for ferrihydrite, ? 0.2 forB. subtilis–ferrihydrite, and –0.1 for E. coli–ferrihydrite). The corresponding S _max values for Cd ^{2 +} and Pb ^{2 +} on ferrihydrite were 0.78 mmole/g and 1.34 mmole/g, respectively. For the B. subtilis–ferrihydrite composites, Cd ^{2 +} and Pb ^{2 +} S _max values were lower at 0.29 mmole/g and 0.5 mmole/g, respectively. Similar values were determined for the E. coli–ferrihydrite composites (0.15 mmole/g and 0.68 mmole/g for Cd ^{2 +} and Pb ^{2 +} , respectively). The sorption of Cd ^{2 +} and Pb ^{2 +} by each of the sorbent systems exhibited a strong dependence on pH with sorption edges in the range of pH 4.0 to 7.3. The observed S _max of the composites were lower than values predicted upon available site additivity (Cd ^{2 +} _{B. subtilis ?ferrihydrite} : 0.29 mmole/g (observed) < 0.57 mmole/g (calculated); Cd ^{2 +} _{E. coli ?ferrihydrite} : 0.15 mmole/g (observed) < 0.44 mmole/ g (calculated); Pb ^{2 +} _{B. subtilis ?ferrihydrite} : 0.5 mmole/g (observed) < 0.805 mmole/g (calculated); Pb ^{2 +} _{E. coli –ferrihydrite} : 0.68 mmole/g (observed) < 0.775 mmole/g (calculated)), implying that a masking of reactive surface sites by attachment had occurred between the bacteria and ferrihydrite. Electrophoretic mobility analysis indicated that the ferrihydrite surface properties dominate the net surface charge for each composite system with lesser contributions from the bacteria.     

α-Tocopherol Modifies Lead Induced Functional Changes at Murine Neuromuscular Junction

Lead impacts neuromuscular junction and might induce skeletal muscle weakness. Antioxidants may prevent toxic actions of lead on muscle. In this study, resting membrane potentials, endplate potentials, miniature endplate potentials (MEPPs) and isometric twitch tensions were recorded to investigate effects of α-tocopherol (Vitamin E) on lead induced changes at murine dorsiflexor muscle. Moreover, levels of endplate nicotinic receptors were measured by receptor autoradiography. Forty rats were divided into four groups (lead alone, α-tocopherol, lead plus α-tocopherol and saline). Lead (1?mg/kg, i.p.), was administered daily for 2 weeks and α-tocopherol (100?mg/kg, i.p.) was given daily for 3 weeks. Lead treatment significantly reduced twitch tension (from 4.4±0.4 to 2.2±0.3?g) and delayed half time of decay. MEPP frequencies and quantal content were also significantly reduced after lead treatment. Pretreatment with α-tocopherol reversed twitch tension reduction (4.1±0.3?g) and modified lead induced delay in half time of decay. Similarly, α-tocopherol modified the negative actions of lead exposure on MEPP frequencies and quantal content. Receptor autoradiographic studies revealed significant increase of nicotinic receptor levels at the endplate region of flexor muscle in lead treated mice. However, animals treated with lead plus α-tocopherol showed significantly decreased levels of nicotinic receptors. α-Tocopherol appears to protect against lead induced neuromuscular dysfunction. These effects of α-tocopherol are possibly mediated via a free radical mechanism or modification of calcium homeostasis.     

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors

Alzheimer's disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice.     

Advancing Drug Innovation for Neglected Diseases—Criteria for Lead Progression

The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.     

Indolin-2-one p38α inhibitors II: Lead optimisation

Optimisation of a series of indolin-2-one p38α inhibitors was achieved via both blocking of a potential metabolic 'hot spot' and by increasing overall polarity of the lead series leading to non-cytotoxic compounds which showed improved oral bioavailabilities in the rat.     

Lead Resistance in Two Bacterial Isolates from Heavy Metal–Contaminated Soils

Abstract Microorganisms have developed mechanisms of coping with a variety of toxic metals; however, few studies have explored microbial resistance to lead. In this study, the overall mechanisms of a lead-resistant Pseudomonas marginalis and a lead-resistant Bacillus megaterium isolated from two different metal-contaminated soils were investigated. The P.marginalis had a higher lead resistance level at 2.5mM total lead as compared to 0.6 mM for B. megaterium. Resistance to soluble lead was much lower, 0.3 and 0.1 mM, respectively. The degree of lead resistance and the mechanism of lead resistance for these two isolates corresponded with their environmental lead exposure. When viewed with transmission electron microscopy, P.marginalis, isolated from a soil contaminated with high total but undetectable soluble lead, showed extracellular lead exclusion. B.megaterium, from a soil with both high total and soluble lead levels, was less resistant with an intracellular cytoplasmic accumulation of lead as observed with TEM. Polarization microscopy indicated that while P.marginalis produced a high amount of an extracellular polymer implicated in the organism's mechanism of lead resistance, B.megaterium produced no discernable extracellular polymeric substances. The study of these two organisms demonstrated differences in how soil microorganisms respond to environmental lead exposure, including the novel mechanism of intracellular sequestration of lead. Received 30 July 1998; Accepted 31 December 1998     

Does Sexual Conflict between Mother and Father Lead to Fertility Decline?

Fertility decline is a great challenge to evolutionary approaches to human behavior. In this study, we apply the perspective of sexual conflict between mother and father to the fertility decline. We predict that, under serial monogamy allowing for mate changes, the ideal number of children for women should be smaller than that for men, because the cost of reproduction for women should be higher than that for men. Our reasoning is that if the cost of child-bearing and child-rearing is higher for women than men, and if women, who therefore would want a smaller number of children than their husbands, have gained more power in reproductive decision-making within a couple owing to the modernization of society, fertility should decline. Until now, few evolutionary studies have analyzed empirical data in modern developed societies with such a perspective. Our questionnaire survey in an urban area in Japan revealed that mothers did experience greater cost during childcare than fathers. However, in contrast to our prediction, we found no sex differences in the ideal number of children between mothers and their husbands in many cases. About 60% of parents remembered wanting two children when they were childless. Moreover, mothers and their husbands had equal power in their decision-making regarding having children. After presenting these results, we discuss some perspectives to advance our understanding of fertility decline in terms of sexual conflict.     

Nonlinear Optical Properties of Tungsten Lead–Pyrophosphate Glasses Containing Metallic Copper Nanoparticles

We have prepared heavy metal oxide glasses containing metallic copper nanoparticles with promising nonlinear optical properties which were determined by Z-scan and pump-probe measurements using femtosecond laser pulses. For the wavelengths within the plasmon band, we have observed saturable absorption and response times of 2.3 ps. For the other regions of the spectrum, reverse saturable absorption and lifetimes shorter than 200 fs were verified. The nonlinear refractive index is about 2.0?×?10^?19 m²/W from visible to telecom region, thus presenting an enhancement effect at wavelengths near the plasmon and Cu⁺² d–d band.     

Does Dysphoria Lead to Divergent Mental Fatigue Effects on a Cognitive Task?

Objective

Tiredness, low energy, and listlessness are common symptoms to be associated with depression. The question remains to what extent these symptoms influence the effects of fatigue on sustained performance tasks, such as impaired task engagement and performance. Based on earlier findings, it was hypothesized that dysphoric (i.e., mildly depressed) individuals, compared to healthy controls, would display earlier fatigue onset and more severe fatigue effects on task engagement and performance during a cognitive task.

Methods

Sixty-one dysphoric and twenty-one non-dysphoric control participants were compared during one hour of continuous performance on a 2-back task. During the task subjective fatigue, subjective engagement, objective task performance, baseline pupil diameter and stimulus-evoked pupil dilation were measured.

Results

While we found that the dysphoric group reported relatively higher subjective fatigue than the healthy control group at the start of the experiment, we did not find any other divergent fatigue effects during the experimental task.

Conclusion

One explanation for the absence of divergent effect is that dysphoria may not have such a profound impact on available cognitive resources, like attention, as initially thought. Based on the results of the present study, we conclude that dysphoria is not necessarily an increased risk factor for impaired sustained performance on cognitive tasks that may induce mental fatigue.     

Efficient and Stable Tin–Lead Perovskite Photoconversion Devices Using Dual-Functional Cathode Interlayer

Tin–lead halide perovskites (TLHPs) are promising photoactive materials for photovoltaics (PVs) due to reduced toxicity and broad light absorption. However, their inherent ionic vacancies facilitate inward metal diffusion, accelerating device degradation. Here, efficient, stable TLHP-based PV and photoelectrochemical (PEC) devices are reported containing a chemically protective cathode interlayer—amine-functionalized perylene diimide (PDINN). Solution-processed PDINN effectively extract electrons and suppress inward-metal diffusion by forming tridentate metal complexes with its nucleophilic sites. The PV device achieved an efficiency of 23.21% (>81% retention after 750 h at 60 °C and >90% retention after 3100 h at 23 ± 4 °C), and the first demonstration of TLHP-based PEC devices exhibit a record-high bias-free solar hydrogen production rate (33.0 mA cm⁻²; ≈3.42 × 10⁻⁶ kg s⁻¹ m⁻²) when coupled with biomass oxidation, which is ≈1.7-fold higher than the ultimate target set by the U.S. Department of Energy for one-sun hydrogen production. These findings demonstrate the potential of TLHPs for efficient, stable photoconversion by the molecular design of the cathode interlayer.     

Environmental Lead Exposure Among Children in Chengdu, China, 2007–2009

Lead poisoning is one of the most significant environmental health threats which children face. The aim of the study was to evaluate the relationship between the blood lead level (BLL) of children and environmental pollution, as well as the effect of BLL on children's heath, in the biggest city in south-west China. A questionnaire survey was administered to 3,624 children's (6 months-7 years old) guardian in urban Chengdu from 2007 to 2009, collecting data on inhabited environment, living habits, and health status. All blood samples were collected for BLL test when the children came to the hospital. The analysis was conducted in West China Second University Hospital, Chengdu, China in December, 2009. A total of 3,624 children were included. The mean BLL was 62.31 μg/L. Three hundred thirty-three (9.2%) of 3,624 children's BLL were above 100 μg/L. Taking Chinese medicinal herbs usually, puffed foods, and substitutes of breast milk were risk factors (P < 0.05).The study shows that Chinese children's lead poisoning prevention and treatment lags far behind developed countries. The findings have implications for environmental health policy.