The mouse anterior chamber angle and trabecular meshwork develop without cell death

BACKGROUND: The iridocorneal angle forms in the mammalian eye from undifferentiated mesenchyme between the root of the iris and cornea. A major component is the trabecular meshwork, consisting of extracellular matrix organized into a network of beams, covered in trabecular endothelial cells. Between the beams, channels lead to Schlemm's canal for the drainage of aqueous humor from the eye into the blood stream. Abnormal development of the iridocorneal angle that interferes with ocular fluid drainage can lead to glaucoma in humans. Little is known about the precise mechanisms underlying angle development. There are two main hypotheses. The first proposes that morphogenesis involves mainly cell differentiation, matrix deposition and assembly of the originally continuous mesenchymal mass into beams, channels and Schlemm's canal. The second, based primarily on rat studies, proposes that cell death and macrophages play an important role in forming channels and beams. Mice provide a potentially useful model to understand the origin and development of angle structures and how defective development leads to glaucoma. Few studies have assessed the normal structure and development of the mouse angle. We used light and electron microscopy and a cell death assay to define the sequence of events underlying formation of the angle structures in mice. RESULTS: The mouse angle structures and developmental sequence are similar to those in humans. Cell death was not detectable during the period of trabecular channel and beam formation. CONCLUSIONS: These results support morphogenic mechanisms involving organization of cellular and extracellular matrix components without cell death or atrophy

Rivastigmine in Chinese patients with subcortical vascular dementia

Vincent Mok1, Adrian Wong1, Simon Ho2, Thomas Leung1, Wynnie WM Lam2, Ka Sing Wong11Department of Medicine and Therapeutics; 2Department of Radiology and Organ Imaging, The Chinese University of Hong Kong, Shatin, Hong Kong, ChinaBackground: We explored the efficacy and tolerability of rivastigmine among Chinese patients with subcortical vascular dementia.Methods: Forty subjects were randomized to either placebo (n = 20) or rivastigmine (n = 20) in a double-blind 26-week trial. Outcome measures were cognition (mini-mental state examination, frontal assessment battery), neuropsychiatric inventory (NPI), instrumental activities of daily living, clinical dementia rating scale, and adverse events.Results: No statistical significant benefit could be observed in the active group in any of the efficacy measures. A trend favoring active group was observed only in the NPI subscore of irritability (p = 0.066) and aberrant motor behavior (p = 0.068). Withdrawal rate was 30% and 15% in the active and placebo group, respectively.Conclusion: Among Chinese subcortical vascular dementia patients, there was no apparent cognitive benefit associated with use of rivastigmine over the 6 months period. A trend favoring rivastigmine was observed in certain behavioral measures. Rivastigmine was associated with more withdrawals relative to placebo.Keywords: rivastigmine, subcortical vascular dementia, Chines

GpnmbR150X allele must be present in bone marrow derived cells to mediate DBA/2J glaucoma

<p>Abstract</p> <p>Background</p> <p>The <it>Gpnmb </it>gene encodes a transmembrane protein whose function(s) remain largely unknown. Here, we assess if a mutant allele of <it>Gpnmb </it>confers susceptibility to glaucoma by altering immune functions. DBA/2J mice have a mutant <it>Gpnmb </it>gene and they develop a form of glaucoma preceded by a pigment dispersing iris disease and abnormalities of the immunosuppressive ocular microenvironment.</p> <p>Results</p> <p>We find that the <it>Gpnmb </it>genotype of bone-marrow derived cell lineages significantly influences the iris disease and the elevation of intraocular pressure. GPNMB localizes to multiple cell types, including pigment producing cells, bone marrow derived F4/80 positive antigen-presenting cells (APCs) of the iris and dendritic cells. We show that APCs of DBA/2J mice fail to induce antigen induced immune deviation (a form of tolerance) when treated with TGFβ2. This demonstrates that some of the immune abnormalities previously identified in DBA/2J mice result from intrinsic defects in APCs. However, the tested APC defects are not dependent on a mutant <it>Gpnmb </it>gene. Finally, we show that the <it>Gpnmb </it>mediated iris disease does not require elevated IL18 or mature B or T lymphocytes.</p> <p>Conclusion</p> <p>These results establish a role for <it>Gpnmb </it>in bone marrow derived lineages. They suggest that affects of <it>Gpnmb </it>on innate immunity influence susceptibility to glaucoma in DBA/2J mice.</p

Genetic context determines susceptibility to intraocular pressure elevation in a mouse pigmentary glaucoma

BACKGROUND: DBA/2J (D2) mice develop an age-related form of glaucoma. Their eyes progressively develop iris pigment dispersion and iris atrophy followed by increased intraocular pressure (IOP) and glaucomatous optic nerve damage. Mutant alleles of the Gpnmb and Tyrp1 genes are necessary for the iris disease, but it is unknown whether alleles of other D2 gene(s) are necessary for the distinct later stages of disease. We initiated a study of congenic strains to further define the genetic requirements and disease mechanisms of the D2 glaucoma. RESULTS: To further understand D2 glaucoma, we created congenic strains of mice on the C57BL/6J (B6) genetic background. B6 double-congenic mice carrying D2-derived Gpnmb and Tyrp1 mutations develop a D2-like iris disease. B6 single-congenics with only the Gpnmb and Tyrp1 mutations develop milder forms of iris disease. Genetic epistasis experiments introducing a B6 tyrosinase mutation into the congenic strains demonstrated that both the single and double-congenic iris diseases are rescued by interruption of melanin synthesis. Importantly, our experiments analyzing mice at ages up to 27 months indicate that the B6 double-congenic mice are much less prone to IOP elevation and glaucoma than are D2 mice. CONCLUSION: As demonstrated here, the Gpnmb and Tyrp1 iris phenotypes are both individually dependent on tyrosinase function. These results support involvement of abnormal melanosomal events in the diseases caused by each gene. In the context of the inbred D2 mouse strain, the glaucoma phenotype is clearly influenced by more genes than just Gpnmb and Tyrp1. Despite the outward similarity of pigment-dispersing iris disease between D2 and the B6 double-congenic mice, the congenic mice are much less susceptible to developing high IOP and glaucoma. These new congenic strains provide a valuable new resource for further studying the genetic and mechanistic complexity of this form of glaucoma

Absence of glaucoma in DBA/2J mice homozygous for wild-type versions of Gpnmb and Tyrp1

BACKGROUND: The glaucomas are a common but incompletely understood group of diseases. DBA/2J mice develop a pigment liberating iris disease that ultimately causes elevated intraocular pressure (IOP) and glaucoma. We have shown previously that mutations in two genes, Gpnmb and Tyrp1, initiate the iris disease. However, mechanisms involved in the subsequent IOP elevation and optic nerve degeneration remain unclear. RESULTS: Here we present new mouse strains with Gpnmb and/or Tyrp1 genes of normal function and with a DBA/2J genetic background. These strains do not develop elevated IOP or glaucoma with age. CONCLUSION: These strains provide much needed controls for studying pathogenic mechanisms of glaucoma using DBA/2J mice. Given the involvement of Gpnmb and/or Tyrp1 in areas such as immunology and tumor development and progression, these strains are also important in other research fields

Rosetta-Alice Observations of Exospheric Hydrogen and Oxygen on Mars

The European Space Agency's Rosetta spacecraft, en route to a 2014 encounter with comet 67P/Churyumov-Gerasimenko, made a gravity assist swing-by of Mars on 25 February 2007, closest approach being at 01:54UT. The Alice instrument on board Rosetta, a lightweight far-ultraviolet imaging spectrograph optimized for in situ cometary spectroscopy in the 750-2000 A spectral band, was used to study the daytime Mars upper atmosphere including emissions from exospheric hydrogen and oxygen. Offset pointing, obtained five hours before closest approach, enabled us to detect and map the HI Lyman-alpha and Lyman-beta emissions from exospheric hydrogen out beyond 30,000 km from the planet's center. These data are fit with a Chamberlain exospheric model from which we derive the hydrogen density at the 200 km exobase and the H escape flux. The results are comparable to those found from the the Ultraviolet Spectrometer experiment on the Mariner 6 and 7 fly-bys of Mars in 1969. Atomic oxygen emission at 1304 A is detected at altitudes of 400 to 1000 km above the limb during limb scans shortly after closest approach. However, the derived oxygen scale height is not consistent with recent models of oxygen escape based on the production of suprathermal oxygen atoms by the dissociative recombination of O2+.Comment: 17 pages, 8 figures, accepted for publication in Icaru

Inducible nitric oxide synthase, Nos2, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model

<p>Abstract</p> <p>Background</p> <p>Nitric oxide synthase 2 (NOS2) contributes to neural death in some settings, but its role in glaucoma remains controversial. NOS2 is implicated in retinal ganglion cell degeneration in a rat glaucoma model in which intraocular pressure (IOP) is experimentally elevated by blood vessel cauterization, but not in a rat glaucoma model where IOP was elevated by injection of hypertonic saline. To test the importance of NOS2 for an inherited glaucoma, in this study we both genetically and pharmacologically decreased NOS2 activity in the DBA/2J mouse glaucoma model.</p> <p>Methods</p> <p>The expression of <it>Nos2 </it>in the optic nerve head was analyzed at both the RNA and protein levels at different stages of disease pathogenesis. To test the involvement of <it>Nos2 </it>in glaucomatous neurodegeneration, a null allele of <it>Nos2 </it>was backcrossed into DBA/2J mice and the incidence and severity of glaucoma was assessed in mice of each <it>Nos2 </it>genotype. Additionally, DBA/2J mice were treated with the NOS2 inhibitor aminoguanidine and the disease compared to untreated mice.</p> <p>Results</p> <p>Optic nerve head <it>Nos2 </it>RNA levels varied and increased during moderate but decreased at early and severe stages of disease. Despite the presence of a few NOS2 positive cells in the optic nerve head, NOS2 protein was not substantially increased during the glaucoma. Genetic deficiency of <it>Nos2 </it>or aminoguanidine treatment did not alter the IOP profile of DBA/2J mice. Additionally, neither <it>Nos2 </it>deficiency nor aminoguanidine had any detectable affect on the glaucomatous optic nerve damage.</p> <p>Conclusion</p> <p>Glaucomatous neurodegeneration in DBA/2J mice does not require NOS2 activity. Further experiments involving various models are needed to assess the general importance of <it>Nos2 </it>in glaucoma.</p

Neural Network Parameterizations of Electromagnetic Nucleon Form Factors

The electromagnetic nucleon form-factors data are studied with artificial feed forward neural networks. As a result the unbiased model-independent form-factor parametrizations are evaluated together with uncertainties. The Bayesian approach for the neural networks is adapted for chi2 error-like function and applied to the data analysis. The sequence of the feed forward neural networks with one hidden layer of units is considered. The given neural network represents a particular form-factor parametrization. The so-called evidence (the measure of how much the data favor given statistical model) is computed with the Bayesian framework and it is used to determine the best form factor parametrization.Comment: The revised version is divided into 4 sections. The discussion of the prior assumptions is added. The manuscript contains 4 new figures and 2 new tables (32 pages, 15 figures, 2 tables

Bang-bang control of fullerene qubits using ultra-fast phase gates

Quantum mechanics permits an entity, such as an atom, to exist in a superposition of multiple states simultaneously. Quantum information processing (QIP) harnesses this profound phenomenon to manipulate information in radically new ways. A fundamental challenge in all QIP technologies is the corruption of superposition in a quantum bit (qubit) through interaction with its environment. Quantum bang-bang control provides a solution by repeatedly applying `kicks' to a qubit, thus disrupting an environmental interaction. However, the speed and precision required for the kick operations has presented an obstacle to experimental realization. Here we demonstrate a phase gate of unprecedented speed on a nuclear spin qubit in a fullerene molecule (N@C60), and use it to bang-bang decouple the qubit from a strong environmental interaction. We can thus trap the qubit in closed cycles on the Bloch sphere, or lock it in a given state for an arbitrary period. Our procedure uses operations on a second qubit, an electron spin, in order to generate an arbitrary phase on the nuclear qubit. We anticipate the approach will be vital for QIP technologies, especially at the molecular scale where other strategies, such as electrode switching, are unfeasible

Meeting the global protein supply requirements of a growing and ageing population

\ua9 The Author(s) 2024.Human dietary patterns are a major cause of environmental transformation, with agriculture occupying ~ 50% of global land space, while food production itself is responsible for ~ 30% of all greenhouse gas emissions and 70% of freshwater use. Furthermore, the global population is also growing, such that by 2050, it is estimated to exceed ~ 9 billion. While most of this expansion in population is expected to occur in developing countries, in high-income countries there are also predicted changes in demographics, with major increases in the number of older people. There is a growing consensus that older people have a greater requirement for protein. With a larger and older population, global needs for protein are set to increase. This paper summarises the conclusions from a Rank Prize funded colloquium evaluating novel strategies to meet this increasing global protein need