Progranulin and TDP-43: Mechanistic Links and Future Directions

Loss-of-function mutations in the multifunctional growth factor progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) with TDP-43 protein accumulation. Nuclear TDP-43 protein with key roles in RNA metabolism is also aggregated in amyotrophic lateral sclerosis (ALS), suggesting that ALS and FTLD constitute a broad disease continuum. However, the fact that mutations in GRN are associated with FTLD, while mutations in TDP-43 cause a preferential loss of motor neurons resulting in ALS-end of the disease spectrum, suggests involvement of both cell-autonomous and non-autonomous mechanisms. Studies on animal models and in vitro studies have been instrumental in understanding the link between GRN and TDP-43 and also their role in neurodegeneration. For instance, in mouse models, allelic deficiencies of Grn do not recapitulate human pathology of TDP-43 brain accumulations, but embryonic neurons derived from these mice do show abnormal TDP-43 accumulation after additional cellular challenges, suggesting that TDP-43 changes observed in GRN mutation carriers might also relate to stress. Recent results have shown that the dual action of GRN in growth modulation and inflammation could be due to its negative regulation of TNF-α signaling. In addition, GRN also interacts with sortilin and is endocytosed, thereby regulating its own levels and possibly also modulating the turnover of other proteins including that of TDP-43. Accumulating evidence suggests that TDP-43 abnormal cellular aggregation causes a possible gain of function, also suggested by recently constructed mouse models of TDP-43 proteinopathy; however, it would be inconvincible that sequestration of physiological TDP-43 within cellular aggregates observed in patients would be innocuous for disease pathogenesis. This review discusses some of these data on the possible link between GRN and TDP-43 as well as mechanisms involved in TDP-43-led neurodegeneration. Continued multitiered efforts on genetic, cell biological, and animal modeling approaches would prove crucial in finding a cure for GRN-related diseases

Hepatotprotective Natural Products

Medicinal herbs are significant source of pharmaceutical drugs. Latest trends have shown increasing demand of phytodrugs and some medicinal herbs have proven hepatotprotective potential. Silymarin, a flavonol lignan mixture) extracted from the Silybum marianum (milk thistle) is a popular remedy for hepatic diseases. Today every herbal company is marketing formulations for liver disorders but the actual scene is that only selected medicinal herbs have been tested for hepatotprotective activity. Some herbal formulations claiming to be hepatoprotective may actually contain chemical constituents having hepatotoxic potential. Andrographolide (Andrographis paniculata), Glycyrrhizin (Glychyrrhiza glabra), Picrrorihzin (Picrorrhiza kurroa) and Hypo-phyllanthin (Phyllanthus niruri) are potential candidates with hepatoprotective activity. The article reviews latest trends in testing of isolated constituents with hepatoprotective activity

Hepatotprotective Natural Products

Medicinal herbs are significant source of pharmaceutical drugs. Latest trends have shown increasing demand of phytodrugs and some medicinal herbs have proven hepatotprotective potential. Silymarin, a flavonol lignan mixture) extracted from the Silybum marianum (milk thistle) is a popular remedy for hepatic diseases. Today every herbal company is marketing formulations for liver disorders but the actual scene is that only selected medicinal herbs have been tested for hepatotprotective activity. Some herbal formulations claiming to be hepatoprotective may actually contain chemical constituents having hepatotoxic potential. Andrographolide (Andrographis paniculata), Glycyrrhizin (Glychyrrhiza glabra), Picrrorihzin (Picrorrhiza kurroa) and Hypo-phyllanthin (Phyllanthus niruri) are potential candidates with hepatoprotective activity. The article reviews latest trends in testing of isolated constituents with hepatoprotective activity

Role of hyperglycemia in the pathogenesis of Na+/K+ disturbance

Background: Electrolytes play an important role in maintaining acid-base balance, blood-clotting, control body fluid, muscle contraction, nerve conduction. The diabetic patients develop frequently a constellation of electrolyte imbalance. Imbalance in electrolyte concentration may affect the course of diabetes and its management. It has been reported that there is an inverse relationship between serum sodium (Na+) and potassium (K+) levels in diabetic patients. The aim of present study was to determine whether such relation is seen in context of Nepal and whether this inverse relation depends upon serum glucose levels in diabetic patients for their glycemic control.Methods: This is a retrospective study performed on records of 135 diabetic patients who were treated at out-patient clinic of Kist Medical College and Teaching Hospital from 15 June 2015-15 July 2015. Fasting blood glucose (FPG) level was analyzed with semiautomatic analyzer- humalyzer 3000 by GOD-POD method and Na+ and K+ levels were analyzed with ion selective electrode- nova electrolyte. The relationship among serum Na+ level, serum K+ levels and Fasting plasma glucose levels were determined by SPSS version 20.Results: Serum Na+ level was insignificantly negatively correlated (r=-0.091, p=0.296) with FPG level while a positive correlation of serum K+ level (r=0.235, p=0.006) was seen with FPG level and an inverse relation between serum Na+ and K+ was found. Age showed insignificant negative correlation with serum Na+ (r= -0.203, p=0.018), insignificant positive correlation with K+ (r=0.067, p=0.443) and insignificant negative correlation with FPG (r= -0.045, p=0.608).Conclusions: Hyperglycemia disrupts the balance of serum Na+ and K+ in uncontrolled diabetes mellitus

Emerging drugs for sickle cell anemia.

INTRODUCTION: The search for effective therapeutic interventions for sickle cell disease (SCD) has been an ongoing endeavor for over 50 years. During this period, only hydroxyurea (HU), which received US FDA approval in February 1998, was identified as an effective therapeutic agent in preventing or ameliorating the frequency of vaso-occlusive crises, acute chest syndrome and the need for blood transfusion. Approximately 25% of patients with sickle cell anemia (SCA), however, do not respond to HU and some patients experiencing serious side effects of this chemotherapeutic agent. Nevertheless, the success of HU opened the sluice gates to identify other effective drug therapies. The objective of this review is to describe the emerging drug therapies for SCA. AREAS COVERED: In this review, we describe the pathophysiology of SCD and provide an in-depth analysis of the current and new pharmacologic therapies in the field. Literature searches involved multiple databases including Medline In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Database of Systematic Reviews, and Scopus. EXPERT OPINION: SCA is a heterogeneous disease that has caused tremendous global morbidity and early mortality. More effective, individualized and inexpensive therapies are needed. New therapies targeting multiple pathways in its complex pathophysiology are under investigation

Tau is central in the genetic Alzheimer-frontotemporal dementia spectrum

In contrast to the common and genetically complex senile form of Alzheimer's disease (AD), the molecular genetic dissection of inherited presenile dementias has given important mechanistic insights into the pathogenesis of degenerative brain disease. Here, we focus on recent genotype-phenotype correlative studies in presenile AD and the frontotemporal dementia (FTD) complex of disorders. Together, these studies suggest that AD and FTD are linked in a genetic spectrum of presenile degenerative brain disorders in which tau appears to be the central player

Bounds for the collapsibility number of a simplicial complex and non-cover complexes of hypergraphs

The collapsibility number of simplicial complexes was introduced by Wegner in order to understand the intersection patterns of convex sets. This number also plays an important role in a variety of Helly type results. There are only a few upper bounds for the collapsibility number of complexes available in literature. In general, it is difficult to establish such non-trivial upper bounds. In this article, we construct a sequence of upper bounds $\theta_k(X)$ for the collapsibility number of a simplicial complex $X$. We also show that the bound given by $\theta_k$ is tight if the underlying complex is $k$-vertex decomposable. We then give an upper bound for $\theta_k$ and therefore for the collapsibility number of the non-cover complex of a hypergraph in terms of its covering number

Tilt Integral Derivative Controller Optimized by Battle Royale Optimization for Wind Generator Connected to Grid

Globally the countries are focusing on reducing the carbon footprint leading to a greater effort for electrical energy generation by renewable energy sources, particularly wind. The wind turbines are invariably using doubly fed asynchronous generator. In this paper a controller has been designed for a doubly fed induction motor. The proposed Tilt Integral Derivate controller for was compared with commonly used PI, PID controllers. Several optimization algorithms were used for tuning of controllers and the best one was selected for each type of controller. The controller has been optimized using battlefield optimization. It had been compared with proportional integral controller, fractional order proportional integral derivative controller. Other controllers were optimized using meta heuristic algorithms. The controller enhanced the system response in terms of settling time, rise time and other parameters. The Tilt controller gave the overall superior performance in terms of parameters like rise time, settling time, settling minimum, peak, and peak time. The results were obtained using MATLAB. This paper discusses operation of doubly fed induction motor operation and optimization methods