Early changes in gene expression in two models of Batten disease

Infantile and juvenile neuronal ceroid lipofuscinosis (NCLs) are progressive neurodegenerative disorders of childhood with distinct ages of clinical onset, but with a similar pathological outcome. Infantile and juvenile NCL are inherited in an autosomal recessive manner due to mutations in the CLN1 and CLN3 genes, respectively. Recently developed Cln1- and Cln3-knockout mouse models share similarities in pathology with the respective human disease. Using oligonucleotide arrays we identified reproducible changes in gene expression in the brains of both 10-week-old Cln1- and Cln3-knockout mice as compared to wild-type controls, and confirmed changes in levels of several of the cognate proteins by immunoblotting. Despite the similarities in pathology, the two mutations affect the expression of different, non-overlapping sets of genes. The possible significance of these changes and the pathological mechanisms underlying NCL diseases are discussed.     

Pure red upconverted and near-infrared luminescence properties of Er3+-doped SnO2 nanocrystals for lighting applications

Tin oxide (SnO₂) nanocrystalline powders doped with erbium ion (Er³⁺) in different molar ratios (0, 3, 5, and 7 mol%) were prepared using a solid-state reaction technique. These samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), ultraviolet-visible absorption, visible upconversion, and near-infrared luminescence techniques. XRD analysis revealed the tetragonal rutile structure of SnO₂ and the average crystallite size was about 32 nm. From Tauc's plots, it was confirmed that the substitution of Er³⁺ ions into the SnO₂ host lattice resulted in the narrowing its band gap. Optical absorption bands at 520 and 654 nm correspond to the 4f electron transitions of Er³⁺ further confirming visible light absorption. Infrared luminescence spectra showed a broad band centred at 1536 nm which is assigned to the ⁴I_13/2 → ⁴I_15/2 transition of Er³⁺. Visible upconverted emission spectra under 980 nm excitation exhibit a strong red luminescence with a main peak at 672 nm which is attributed to the ⁴F_9/2 → ⁴I_15/2 transition of Er³⁺. Power-dependent upconversion spectra confirmed that two photons participated in the upconversion mechanism. Enhancement in the intensities of both visible and infrared luminescence was observed when raising the concentration. The results pave the way for the potential applications of these nanocrystalline powders in energy harvesting applications such as infrared light upconverting layer in solar cells, light emitting diodes, infrared broadband sources and amplifiers, and biological labelling.     

Overexpression of citrate operon in Herbaspirillum seropedicae Z67 enhances organic acid secretion,mineral phosphate solubilization and growth promotion of Oryza sativa

Background and aims

Herbaspirillum seropedicae Z67, nitrogen fixing endophyte, significantly promotes the growth of cereals. Organic acid secreting nitrogen fixing rhizobacteria have better plant growth promotion abilities due to mineral phosphate solubilization.

Method

Plasmids pAB7, pJNK3 and pJNK4 containing Escherichia coli cs (gltA), NADH insensitive cs (gltA1), and citrate operon consisting of gltA1 gene along with Salmonella typhimurium Na⁺ dependent citrate transporter (citC) gene under constitutive lac promoter were constructed in broad host range plasmid pUCPM18-Km^r. The plasmid transformants of H. seropedicae Z67 were obtained by electroporation.

Results

Hs (pAB7) and Hs (pJNK3) had increased CS activity but citric acid secretion was not significant. Hs (pJNK3) secreted 45 mM acetic acid while Hs (pJNK4) secreted 2.7 mM citric and 51 mM acetic acids. Hs (pJNK3) and Hs (pJNK4) released 80 μM and 110 μM amount of P from rock phosphate, respectively, in buffered medium under both aerobic and micro aerobic conditions. These transformants showed better plant growth promoting factors. Upon inoculation to rice plants (Gujarat – 17), increase of Fresh weight, Dry weight N, P and K content was observed.

Conclusion

Thus the study demonstrates that artificial citrate operon in H. seropedicae Z67 enhances phosphate solubilization and plant growth promotion abilities.     

Tumor necrosis factor inhibitor therapy but not standard therapy is associated with resolution of erosion in the sacroiliac joints of patients with axial spondyloarthritis

Introduction

Radiography is an unreliable and insensitive tool for the assessment of structural lesions in the sacroiliac joints (SIJ). Magnetic resonance imaging (MRI) detects a wider spectrum of structural lesions but has undergone minimal validation in prospective studies. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI Sacroiliac Joint (SIJ) Structural Score (SSS) assesses a spectrum of structural lesions (erosion, fat metaplasia, backfill, ankylosis) and its potential to discriminate between therapies requires evaluation.

Methods

The SSS score assesses five consecutive coronal slices through the cartilaginous portion of the joint on T1-weighted sequences starting from the transitional slice between cartilaginous and ligamentous portions of the joint. Lesions are scored dichotomously (present/absent) in SIJ quadrants (fat metaplasia, erosion) or halves (backfill, ankylosis). Two readers independently scored 147 pairs (baseline, 2 years) of scans from a prospective cohort of patients with SpA who received either standard (n = 69) or tumor necrosis factor alpha (TNFα) inhibitor (n = 78) therapy. Smallest detectable change (SDC) was calculated using analysis of variance (ANOVA), discrimination was assessed using Guyatt’s effect size, and treatment group differences were assessed using t-tests and the Mann–Whitney test. We identified baseline demographic and structural damage variables associated with change in SSS score by univariate analysis and analyzed the effect of treatment by multivariate stepwise regression adjusted for severity of baseline structural damage and demographic variables.

Results

A significant increase in mean SSS score for fat metaplasia (P = 0.017) and decrease in mean SSS score for erosion (P = 0.017) was noted in anti-TNFα treated patients compared to those on standard therapy. Effect size for this change in SSS fat metaplasia and erosion score was moderate (0.5 and 0.6, respectively). Treatment and baseline SSS score for erosion were independently associated with change in SSS erosion score (β = 1.75, P = 0.003 and β = 0.40, P < 0.0001, respectively). Change in ASDAS (β = −0.46, P = 0.006), SPARCC MRI SIJ inflammation (β = −0.077, P = 0.019), and baseline SSS score for fat metaplasia (β = 0.085, P = 0.034) were independently associated with new fat metaplasia.

Conclusion

The SPARCC SSS method for assessment of structural lesions has discriminative capacity in demonstrating significantly greater reduction in erosion and new fat metaplasia in patients receiving anti-TNFα therapy.     

A chemocentric approach to the identification of cancer targets

A novel chemocentric approach to identifying cancer-relevant targets is introduced. Starting with a large chemical collection, the strategy uses the list of small molecule hits arising from a differential cytotoxicity screening on tumor HCT116 and normal MRC-5 cell lines to identify proteins associated with cancer emerging from a differential virtual target profiling of the most selective compounds detected in both cell lines. It is shown that this smart combination of differential in vitro and in silico screenings (DIVISS) is capable of detecting a list of proteins that are already well accepted cancer drug targets, while complementing it with additional proteins that, targeted selectively or in combination with others, could lead to synergistic benefits for cancer therapeutics. The complete list of 115 proteins identified as being hit uniquely by compounds showing selective antiproliferative effects for tumor cell lines is provided.     

Coral reefs studies and threats in Malaysia: a mini review

Coral reefs in Malaysia are about 4,006 km² with over 550 species contributed to nation’s economy. Coral reefs studies and threats in Malaysia have been reviewed briefly. Perspectives are addressed as coral reefs studies, threats, gaps and future studies. Coral reefs in Malaysia are being damaged at an increasing rate where it faces natural and anthropogenic stresses. Excellent summaries are available in terms of coral reefs cover throughout Malaysia however scarce in terms of qualitative, quantitative and biogeographical data. There are also limited studies on heavy metals concentration in corals skeleton studies. Poor to fair conditions of coral reefs in Peninsular Malaysia is due to increases of sedimentation and tourism impacts. Overfishing and fish blasting were main threats of coral reefs damage in Sabah. In Sarawak, coral reefs are threatened by high sedimentation and sand mining. The 1998–1999 bleaching event also affected coral reefs in Malaysia due to climate change. Gaps in coral reefs studies can be completed by continuous collaborations between local and international researchers as well as research by local universities. Economic valuation, policy analysis and community participation are directions in future coral reefs studies in Malaysia. Future studies are to understand effects of management on coral reefs health and impact of pollution on coral reefs growth with a standard coral reefs methodology. Established legal systems to reduce threats received by coral reefs are also need to be introduced. Role of science-driven management with community participation and media mass are also gaps to be highlighted in future studies.     

CO2 exchange and evapotranspiration across dryland ecosystems of southwestern North America

Global‐scale studies suggest that dryland ecosystems dominate an increasing trend in the magnitude and interannual variability of the land CO₂ sink. However, such analyses are poorly constrained by measured CO₂ exchange in drylands. Here we address this observation gap with eddy covariance data from 25 sites in the water‐limited Southwest region of North America with observed ranges in annual precipitation of 100–1000 mm, annual temperatures of 2–25°C, and records of 3–10 years (150 site‐years in total). Annual fluxes were integrated using site‐specific ecohydrologic years to group precipitation with resulting ecosystem exchanges. We found a wide range of carbon sink/source function, with mean annual net ecosystem production (NEP) varying from ‐350 to +330 gCm^?2 across sites with diverse vegetation types, contrasting with the more constant sink typically measured in mesic ecosystems. In this region, only forest‐dominated sites were consistent carbon sinks. Interannual variability of NEP, gross ecosystem production (GEP), and ecosystem respiration (R_eco) was larger than for mesic regions, and half the sites switched between functioning as C sinks/C sources in wet/dry years. The sites demonstrated coherent responses of GEP and NEP to anomalies in annual evapotranspiration (ET), used here as a proxy for annually available water after hydrologic losses. Notably, GEP and R_eco were negatively related to temperature, both interannually within site and spatially across sites, in contrast to positive temperature effects commonly reported for mesic ecosystems. Models based on MODIS satellite observations matched the cross‐site spatial pattern in mean annual GEP but consistently underestimated mean annual ET by ~50%. Importantly, the MODIS‐based models captured only 20–30% of interannual variation magnitude. These results suggest the contribution of this dryland region to variability of regional to global CO₂ exchange may be up to 3–5 times larger than current estimates.     

Synthesis, SAR, and antibacterial activity of novel oxazolidinone analogues possessing urea functionality

The syntheses of a number of novel oxazolidinone analogues possessing an urea functionality are reported. While the urea derivatives possessing aliphatic and aromatic groups were prepared by the more conventional isocyanate method, the derivatives possessing heterocyclic rings were synthesized by a relatively uncommon but otherwise efficient carbamate chemistry. Though the SAR resulted in novel compounds possessing in vitro activity equivalent to Linezolid, the compounds possess a range of substituents that are amenable for altering physicochemical properties of the resultant drug. The antibacterial activity was found to be not sensitive to the functional groups attached to the urea site regardless of the size and electronic characteristics. Based on in vivo results, one molecule has been identified as a candidate and additional work such as salt selection, scale-up, etc., are currently underway to take the molecule further through development.     

Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2)

Infantile and classical late infantile neuronal ceroid lipofuscinoses (NCL) are two recent additions to the expanding spectrum of lysosomal storage disorders caused by deficiencies in lysosomal hydrolases. They are latecomers to the lysosomal storage disorders, probably because of the heterogeneous nature of the storage material, which precluded meaningful biochemical analysis. Infantile NCL is caused by deficiency in palmitoyl-protein thioesterase, an enzyme that hydrolyzes fatty acids from cysteine residues in lipid-modified proteins. Classical late-infantile NCL is caused by a deficiency in tripeptidyl amino peptidase-I, a lysosomal peptidase that removes three amino acids from the free amino terminus of peptides or small proteins. Late-onset forms of these disorders have been described. The clinical, biochemical, and molecular genetic aspects of these two latest lysosomal storage disorders are discussed in this review. In addition, approaches to treatment and future directions for research are examined.     

Performance of 4,5-diphenyl-1H-imidazole derived highly selective ‘Turn-Off’ fluorescent chemosensor for iron(III) ions detection and biological applications

Two fluorescent chemosensors, denoted as chemosensor 1 and chemosensor 2 , were synthesized and subjected to comprehensive characterization using various techniques. The characterization techniques employed were Fourier-transform infrared (FTIR), proton (¹H)- and carbon-13 (¹³C)-nuclear magnetic resonance (NMR) spectroscopy, electrospray ionization (ESI) mass spectrometry, and single crystal X-ray diffraction analysis. Chemosensor 1 is composed of a 1H-imidazole core with specific substituents, including a 4-(2-(4,5-c-2-yl)naphthalene-3-yloxy)butoxy)naphthalene-1-yl moiety. However, chemosensor 2 features a 1H-imidazole core with distinct substituents, such as 4-methyl-2-(4,5-diphenyl-1H-imidazole-2-yl)phenoxy)butoxy)-5-methylphenyl. Chemosensor 1 crystallizes in the monoclinic space group C2/c. Both chemosensors 1 and 2 exhibit a discernible fluorescence quenching response selectively toward iron(III) ion (Fe³⁺) at 435 and 390 nm, respectively, in dimethylformamide (DMF) solutions, distinguishing them from other tested cations. This fluorescence quenching is attributed to the established mechanism of chelation quenched fluorescence (CHQF). The binding constants for the formation of the 1 + Fe³⁺ and 2 + Fe³⁺ complexes were determined using the modified Benesi–Hildebrand equation, yielding values of approximately 2.2 × 10³ and 1.3 × 10⁴ M⁻¹, respectively. The calculated average fluorescence lifetimes for 1 and 1 + Fe³⁺ were 2.51 and 1.17 ns, respectively, while for 2 and 2 + Fe³⁺, the lifetimes were 1.13 and 0.63 ns, respectively. Additionally, the applicability of chemosensors 1 and 2 in detecting Fe³⁺ in live cells was demonstrated, with negligible observed cell toxicity.