Refractory seizures with global developmental delay: A rare cause

Aicardi syndrome is a genetic disorder characterized by the triad of infantile spasm in flexion, callosal agenesis and ocular abnormalities (chorioretinal lacunae, coloboma of optic disc). We report a typical case of Aicardi syndrome with all the classical features.     

Assembling Fe/S-clusters and modifying tRNAs: ancient co-factors meet ancient adaptors

Trypanosoma brucei undergoes two clearly distinct develomental stages: in the insect vector (procyclic stage) the cells generate the bulk of their energy through respiration, whereas in the bloodstream of the mammalian host (bloodstream stage) they grow mostly glycolytically. Several mitochondrial respiratory proteins require iron-sulfur clusters for activity, and their activation coincides with developmental changes. Likewise some tRNA modification enzymes either require iron-sulfur clusters or use components of the iron-sulfur cluster assembly pathway for activity. These enzymes affect the anticodon loop of various tRNAs and can impact protein synthesis. Herein, the possibility of these pathways being integrated and exploited by T. brucei to carefully coordinate energy demands to translational rates in response to enviromental changes is examined.     

How a neutral evolutionary ratchet can build cellular complexity

Complex cellular machines and processes are commonly believed to be products of selection, and it is typically understood to be the job of evolutionary biologists to show how selective advantage can account for each step in their origin and subsequent growth in complexity. Here, we describe how complex machines might instead evolve in the absence of positive selection through a process of "presuppression," first termed constructive neutral evolution (CNE) more than a decade ago. If an autonomously functioning cellular component acquires mutations that make it dependent for function on another, pre-existing component or process, and if there are multiple ways in which such dependence may arise, then dependence inevitably will arise and reversal to independence is unlikely. Thus, CNE is a unidirectional evolutionary ratchet leading to complexity, if complexity is equated with the number of components or steps necessary to carry out a cellular process. CNE can explain "functions" that seem to make little sense in terms of cellular economy, like RNA editing or splicing, but it may also contribute to the complexity of machines with clear benefit to the cell, like the ribosome, and to organismal complexity overall. We suggest that CNE-based evolutionary scenarios are in these and other cases less forced than the selectionist or adaptationist narratives that are generally told.     

Potential impact of antiretroviral therapy and screening on cervical cancer mortality in HIV-positive women in sub-Saharan Africa: a simulation

Background

Despite having high cervical cancer incidence and mortality rates, screening for cervical precancerous lesions remains infrequent in sub-Saharan Africa. The need to screen HIV-positive women because of the higher prevalence and faster progression of cervical precancerous lesions may be heightened by the increased access to highly-active antiretroviral therapy (HAART). Policymakers need quantitative data on the effect of HAART and screening to better allocate limited resources. Our aim was to quantify the potential effect of these interventions on cervical cancer mortality.

Methods and Findings

We constructed a Markov state-transition model of a cohort of HIV-positive women in Cameroon. Published data on the prevalence, progression and regression of lesions as well as mortality rates from HIV, cervical cancer and other causes were incorporated into the model. We examined the potential impact, on cumulative cervical cancer mortality, of four possible scenarios: no HAART and no screening (NHNS), HAART and no screening (HNS), HAART and screening once on HAART initiation (HSHI), and HAART and screening once at age 35 (HS35). Our model projected that, compared to NHNS, lifetime cumulative cervical cancer mortality approximately doubled with HNS. It will require 262 women being screened at HAART initiation to prevent one cervical cancer death amongst women on HAART. The magnitudes of these effects were most sensitive to the rate of progression of precancerous lesions.

Conclusions

Screening, even when done once, has the potential of reducing cervical cancer mortality among HIV-positive women in Africa. The most feasible and cost-effective screening strategy needs to be determined in each setting.     

Synthesis of functionalized amphiphilic polymers for coating quantum dots

Quantum dots (QDs) need to be attached to other chemical species if they are to be used as biomarkers, therapeutic agents or sensors. These materials also need to disperse well in water and have well-defined functional groups on their surfaces. QDs are most often synthesized in the presence of ligands such as trioctylphosphine oxide, which render the nanoparticle surfaces hydrophobic. We present a complete protocol for the synthesis and water solubilization of hydrophobic CdSe/ZnS QDs using designer amphiphilic polymeric coatings. The method is based on functionalization of an anhydride polymer backbone with nucleophilic agents. Small functional groups, bulky cyclic compounds and polymeric chains can be integrated into the coating prior to solubilization. We describe the preparation of acetylene- and azide-functionalized QDs for 'click' chemistry. The method is universal and applicable to any type of nanoparticle stabilized with hydrophobic ligands able to interact with the alkyl chains in the coating in water.     

MRI-based finite-element analysis of left ventricular aneurysm

Tagged MRI and finite-element (FE) analysis are valuable tools in analyzing cardiac mechanics. To determine systolic material parameters in three-dimensional stress-strain relationships, we used tagged MRI to validate FE models of left ventricular (LV) aneurysm. Five sheep underwent anteroapical myocardial infarction (25% of LV mass) and 22 wk later underwent tagged MRI. Asymmetric FE models of the LV were formed to in vivo geometry from MRI and included aneurysm material properties measured with biaxial stretching, LV pressure measurements, and myofiber helix angles measured with diffusion tensor MRI. Systolic material parameters were determined that enabled FE models to reproduce midwall, systolic myocardial strains from tagged MRI (630 +/- 187 strain comparisons/animal). When contractile stress equal to 40% of the myofiber stress was added transverse to the muscle fiber, myocardial strain agreement improved by 27% between FE model predictions and experimental measurements (RMS error decreased from 0.074 +/- 0.016 to 0.054 +/- 0.011, P < 0.05). In infarct border zone (BZ), end-systolic midwall stress was elevated in both fiber (24.2 +/- 2.7 to 29.9 +/- 2.4 kPa, P < 0.01) and cross-fiber (5.5 +/- 0.7 to 11.7 +/- 1.3 kPa, P = 0.02) directions relative to noninfarct regions. Contrary to previous hypotheses but consistent with biaxial stretching experiments, active cross-fiber stress development is an integral part of LV systole; FE analysis with only uniaxial contracting stress is insufficient. Stress calculations from these validated models show 24% increase in fiber stress and 115% increase in cross-fiber stress at the BZ relative to remote regions, which may contribute to LV remodeling.     

Platelet-derived growth factor D, tissue-specific expression in the eye, and a key role in control of lens epithelial cell proliferation

Platelet-derived growth factor D (PDGF-D), also known as Iris-expressed growth factor, is a member of the PDGF/vascular endothelial growth factor family. The expression of PDGF-D in the eye is tissue-specific. In the anterior segment, it is localized to iris and ciliary body, whereas in the retina, PDGF-D is restricted to the outer plexiform layer. PDGF-D is present in aqueous humor but is not detectable in mature lens or in mouse lens-derived alphaTN4-1 cells. However, it is expressed in rabbit lens-derived N/N1003A cells. N/N1003A cell-conditioned medium stimulates proliferation in rat lens explants, and this is blocked by immunodepletion of PDGF-D. Immunopurified PDGF-D also stimulates cell proliferation in rat lens explants and in NIH 3T3 cells. In organ culture of rat eye anterior segments, anti-PDGF-D strongly inhibits lens epithelial cell proliferation. This finding suggests a major in vivo role for PDGF-D in the mechanisms of coordinated growth of eye tissues. Intervention in the PDGF-D pathway in the eye, perhaps by antibody or blocking peptide, could be useful in the treatment of certain cataracts, including post-operative secondary cataract.