Transient global cerebral ischemia induces up-regulation of MLTKα in hippocampal CA1 neurons

MLTK (mixed-lineage kinase-like mitogen-activated protein triple kinase) is a member of the mitogen-activated protein kinase family and functioned as a mitogen activated kinase kinase kinase. MLTKα, one of the alternatively spliced forms of MLTK, could activate the c-Jun N-terminal kinase pathway, which involved in cellular stress responses and apoptosis. But the role of MLTKα in neural apoptosis was still unclear. Here, we performed a transient global cerebral ischemia model (TGCI) in adult rats and detected the dynamic changes of MLTKα in hippocampal CA1 neurons and brain cortex. We found the MLTKα expression was increased shortly after TGCI and peaked after 8 h. In spatial distribution, MLTKα was widely located in neurons rather than astrocytes and microglia. Moreover, there was a concomitant up-regulation of active caspase-3. Taken together, we hypothesized the up-regulation of MLTKα played an essential role in the apoptosis of hippocampal CA1 neurons.     

Why is the subendocardium more vulnerable to ischemia? A new paradigm

Myocardial ischemia is transmurally heterogeneous where the subendocardium is at higher risk. Stenosis induces reduced perfusion pressure, blood flow redistribution away from the subendocardium, and consequent subendocardial vulnerability. We propose that the flow redistribution stems from the higher compliance of the subendocardial vasculature. This new paradigm was tested using network flow simulation based on measured coronary anatomy, vessel flow and mechanics, and myocardium-vessel interactions. Flow redistribution was quantified by the relative change in the subendocardial-to-subepicardial perfusion ratio under a 60-mmHg perfusion pressure reduction. Myocardial contraction was found to induce the following: 1) more compressive loading and subsequent lower transvascular pressure in deeper vessels, 2) consequent higher compliance of the subendocardial vasculature, and 3) substantial flow redistribution, i.e., a 20% drop in the subendocardial-to-subepicardial flow ratio under the prescribed reduction in perfusion pressure. This flow redistribution was found to occur primarily because the vessel compliance is nonlinear (pressure dependent). The observed thinner subendocardial vessel walls were predicted to induce a higher compliance of the subendocardial vasculature and greater flow redistribution. Subendocardial perfusion was predicted to improve with a reduction of either heart rate or left ventricular pressure under low perfusion pressure. In conclusion, subendocardial vulnerability to a acute reduction in perfusion pressure stems primarily from differences in vascular compliance induced by transmural differences in both extravascular loading and vessel wall thickness. Subendocardial ischemia can be improved by a reduction of heart rate and left ventricular pressure.     

Why are bacteria refractory to antimicrobials?

The incidence of antibiotic resistance in pathogenic bacteria is rising. Antibiotic resistance can be achieved via three distinct routes: inactivation of the drug, modification of the target of action, and reduction in the concentration of drug that reaches the target. It has long been recognized that specific antibiotic resistance mechanisms can be acquired through mutation of the bacterial genome or by gaining additional genes through horizontal gene transfer. Recent attention has also brought to light the importance of different physiological states for the survival of bacteria in the presence of antibiotics. It is now apparent that bacteria have complex, intrinsic resistance mechanisms that are often not detected in the standard antibiotic sensitivity tests performed in clinical laboratories. The development of resistance in bacteria found in surface-associated aggregates or biofilms, owing to these intrinsic mechanisms, is paramount.     

Developmental susceptibility of neurons to transient tetrahydrobiopterin insufficiency and antenatal hypoxia–ischemia in fetal rabbits

Tetrahydrobiopterin (BH₄) is important for normal brain development as congenital BH₄ deficiencies manifest movement disorders at various childhood ages. BH₄ transitions from very low levels in fetal brains to higher “adult” levels postnatally, with the highest levels in the thalamus. Maternal supplementation with the BH₄ precursor sepiapterin reduces postnatal motor deficits and perinatal deaths after 40-min fetal hypoxia–ischemia (HI) at 70% gestation, suggesting that brain BH₄ is important in improving function after HI. We tested the hypothesis that the intrinsically low concentrations of BH₄ made fetal neurons vulnerable to added insults. Brains were obtained from naïve fetal rabbits or after 40-min HI, at 70% (E22) and 92% gestation (E29). Neuronal cultures were prepared from basal ganglia, cortex, and thalamus, regions with different intrinsic levels of BH₄. Cultures were grown with or without added BH₄ for 48 h. Cell survival and mitochondrial function were determined by flow cytometry. At E22, thalamic cells had the lowest survival rate in a BH₄-free milieu, in both control and HI groups, whereas BH₄ supplementation ex vivo increased neuronal survival only in HI cells. Neuronal survival was similar in all regions without BH₄ at E29. BH₄ supplementation increased cell survival and cells with intact mitochondrial membrane potential, from basal ganglia and cortex, but not thalamus. After E29 HI, however, the benefit of BH₄ was limited to cortical neurons. We conclude that BH₄ is important for fetal neuronal survival after HI especially in the premature thalamus. Supplementation of BH₄ has a greater benefit at an earlier gestational age.     

Why is Deinococcus radiodurans so resistant to ionizing radiation?

When exponential-phase cultures of Deinococcus radiodurans are exposed to a 5000-Gray dose of gamma radiation, individual cells suffer massive DNA damage. Despite this insult to their genetic integrity, these cells survive without loss of viability or evidence of mutation, repairing the damage by as-yet-poorly-understood mechanisms.     

Why are some weta (Orthoptera: Stenopelmatidae) vulnerable yet others are common?

The large (4 g) to very large (40 g) stenopelmatid orthopterans of New Zealand are known collectively as weta. A consideration of 20 species of Hemideina, Deinacrida and tusked weta reveals that at one end of a vulnerability gradient are those species which thrive in the presence of key predators (rats), while at the other end are species that have become extinct on the mainland but still survive on predator-free island refuges. Habitat modification does not appear to be a factor in these extinctions. This paper reviews the lifestyles and some important biotic parameters that seem to determine their relative vulnerability along this gradient. When predators are present, the factors leading to extinction are large body size, use of temporary refuges, protective quality of the refuges, time spent on the ground and the effectiveness of their defensive behaviour.     

Why are women predisposed to autoimmune rheumatic diseases?

The majority of autoimmune diseases predominate in females. In searching for an explanation for this female excess, most attention has focused on hormonal changes - both exogenous changes (for example, oral contraceptive pill) and fluctuations in endogenous hormone levels particularly related to menstruation and pregnancy history. Other reasons include genetic differences, both direct (influence of genes on sex chromosomes) and indirect (such as microchimerism), as well as gender differences in lifestyle factors. These will all be reviewed, focusing on the major autoimmune connective tissue disorders: rheumatoid arthritis, systemic lupus erythematosus and scleroderma.     

Why are dendritic cells central to cancer immunotherapy?

Dendritic cell (DC)-based immunotherapy is rapidly emerging as a viable alternative to radiation or chemotherapy in the treatment of cancer. The resurgence of interest in cancer immunotherapy reflects the promising results that have been obtained in both animal models and early clinical trials with the DC-based approach. Here I suggest that this optimism is justified because the efficient capture and presentation of antigens by DCs is central to the induction of an immune response. I argue that the mechanism by which DCs capture antigen suggests that the immune system might actually be 'blind' to tumours, thereby challenging the theory of immune surveillance.     

Why is the polymerase chain reaction resistant to in vitro evolution?

A variety of methods have been developed to amplify DNA and RNA. These methods vary in their susceptibility to evolve new molecular species differing from the starting template. PCR is exceptionally resistant to in vitro evolution, whereas methods such as Q replicase and 3SR are much less robust. This paper develops some simple mathematical models which suggest that PCR is resistant to in vitro evolution because the reaction controls replication in discrete cycles: fast replication is of little advantage during PCR because the reaction limits fast replicators as well as slow ones to a single copy per cycle. In contrast, continuous (isothermal) reactions, as in the Q replicase reaction, favor fast replicators. The advantage of fast replication is compounded in continuous reactions, because a fast replicator can complete many generations of replication during the time it takes a slow replicator to complete one generation. These models suggest that continuous amplication protocols will never achieve the robustness against in vitro evolution observed with PCR.Correspondence to: J.J. Bull     

Why are living things sensitive to weak magnetic fields?

There is evidence for robust interactions of weak ELF magnetic fields with biological systems. Quite apart from the difficulties attending a proper physical basis for such interactions, an equally daunting question asks why these should even occur, given the apparent lack of comparable signals in the long-term electromagnetic environment. We suggest that the biological basis is likely to be found in the weak (～50?nT) daily swing in the geomagnetic field that results from the solar tidal force on free electrons in the upper atmosphere, a remarkably constant effect exactly in phase with the solar diurnal change. Because this magnetic change is locked into the solar-derived everyday diurnal response in living things, one can argue that it acts as a surrogate for the solar variation, and therefore plays a role in chronobiological processes. This implies that weak magnetic field interactions may have a chronodisruptive basis, homologous to the more familiar effects on the biological clock arising from sleep deprivation, phase-shift employment and light at night. It is conceivable that the widespread sensitivity of biological systems to weak ELF magnetic fields is vestigially derived from this diurnal geomagnetic effect.     

Zn2+-Aβ40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons

The roles of metal ions in promoting amyloid β-protein (Aβ) oligomerization associated with Alzheimer disease are increasingly recognized. However, the detailed structures dictating toxicity remain elusive for Aβ oligomers stabilized by metal ions. Here, we show that small Zn(2+)-bound Aβ1-40 (Zn(2+)-Aβ40) oligomers formed in cell culture medium exhibit quasi-spherical structures similar to native amylospheroids isolated recently from Alzheimer disease patients. These quasi-spherical Zn(2+)-Aβ40 oligomers irreversibly inhibit spontaneous neuronal activity and cause massive cell death in primary hippocampal neurons. Spectroscopic and x-ray diffraction structural analyses indicate that despite their non-fibrillar morphology, the metastable Zn(2+)-Aβ40 oligomers are rich in β-sheet and cross-β structures. Thus, Zn(2+) promotes Aβ40 neurotoxicity by structural organization mechanisms mediated by coordination chemistry.     

Time-course alterations of Toll-like receptor 4 and NF-κB p65, and their co-expression in the gerbil hippocampal CA1 region after transient cerebral ischemia

Innate immune system is very important to modulate the host defense against a large variety of pathogens. Toll-like receptors (TLRs) play a key role in controlling innate immune response. Among TLRs, TLR4 is a specific receptor for lipopolysaccharide and associated with the release of pro-inflammatory cytokines. In the present study, we investigated ischemia-related changes of TLR4 immunoreactivity and its protein level, and nuclear factor κB (NF-κB) p65 immunoreactivity regarding inflammatory responses in the hippocampal CA1 region after 5 min of transient cerebral ischemia to identify the correlation between transient ischemia and inflammation. In the sham-operated group, TLR4 immunoreactivity was easily detected in pyramidal neurons of the hippocampal CA1 region (CA1). TLR4 immunoreactivity in pyramidal neurons was distinctively decreased after ischemia/reperfusion (I/R); instead, based on double immunofluorescence study, TLR4 immunoreactivity was expressed in non-pyramidal neurons and astrocytes from 2 days postischemia. In addition, TLR4 protein level was lowest at 1 day postischemia and highest 4 days after I/R. On the other hand, NF-κB p65 immunoreactivity was not detected in the CA1 of the sham-operated group, and NF-κB p65 immunoreactivity was not observed until 1 day after I/R. However, NF-κB p65 immunoreactivity began to be expressed in astrocytes at 2 days postischemia, and the immunoreactivity was strong 4 days postischemia. Our results indicate that TLR4 and NF-κB p65 immunoreactivity are changed in CA1 pyramidal neurons and newly expressed in astrocytes, not in microglia, in the CA1 region after transient cerebral ischemia.     

How vulnerable are holoparasitic plants with obligate hosts to negative climate change impacts?

One of the anthropogenic causes affecting species distribution is climate change, which has significant implications for species conservation. However, little is known about the effects of changes in parasitic plant distribution on community-level interactions. Parasitic flowering plants make a limited numerical contribution to biodiversity. Their lifestyle may exhibit a moderate to the high degree of host dependence. Because of this host dependence, parasites may be more affected by environmental changes, such as climate change, compared to autotrophic representatives. To our knowledge, the effects of different climate change scenarios and their environmental variables on parasitic plants and their hosts have not yet been studied. This study aimed to construct a model which shows the current and future potential effects of climate change on the distribution of the two holoparasitic plants Hydnora abyssinica A.Br., and H. africana Thunb. in comparison to their respective Fabaceae and Euphorbiaceae hosts. We projected the future distribution of these species and their host plants using five models, nine bioclimatic, and five environmental variables. The global circulation model (CMIP5) for the years 2050 and 2070, applying two representative concentration pathways scenarios (RCP4.5 and RCP8.5) projected a 41–64% contraction of suitable habitats for H. abyssinica. For H. africana, more stable conditions are estimated, with a 12–28% contraction in suitable habitats, making this species putatively less prone to climate change effects, although this species has a more restricted distribution compared to H. abyssinica. Because climate change could affect the host differently than the parasites, the impact on the parasite could potentially be exacerbated due to host plant dependence. The models predict that the host plant distribution will be less affected, except for Vachelia Karroo, Vachellia xanthophloea, and Euphorbia gregaria, which indicated high contraction (40–66%). The predicted host species distribution ranges will only partially overlap with the respective distribution of the parasite.     

β-Catenin stabilization in skeletal muscles, but not in motor neurons, leads to aberrant motor innervation of the muscle during neuromuscular development in mice

β-Catenin, a key component of the Wnt signaling pathway, has been implicated in the development of the neuromuscular junction (NMJ) in mice, but its precise role in this process remains unclear. Here we use a β-catenin gain-of-function mouse model to stabilize β-catenin selectively in either skeletal muscles or motor neurons. We found that β-catenin stabilization in skeletal muscles resulted in increased motor axon number and excessive intramuscular nerve defasciculation and branching. In contrast, β-catenin stabilization in motor neurons had no adverse effect on motor innervation pattern. Furthermore, stabilization of β-catenin, either in skeletal muscles or in motor neurons, had no adverse effect on the formation and function of the NMJ. Our findings demonstrate that β-catenin levels in developing muscles in mice are crucial for proper muscle innervation, rather than specifically affecting synapse formation at the NMJ, and that the regulation of muscle innervation by β-catenin is mediated by a non-cell autonomous mechanism.