Suppression of HIV-1 infection by a small molecule inhibitor of the ATM kinase

Chemotherapy that is used to treat human immunodeficiency virus type-1 (HIV-1) infection focuses primarily on targeting virally encoded proteins. However, the combination of a short retroviral life cycle and high mutation rate leads to the selection of drug-resistant HIV-1 variants. One way to address this problem is to inhibit non-essential host cell proteins that are required for viral replication. Here we show that the activity of HIV-1 integrase stimulates an ataxia-telangiectasia-mutated (ATM)-dependent DNA damage response, and that a deficiency of this ATM kinase sensitizes cells to retrovirus-induced cell death. Consistent with these observations, we demonstrate that a novel and specific small molecule inhibitor of ATM kinase activity, KU-55933, is capable of suppressing the replication of both wild-type and drug-resistant HIV-1.     

ALG-2: a Ca2+ -binding modulator protein involved in cell proliferation and in cell death

During the development of an organism, cell proliferation, differentiation and cell death are tightly balanced, and are controlled by a number of different regulators. Alterations in this balance are often observed in a variety of human diseases. The role of Ca(2+) as one of the key regulators of the cell is discussed with respect to a recently discovered Ca(2+)-binding protein, ALG-2, which is highly upregulated in cancerous tissues of different origins. The role of ALG-2 as a possible clinical marker and, molecularly, as a possible modulator at the interface between cell proliferation and cell death is discussed.     

Amniotic Fluid Enhances Allogeneic Cytotoxic T Cell Responses,Whereas It Suppresses Mitogen-Stimulated Lymphocyte Proliferation

Mouse amniotic fluid has been shown to suppress T lymphocyte proliferation and suggested to be important in regulating immunity during pregnancy. In allogeneic pregnancy, cytotoxic T cells in pregnant lymphocytes against paternal transplantation antigen are impaired. We examined the effect of amniotic fluid to the alloreactive CTL responses. Although the amniotic fluid suppressed Con A or LPS stimulated lymphocyte proliferation as previously reported, the amniotic fluid taken from syngeneic C57BL/6 pregnant mice or allogeneic C57BL/6 × BALB/c pregnant mice enhanced the anti-H-2^d or anti-H-2^k CTL responses dose-dependently. We speculate that amniotic fluid contains not only immunosuppressive factors but also immunoenhancing factors which upregulate the allogeneic CTL responses.     

Convenient rapid determination of picomole amounts of oxaloacetate and aspartate

The assay of oxaloacetate based on the citrate synthase catalyzed conversion of labeled acetyl-CoA to citrate has been greatly simplified by the development of a charcoal separation method for the selective adsorption of acetyl-CoA. An application of this procedure for the determination of oxaloacetate in rat livers is described. By coupling to glutamate oxaloacetate transaminase, the procedure enables determination of aspartate. It allows also a sensitive assay of glutamate oxaloacetate transaminase activity.     

Huntington’s Disease and Mitochondrial DNA Deletions: Event or Regular Mechanism for Mutant Huntingtin Protein and CAG Repeats Expansion?!

The mitochondrial DNA (mtDNA) may play an essential role in the pathogenesis of the respiratory chain complex activities in neurodegenerative disorders such as Huntington's disease (HD). Research studies were conducted to determine the possible levels of mitochondrial defect (deletion) in HD patients and consideration of interaction between the expanded Huntingtin gene as a nuclear gene and mitochondria as a cytoplasmic organelle. To determine mtDNA damage, we investigated deletions based in four areas of mitochondrial DNA, in a group of 60 Iranian patients clinically diagnosed with HD and 70 healthy controls. A total of 41 patients out of 60 had CAG expansion (group A). About 19 patients did not show expansion but had the clinical symptoms of HD (group B). MtDNA deletions were classified into four groups according to size; 9 kb, 7.5 kb, 7 kb, and 5 kb. We found one of the four-mtDNA deletions in at least 90% of samples. Multiple deletions have also been observed in 63% of HD patients. None of the normal control (group C) showed mtDNA deletions. The sizes or locations of the deletions did not show a clear correlation with expanded CAG repeat and age in our samples. The study presented evidence that HD patients had higher frequencies of mtDNA deletions in lymphocytes in comparison to the controls. It is thus proposed that CAG repeats instability and mutant Htt are causative factor in mtDNA damage.     

Community Based Fisheries Management and Fisher Livelihoods: Bangladesh Case Studies

Poor fishers in Bangladesh have been disadvantaged by policies that favored powerful people leasing fishing rights. Community-based management was expected to improve fisher access, livelihoods, and the sustainability of fisheries. The impacts of community management in three floodplain waterbodies differed according to the environment and property rights. Where a set of fishers jointly held exclusive rights to a small enclosed lake they increased production by stocking fish and shared the returns. This strategy is productive but attracts competition for profits and fish consumption was unchanged. Access to capture fisheries in floodplain waterbodies enables the poor to catch diverse small fish for their consumption. Yet sustainability requires limits on fishing. Fish sanctuaries were respected, yet catches per day fell when more people from several villages increased fishing effort in a large wetland, while a tightly knit community restored the fishery in a smaller floodplain. Community organizations will need recognition of their long-term use rights to overcome future threats.

Hybrid poly-l-lactic acid/poly(ε-caprolactone) nanofibrous scaffold can improve biochemical and molecular markers of human induced pluripotent stem cell-derived hepatocyte-like cells

A suitable alternative strategy for liver transplantation is the use of nanofibrous scaffolds together with stem cells. In this study, a random hybrid of poly-l -lactic acid (PLLA) and poly(ε-caprolactone) (PCL) was used as a three-dimensional (3D) culture for differentiation of hepatocyte-like cells and compared with routine culture (two-dimensional [2D]). The expression of the endodermal marker, forkhead box A2 (FOXA2), was assessed on Day 3 and the hepatic markers; albumin (ALB), α-1 antitrypsin (AAT), and cytokeratin-18 (CK-18) were evaluated on Day 18 using quantitative polymerase chain reaction qPCR. As well as, ALB, α-fetoprotein (AFP), and low-density lipoprotein (LDL) uptake were evaluated using immunocytochemistry; moreover, periodic acid-Schiff and Oil Red were done by cell staining. In addition, AFP and urea production were evaluated by chemiluminescence and colorimetric assays. Light and scanning electron microscopy (SEM) showed changes in the cells in 2D and 3D models. The gene expression of hepatic markers was significantly higher in the 3D cultures. In addition, immunocytochemistry and cell staining showed that ALB, AFP, LDL-uptake, periodic acid-Schiff, and Oil Red were expressed in both cells derived on 2D and 3D. Furthermore, the evaluation of AFP and urea secretion was significantly different between 2D and 3D strategies. These findings suggest that functionally cells cultured on a PLLA/PCL scaffold may be suitable for cell therapy and regenerative medicine.     

Genetic discoveries and advances in late-onset Alzheimer’s disease

Alzheimer’s disease (AD) is a heterogeneous disorder with multiple patterns of clinical manifestations. Recently, due to the advance of linkage studies, next-generation sequencing and genome-wide association studies, a large number of putative risk genes for AD have been identified using acquired genome mega data. The genetic association between three causal genes, including amyloid precursor protein, presenilin1, and presenilin2 in early-onset AD (EOAD), was discovered over the past few decades. These discoveries showed that there should be additional genetic risk factors for both EOAD and late-onset AD (LOAD) to help fully explain the leading molecular mechanisms in a single pathophysiological entity. This study reviews the clinical features and genetic etiology of LOAD and discusses a variety of AD-mediated genes that are involved in cholesterol and lipid metabolism, endocytosis, and immune response according to their mutations for more efficient selection of functional candidate genes for LOAD. New mechanisms and pathways have been identified as a result.     

Water use dynamics of dryland canola (Brassica napus L.) grown on contrasting soils under elevated CO2

Plant and Soil - Increasing atmospheric carbon dioxide concentration ([CO2]) stimulates the leaf-level (intrinsic) water use efficiency (iWUE), which may mitigate the adverse effects of drought by...