On the Mechanism of Cationic Amphiphile-mediated Transfection. To Fuse or not to Fuse: Is that the Question?

Due to charge interaction, cationic lipids spontaneously associate with nucleic acids, resulting in the formation of so-called lipoplexes. Lipoplexes are membranous structures that are capable of transducing genes into cells, eventually leading to expression of the genes (transfection). The mechanism involved in the cellular uptake of lipoplexes is most likely endocytosis, which occurs after nonspecific charge-mediated binding to cellular receptors. An important step in the transfection process following the actual internalization of lipoplexes is the release of the lipoplex and/or its DNA into the cytoplasm in order to evade lysosomal degradation. Here, the membranous nature of the lipoplex seems to be crucial in that it allows the exchange of lipids between the endosomal membrane and the lipoplex, which results in membrane perturbations that are a prerequisite in the endosomal escape of DNA. Interestingly, a hexagonal phase of the lipoplexes has been correlated with efficient transfection and it can be envisaged that such a phase could be instrumental in the creation of membrane perturbations. Subsequent to its release into the cytoplasm, the DNA has to be transferred into the nucleus. The nuclear import of DNA is most likely a protein-mediated process. In addition, the nuclear uptake of DNA may be facilitated at the time of nuclear envelope disassembly during mitosis. Currently, cationic liposomes are widely used as gene carrier system to deliver nucleic acids into cells in culture to study the cell-biological functioning of genes plus accompanying proteins. Ultimately, cationic lipids may be used in gene therapeutic protocols.     

Why not harvest existing invaders for bioethanol?

Some ecologists and environmentalists have asked whether existing plant invaders could be used as sources of lignocellulosic ethanol, as an alternative to the introduction of potentially invasive non-native energy crops. Although the idea is tempting and could theoretically motivate the control or eradication of large invasive populations, we recognize that a number of major economic, logistic, and legal barriers currently prevent adoption of this plan. Here, we enumerate these barriers in detail, but conclude with an idealistic vision for the role of invasive biomass in the bioenergy industry.     

BMI and Risk Factors for Suicide: Why Is BMI Inversely Related to Suicide?

Higher BMI has been associated with a lower risk of suicide in large prospective studies, but the mechanisms for this link require elucidation. In the 2002 and 2004 iterations of the Behavioral Risk Factor Surveillance System (BRFSS), a large, population‐based telephone survey of US adults conducted by the Centers for Disease Control and Prevention, participants reported their height, weight, and several potential risk factors for suicide, including alcohol use, mental health, marital status, firearm ownership, and risk‐taking behaviors. We assessed whether BMI was associated with these risk factors among 224,247 eligible respondents in 2002 and 275,194 in 2004 after sample‐weighted adjustment for age, race, region, smoking, and education. Alcohol‐related risk factors tended to be lower with heavier BMI among women, while firearm‐related risk factors tended to be higher with heavier BMI among men. Heavier BMI also tended to be associated with unmarried status and poor mental health, especially among women, and with infrequent seat belt use in men and women. No potential risk factors were consistently inversely associated with BMI in both sexes and years. In summary, in these samples of the US population, conventional risk factors for suicide were inconsistently associated with BMI, making them unlikely mediators for the observed relationship of BMI with lower risk of suicide. In some cases, risk factors were actually greater with heavier BMI. Further study of the relationship of BMI and suicide may yield novel modifiable risk factors that could cause or prevent this important cause of death.     

Why the club of earth?

Recently, a small group of ecologists and evolutionary biologists anointed themselves The Club of Earth and made a public pronouncement on the importance of preserving biological diversity. For me, the most frequent result of being a member has been a series of queries about why the group had been formed.     

Why test animals to treat humans? On the validity of animal models

Critics of animal modeling have advanced a variety of arguments against the validity of the practice. The point of one such form of argument is to establish that animal modeling is pointless and therefore immoral. In this article, critical arguments of this form are divided into three types, the pseudoscience argument, the disanalogy argument, and the predictive validity argument. I contend that none of these criticisms currently succeed, nor are they likely to. However, the connection between validity and morality is important, suggesting that critical efforts would be instructive if they addressed it in a more nuanced way.     

Why does the brain (not) have glycogen?

In the present paper we formulate the hypothesis that brain glycogen is a critical determinant in the modulation of carbohydrate supply at the cellular level. Specifically, we propose that mobilization of astrocytic glycogen after an increase in AMP levels during enhanced neuronal activity controls the concentration of glucose phosphates in astrocytes. This would result in modulation of glucose phosphorylation by hexokinase and upstream cell glucose uptake. This mechanism would favor glucose channeling to activated neurons, supplementing the already rich neuron-astrocyte metabolic and functional partnership with important implications for the energy compounds used to sustain neuronal activity. The hypothesis is based on recent modeling evidence suggesting that rapid glycogen breakdown can profoundly alter the short-term kinetics of glucose delivery to neurons and astrocytes. It is also based on review of the literature relevant to glycogen metabolism during physiological brain activity, with an emphasis on the metabolic pathways identifying both the origin and the fate of this glucose reserve.     

Why do we not have a cure for rheumatoid arthritis?

There are currently unprecedented opportunities to treat rheumatoid arthritis using well-designed, highly effective, targeted therapies. This will result in a substantial improvement in the outcome of this disorder for most affected individuals, if they can afford these therapies. Yet our lack of understanding of the basic mechanisms that initiate and sustain this disease remains a major obstacle in the search for a definitive cure. It is possible, if not likely, that our best approach will be to identify individuals at risk and devise reliable, safe methods of preventing the disease before it occurs. The means to do this are currently unknown but should serve as a major focus of research.     

Why Has the Continuous Decline in German Suicide Rates Stopped in 2007?

Background

Whereas German suicide rates had a clear decreasing tendency between 1991 and 2006, they increased from 2007 to 2010. Deeper analyses of suicide data might help to understand better this change. The aim of this study was to analyze 1) whether recent trends can be related to changes in specific suicide methods and diverge by gender and age; 2) whether the decrease of suicide rates before 2007 as well as the increase from 2007 to 2010 are driven by the same suicide method.

Methods

Analyses were based on suicide data from the Federal Statistical Office of Germany. For 1998–2010, 136.583 suicide cases of men and women with known age and suicide method could be identified. These data were analyzed by joinpoint regression analysis, allowing identification of the best fitting point in time (“joinpoint”) at which the suicide rate significantly changes in magnitude or direction.

Results

The national downward trend between 1998 and 2007 was mainly due to corresponding changes in self-poisoning by other means than drugs (e.g., pesticides) (annual percentage change (APC) ≤ −4.33), drowning (APC ≤ −2.73), hanging (APC ≤ −2.69) and suicides by firearms (APC ≤ −1.46) in both genders. Regarding the overall increase of age-adjusted suicide rates in Germany 2007–2010, mainly the increase of self-poisoning (e.g., by drugs) and “being overrun” (APC ≥ 1.50) contributed to this trend.

Limitations

The true suicide rates might have been underestimated because of errors in the official death certificates.

Conclusions

Increase in suicide rates in Germany since 2007 went along with corresponding changes for “being overrun” and “self-poisoning”. Copycat suicides following the railway suicide of the goalkeeper Robert Enke partly contributed to the results. Thus, prevention of Werther effects and limitation of the availability of high pack sizes for drugs are of special relevance for the reversal of this trend.     

Why are programmes for offenders with personality disorder not informed by the relevant scientific findings?

This paper examines the evidence to justify intervening in those with personality disorder, specifically antisocial personality disorder (ASPD) as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV, American Psychiatric Association 1994). The evidence from randomized controlled trials in the mental health literature is reviewed and found to be deficient with only five trials satisfying Cochrane criteria, all of which had a reduction in substance misuse as their primary outcome, rather than a change in the personality disorder per se.Next, I consider the contribution of Thomas Kuhn to explain why it is difficult to develop a scientific basis in forensic mental health. I argue that, because forensic mental health is inclusive in its purpose (interacting with the law, social services and the penal system, all of which have different rules and agendas), it is difficult to develop a consensus on fundamentals, this consensus being a hallmark of a science.Finally, I argue that despite the absence of evidence from mental health, providers for ASPD are in a fortunate position in being able to draw upon the correctional literature. This is relevant, provided that we agree that a reduction in offending is the primary outcome. While mental health can learn much from correctional practice, it can also enhance the efficacy of the latter by, for instance, drawing attention to the specific vulnerabilities of the personality structure that might impede programme delivery in correctional settings. Means of achieving a conjunction of mental health and correctional practice are urgently required as this would be beneficial to both.     

Why does the gut choose apolipoprotein B48 but not B100 for chylomicron formation?

Chylomicrons produced by the human gut contain apolipoprotein (apo) B48, whereas very-low-density lipoproteins made by the liver contain apo B100. To study how these molecules function during lipid absorption, we examined the process as it occurs in apobec-1 knockout mice (able to produce only apo B100; KO) and in wild-type mice (of which the normally functioning intestine makes apo B48, WT). Using the lymph fistula model, we studied the process of lipid absorption when animals were intraduodenally infused with a lipid emulsion (4 or 6 micromol/h of triolein). KO mice transported triacylglycerol (TG) as efficiently as WT mice when infused with the lower lipid dose; when infused with 6 micromol/h of triolein, however, KO mice transported significantly less TG to lymph than WT mice, leading to the accumulation of mucosal TG. Interestingly, the size of lipoprotein particles from both KO and WT mice were enlarged to chylomicron-size particles during absorption of the higher dose. These increased-size particles produced by KO mice were not associated with increased apo AIV secretion. However, we found that the gut of the KO mice secreted fewer apo B molecules to lymph (compared with WT), during both fasting and lipid infusion, leading us to conclude that the KO gut produced fewer numbers of TG-rich lipoproteins (including chylomicron) than the wild-type animals. The reduced apo B secretion in KO mice was not related to reduced microsomal triglyceride transfer protein lipid transfer activity. We propose that apo B48 is the preferred protein for the gut to coat chylomicrons to ensure efficient chylomicron formation and lipid absorption.