CaMKK2 as an emerging treatment target for bipolar disorder

Current pharmacological treatments for bipolar disorder are inadequate and based on serendipitously discovered drugs often with limited efficacy, burdensome side-effects, and unclear mechanisms of action. Advances in drug development for the treatment of bipolar disorder remain incremental and have come largely from repurposing drugs used for other psychiatric conditions, a strategy that has failed to find truly revolutionary therapies, as it does not target the mood instability that characterises the condition. The lack of therapeutic innovation in the bipolar disorder field is largely due to a poor understanding of the underlying disease mechanisms and the consequent absence of validated drug targets. A compelling new treatment target is the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme. CaMKK2 is highly enriched in brain neurons and regulates energy metabolism and neuronal processes that underpin higher order functions such as long-term memory, mood, and other affective functions. Loss-of-function polymorphisms and a rare missense mutation in human CAMKK2 are associated with bipolar disorder, and genetic deletion of Camkk2 in mice causes bipolar-like behaviours similar to those in patients. Furthermore, these behaviours are ameliorated by lithium, which increases CaMKK2 activity. In this review, we discuss multiple convergent lines of evidence that support targeting of CaMKK2 as a new treatment strategy for bipolar disorder

Senescent ground tree rewrite systems

Ground Tree Rewrite Systems with State are known to have an undecidable control state reachability problem. Taking inspiration from the recent introduction of scope-bounded multi-stack pushdown systems, we define Senescent Ground Tree Rewrite Systems. These are a restriction of ground tree rewrite systems with state such that nodes of the tree may no longer be rewritten after having witnessed an a priori fixed number of control state changes. As well as generalising scope-bounded multi-stack pushdown systems, we show --- via reductions to and from reset Petri-nets --- that these systems have an Ackermann-complete control state reachability problem. However, reachability of a regular set of trees remains undecidable

Glucose Recovery from Different Corn Stover Fractions Using Dilute Acid and Alkaline Pretreatment Techniques

Background: Limited availability of corn stover due to the competing uses (organic manure, animal feed, bio-materials, and bioenergy) presents a major concern for its future in the bio-economy. Furthermore, biomass research has exhibited different results due to the differences in the supply of enzymes and dissimilar analytical methods. The effect of the two leading pretreatment techniques (dilute acid and alkaline) on glucose yield from three corn stover fractions (cob, stalk, and leaf) sourced from a single harvest in Uganda were studied at temperatures 100, 120, 140, and 160 °C over reaction times of 5, 10, 30, and 60 min. Results: From this study, the highest glucose concentrations obtained from the dilute acid (DA) pretreated cobs, stalks, and leaves were 18.4 g/L (66.8% glucose yield), 16.2 g/L (64.1% glucose yield), and 11.0 g/L (49.5% glucose yield), respectively. The optimal pretreatment settings needed to obtain these yields from the DA pretreated samples were at a temperature of 160 °C over an incubation time of 30 min. The highest glucose concentrations obtained from the alkaline (AL) pretreated cobs, stalks, and leaves were 24.7 g/L (81.73% glucose yield), 21.3 g/L (81.23% glucose yield), and 15.0 g/L (51.92% glucose yield), respectively. To be able to achieve these yields, the optimal pretreatment settings for the cobs and stalks were 140 °C and for a retention time of 30 min, while the leaves require optimal conditions of 140 °C and for a retention time of 60 min. Conclusions: The study recommends that the leaves could be left on the field during harvesting since the recovery of glucose from the pretreated cobs and stalks is higher

Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population

BACKGROUND: Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease--antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies. METHODS: To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history. RESULTS: Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV. CONCLUSIONS: Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity

Understanding the reductions in US corn ethanol production costs: an experience curve approach

The US is currently the world's largest ethanol producer. An increasing percentage is used as transportation fuel, but debates continue on its costs competitiveness and energy balance. In this study, technological development of ethanol production and resulting cost reductions are investigated by using the experience curve approach, scrutinizing costs of dry grind ethanol production over the timeframe 1980–2005. Cost reductions are differentiated between feedstock (corn) production and industrial (ethanol) processing. Corn production costs in the US have declined by 62% over 30 years, down to 100$2005/tonne in 2005, while corn production volumes almost doubled since 1975. A progress ratio (PR) of 0.55 is calculated indicating a 45$2005/m3 in 2005 (excluding costs for corn and capital), equivalent to a PR of 0.87. Total ethanol production costs (including capital and net corn costs) have declined approximately 60% from 800$2005/m3 in the early 1980s, to 300$2005/m3 in 2005. Higher ethanol yields, lower energy use and the replacement of beverage alcohol-based production technologies have mostly contributed to this substantial cost decline. In addition, the average size of dry grind ethanol plants increased by 235% since 1990. For the future it is estimated that solely due to technological learning, production costs of ethanol may decline 28–44%, though this excludes effects of the current rising corn and fossil fuel costs. It is also concluded that experience curves are a valuable tool to describe both past and potential future cost reductions in US corn-based ethanol production

Long-Term Follow-Up of Isolated Epicardial Left Ventricular Lead Implant Using a Minithoracotomy Approach for Cardiac Resynchronization Therapy.

BACKGROUND Transvenous left ventricular (LV) lead placement for cardiac resynchronization therapy is unsuccessful in 5-10% of reported cases. These patients may benefit from isolated surgical placement of an epicardial LV lead via minithoracotomy approach. AIM To evaluate the success of this approach at long-term follow-up. METHODS Retrospective evaluation of all consecutive patients undergoing isolated epicardial LV lead placement after failed transvenous attempt over a 6-year period. Data collected on baseline parameters, procedural details, and outcome at follow-up (hospital stay, complications, mortality, and clinical response). RESULTS Forty-two patients underwent epicardial lead implant. Five died within 1 year (11.9%): two (4.8%) died within 30-days post op (one from intraoperative hemorrhage, the other from multiple organ failure); 39 (95.1%) were admitted to the high dependency unit and transferred to the ward <24 hours. Median hospital stay was 3.4 ± 1.9 days. The overall complication rate was 17.5% (n = 7): 15.0% (n = 6) short term and 2.5% (n = 1) long term; these included three (7.5%) LV noncapture events all treated with reprogramming. There were two (5.0%) wound infections requiring oral antibiotics and two (5.0%) device infections requiring intravenous antibiotics (one had device resiting, the other developed septic shock requiring intensive care admission). Assessment of clinical response was possible in 34 (81.0%) at follow-up: 21 (61.8%) were responders and 13 (28.2%) nonresponders with no significant differences between these groups; no clinical predictors of response were identified. CONCLUSION Isolated epicardial LV lead implant using minithoracotomy is relatively safe and effective at successful LV pacing. Response rate and postoperative recovery at long-term follow-up are reasonable in these high-risk patients