The endoplasmic reticulum remains functionally connected by vesicular transport after its fragmentation in cells expressing Z-alpha(1)-antitrypsin

α1-Antitrypsin is a serine protease inhibitor produced in the liver that is responsible for the regulation of pulmonary inflammation. The commonest pathogenic gene mutation yields Z-α1-antitrypsin, which has a propensity to self-associate forming polymers that become trapped in inclusions of endoplasmic reticulum (ER). It is unclear whether these inclusions are connected to the main ER network in Z-α1-antitrypsin-expressing cells. Using live cell imaging, we found that despite inclusions containing an immobile matrix of polymeric α1-antitrypsin, small ER resident proteins can diffuse freely within them. Inclusions have many features to suggest they represent fragmented ER, and some are physically separated from the tubular ER network, yet we observed cargo to be transported between them in a cytosol-dependent fashion that is sensitive to N-ethylmaleimide and dependent on Sar1 and sec22B. We conclude that protein recycling occurs between ER inclusions despite their physical separation.—Dickens, J. A., Ordóñez, A., Chambers, J. E., Beckett, A. J., Patel, V., Malzer, E., Dominicus, C. S., Bradley, J., Peden, A. A., Prior, I. A., Lomas, D. A., Marciniak, S. J. The endoplasmic reticulum remains functionally connected by vesicular transport after its fragmentation in cells expressing Z-α1-antitrypsin

Ion beam generated surface ripples: new insight in the underlying mechanism

A new hydrodynamic mechanism is proposed for the ion beam induced surface patterning on solid surfaces. Unlike the standard mechanisms based on the ion beam impact generated erosion and mass redistribution at the free surface (proposed by Bradley-Harper (BH) and its extended theories), the new mechanism proposes that the ion beam induced saltation and creep processes, coupled with incompressible solid flow in amorphous layer, leads to the formation of ripple patterns at the amorphous/crystalline (a/c) interface and hence at the free surface. Ion beam stimulated solid flow inside the amorphous layer controls the wavelength, where as the amount of material transported and re-deposited at a/c interface control the amplitude of ripples. The new approach is verified by designed experiments and supported by the discrete simulation method.Comment: 12 pages, 6 figures. arXiv admin note: substantial text overlap with arXiv:1206.082

Non-polynomial Worst-Case Analysis of Recursive Programs

We study the problem of developing efficient approaches for proving worst-case bounds of non-deterministic recursive programs. Ranking functions are sound and complete for proving termination and worst-case bounds of nonrecursive programs. First, we apply ranking functions to recursion, resulting in measure functions. We show that measure functions provide a sound and complete approach to prove worst-case bounds of non-deterministic recursive programs. Our second contribution is the synthesis of measure functions in nonpolynomial forms. We show that non-polynomial measure functions with logarithm and exponentiation can be synthesized through abstraction of logarithmic or exponentiation terms, Farkas' Lemma, and Handelman's Theorem using linear programming. While previous methods obtain worst-case polynomial bounds, our approach can synthesize bounds of the form $\mathcal{O}(n\log n)$ as well as $\mathcal{O}(n^r)$ where $r$ is not an integer. We present experimental results to demonstrate that our approach can obtain efficiently worst-case bounds of classical recursive algorithms such as (i) Merge-Sort, the divide-and-conquer algorithm for the Closest-Pair problem, where we obtain $\mathcal{O}(n \log n)$ worst-case bound, and (ii) Karatsuba's algorithm for polynomial multiplication and Strassen's algorithm for matrix multiplication, where we obtain $\mathcal{O}(n^r)$ bound such that $r$ is not an integer and close to the best-known bounds for the respective algorithms.Comment: 54 Pages, Full Version to CAV 201

The dosimetric effects of limited elective nodal irradiation in volumetric modulated arc therapy treatment planning for locally advanced non-small cell lung cancer

Objective—Contemporary radiotherapy guidelines for locally advanced non-small cell lung carcinoma (LA-NSCLC) recommend omitting elective nodal irradiation, despite the fact that evidence supporting this came primarily from older reports assessing comprehensive nodal coverage using 3D conformal techniques. Herein, we evaluated the dosimetric implications of the addition of limited elective nodal irradiation (LENI) to standard involved field irradiation (IFI) using volumetric modulated arc therapy (VMAT) planning. Method—Target volumes and organs-at-risk (OARs) were delineated on CT simulation images of 20 patients with LA-NSCLC. Two VMAT plans (IFI and LENI) were generated for each patient. Involved sites were treated to 60 Gy in 30 fractions for both IFI and LENI plans. Adjacent uninvolved nodal regions, considered high risk based on the primary tumor site and extent of nodal involvement, were treated to 51 Gy in 30 fractions in LENI plans using a simultaneous integrated boost approach. Results—All planning objectives for PTVs and OARs were achieved for both IFI and LENI plans. LENI resulted in significantly higher esophagus Dmean (15.3 vs. 22.5 Gy, p \u3c 0.01), spinal cord Dmax (34.9 vs. 42.4 Gy, p = 0.02) and lung Dmean (13.5 vs. 15.9 Gy, p = 0.02), V20 (23.0 vs. 27.9%, p = 0.03), and V5 (52.6 vs. 59.4%, p = 0.02). No differences were observed in heart parameters. On average, only 32.2% of the high-risk nodal volume received an incidental dose of 51 Gy when untargeted in IFI plans. Conclusion—The addition of LENI to VMAT plans for LA-NSCLC is feasible, with only modestly increased doses to OARs and marginal expected increase in associated toxicity

Pancreatic pseudocystwith stent placement in the background of narcotic use: a case report

A 49 year old gentleman presents with recurrent abdominal pain. The patient has a known history of chronic pancreatitis, alcoholism and narcotic addiction. Work-up, including computed tomography (CT) of the abdomen, demonstrated a 5.6 × 5.8 cm fluid collection contiguous with the pancreas. This was not seen on CT 18 months earlier. The patient's pain did not improve with bowel rest and pain control. He was transferred to another institution for endoscopic placement of a transgastric pancreatic stent. The procedure decreased the size the cyst and the patient's pain became more manageable

Developing cardiac and skeletal muscle share fast-skeletal myosin heavy chain and cardiac troponin-I expression

Skeletal muscle derived stem cells (MDSCs) transplanted into injured myocardium can differentiate into fast skeletal muscle specific myosin heavy chain (sk-fMHC) and cardiac specific troponin-I (cTn-I) positive cells sustaining recipient myocardial function. We have recently found that MDSCs differentiate into a cardiomyocyte phenotype within a three-dimensional gel bioreactor. It is generally accepted that terminally differentiated myocardium or skeletal muscle only express cTn-I or sk-fMHC, respectively. Studies have shown the presence of non-cardiac muscle proteins in the developing myocardium or cardiac proteins in pathological skeletal muscle. In the current study, we tested the hypothesis that normal developing myocardium and skeletal muscle transiently share both sk-fMHC and cTn-I proteins. Immunohistochemistry, western blot, and RT-PCR analyses were carried out in embryonic day 13 (ED13) and 20 (ED20), neonatal day 0 (ND0) and 4 (ND4), postnatal day 10 (PND10), and 8 week-old adult female Lewis rat ventricular myocardium and gastrocnemius muscle. Confocal laser microscopy revealed that sk-fMHC was expressed as a typical striated muscle pattern within ED13 ventricular myocardium, and the striated sk-fMHC expression was lost by ND4 and became negative in adult myocardium. cTn-I was not expressed as a typical striated muscle pattern throughout the myocardium until PND10. Western blot and RT-PCR analyses revealed that gene and protein expression patterns of cardiac and skeletal muscle transcription factors and sk-fMHC within ventricular myocardium and skeletal muscle were similar at ED20, and the expression patterns became cardiac or skeletal muscle specific during postnatal development. These findings provide new insight into cardiac muscle development and highlight previously unknown common developmental features of cardiac and skeletal muscle. © 2012 Clause et al

Action video game playing is associated with improved visual sensitivity, but not alterations in visual sensory memory

Action video game playing has been experimentally linked to a number of perceptual and cognitive improvements. These benefits are captured through a wide range of psychometric tasks and have led to the proposition that action video game experience may promote the ability to extract statistical evidence from sensory stimuli. Such an advantage could arise from a number of possible mechanisms: improvements in visual sensitivity, enhancements in the capacity or duration for which information is retained in visual memory, or higher-level strategic use of information for decision making. The present study measured the capacity and time course of visual sensory memory using a partial report performance task as a means to distinguish between these three possible mechanisms. Sensitivity measures and parameter estimates that describe sensory memory capacity and the rate of memory decay were compared between individuals who reported high evels and low levels of action video game experience. Our results revealed a uniform increase in partial report accuracy at all stimulus-to-cue delays for action video game players but no difference in the rate or time course of the memory decay. The present findings suggest that action video game playing may be related to enhancements in the initial sensitivity to visual stimuli, but not to a greater retention of information in iconic memory buffers

Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA

Zinc status alters Alzheimer's disease progression through NLRP3-dependent inflammation

Alzheimer's disease is a devastating neurodegenerative disease with a dramatically increasing prevalence and no disease-modifying treatment. Inflammatory lifestyle factors increase the risk of developing Alzheimer's disease. Zinc deficiency is the most prevalent malnutrition in the world and may be a risk factor for Alzheimer's disease potentially through enhanced inflammation, although evidence for this is limited. Here we provide epidemiological evidence suggesting that zinc supplementation was associated with reduced risk and slower cognitive decline, in people with Alzheimer's disease and mild cognitive impairment. Using the APP/PS1 mouse model of Alzheimer's disease fed a control (35mg/kg zinc) or diet deficient in zinc (3mg/kg zinc), we determined that zinc deficiency accelerated Alzheimer's-like memory deficits without modifying amyloid b plaque burden in the brains of male mice. The NLRP3-inflammasome complex is one of the most important regulators of inflammation, and we show here that zinc deficiency in immune cells, including microglia, potentiated NLRP3 responses to inflammatory stimuli in vitro, including amyloid oligomers, while zinc supplementation inhibited NLRP3 activation. APP/PS1 mice deficient in NLRP3 were protected against the accelerated cognitive decline with zinc deficiency. Collectively, this research suggests that zinc status is linked to inflammatory reactivity and may be modified in people to reduce the risk and slow the progression of Alzheimer's disease