A model of toxic neuropathy in Drosophila reveals a role for MORN4 in promoting axonal degeneration

Axonal degeneration is a molecular self-destruction cascade initiated following traumatic, toxic, and metabolic insults. Its mechanism underlies a number of disorders including hereditary and diabetic neuropathies and the neurotoxic side effects of chemotherapy drugs. Molecules that promote axonal degeneration could represent potential targets for therapy. To identify such molecules, we designed a screening platform based on intoxication of Drosophila larvae with paclitaxel (taxol), a chemotherapeutic agent that causes neuropathy in cancer patients. In Drosophila, taxol treatment causes swelling, fragmentation, and loss of axons in larval peripheral nerves. This axonal loss is not due to apoptosis of neurons. Taxol-induced axonal degeneration in Drosophila shares molecular execution mechanisms with vertebrates, including inhibition by both NMNAT (nicotinamide mononucleotide adenylyltransferase) expression and loss of wallenda/DLK (dual leucine zipper kinase). In a pilot RNAi-based screen we found that knockdown of retinophilin (rtp), which encodes a MORN (membrane occupation and recognition nexus) repeat-containing protein, protects axons from degeneration in the presence of taxol. Loss-of-function mutants of rtp replicate this axonal protection. Knockdown of rtp also delays axonal degeneration in severed olfactory axons. We demonstrate that the mouse ortholog of rtp, MORN4, promotes axonal degeneration in mouse sensory axons following axotomy, illustrating conservation of function. Hence, this new model can identify evolutionarily conserved genes that promote axonal degeneration, and so could identify candidate therapeutic targets for a wide-range of axonopathies

A simulated study of implicit feedback models

In this paper we report on a study of implicit feedback models for unobtrusively tracking the information needs of searchers. Such models use relevance information gathered from searcher interaction and can be a potential substitute for explicit relevance feedback. We introduce a variety of implicit feedback models designed to enhance an Information Retrieval (IR) system's representation of searchers' information needs. To benchmark their performance we use a simulation-centric evaluation methodology that measures how well each model learns relevance and improves search effectiveness. The results show that a heuristic-based binary voting model and one based on Jeffrey's rule of conditioning [5] outperform the other models under investigation

Effects of dietary energy on reproductive function and production in suckled beef cows

Twenty-eight Hereford x Angus cows were utilized to determine the effects of dietary energy level before and after calving on reproductive function and production in suckled beef cows. Low levels of dietary energy before calving resulted in losses of body composition prior to calving, reduced calf birth weight, lengthened intervals from calving to ovulation, and decreased milk production and calf weight at 70 d of age (P\u3c.05). Low levels of dietary energy after calving decreased measures of body composition after calving, reduced the percentage of cows that ovulated following calving, and decreased cow milk production and calf weight at 70 d of age (P\u3c .05). We conclude that dietary energy before and after calving impacts the reproductive function and production of suckled beef cows

Influence of source and amount of dietary protein on the performance and reproductive function of first-calf heifers

Increasing the amount of dietary protein above the NRC requirement increased weight gain of nursing first-calf heifers. Feeding a protein source with higher ruminal escape potential and increasing protein in the diet both improved calf gains. No significant changes in reproductive function or milk production were observed from either source or amount of dietary protein

TMEM184b promotes axon degeneration and neuromuscular junction maintenance

UNLABELLED: Complex nervous systems achieve proper connectivity during development and must maintain these connections throughout life. The processes of axon and synaptic maintenance and axon degeneration after injury are jointly controlled by a number of proteins within neurons, including ubiquitin ligases and mitogen activated protein kinases. However, our understanding of these molecular cascades is incomplete. Here we describe the phenotype resulting from mutation of TMEM184b, a protein identified in a screen for axon degeneration mediators. TMEM184b is highly expressed in the mouse nervous system and is found in recycling endosomes in neuronal cell bodies and axons. Disruption of TMEM184b expression results in prolonged maintenance of peripheral axons following nerve injury, demonstrating a role for TMEM184b in axon degeneration. In contrast to this protective phenotype in axons, uninjured mutant mice have anatomical and functional impairments in the peripheral nervous system. Loss of TMEM184b causes swellings at neuromuscular junctions that become more numerous with age, demonstrating that TMEM184b is critical for the maintenance of synaptic architecture. These swellings contain abnormal multivesicular structures similar to those seen in patients with neurodegenerative disorders. Mutant animals also show abnormal sensory terminal morphology. TMEM184b mutant animals are deficient on the inverted screen test, illustrating a role for TMEM184b in sensory-motor function. Overall, we have identified an important function for TMEM184b in peripheral nerve terminal structure, function, and the axon degeneration pathway. SIGNIFICANCE STATEMENT: Our work has identified both neuroprotective and neurodegenerative roles for a previously undescribed protein, TMEM184b. TMEM184b mutation causes delayed axon degeneration following peripheral nerve injury, indicating that it participates in the degeneration process. Simultaneously, TMEM184b mutation causes progressive structural abnormalities at neuromuscular synapses and swellings within sensory terminals, and animals with this mutation display profound weakness. Thus, TMEM184b is necessary for normal peripheral nerve terminal morphology and maintenance. Loss of TMEM184b results in accumulation of autophagosomal structures in vivo, fitting with emerging studies that have linked autophagy disruption and neurological disease. Our work recognizes TMEM184b as a new player in the maintenance of the nervous system

Localized modes at a D-brane--O-plane intersection and heterotic Alice strings

We study a system of $N_c$ $D3$-branes intersecting $D7$-branes and $O7$-planes in 1+1-dimensions. We use anomaly cancellation and string dualities to argue that there must be chiral fermion zero-modes on the $D3$-branes which are localized near the $O7$-planes. Away from the orientifold limit we verify this by using index theory as well as explicit construction of the zero-modes. This system is related to F-theory on K3 and heterotic matrix string theory, and the heterotic strings are related to Alice string defects in $\mathcal{N}=4$ Super-Yang-Mills. In the limit of large $N_c$ we find an $AdS_3$ dual of the heterotic matrix string CFT.Comment: 44 pages, typos corrected, version published in JHE

Kinetics and Mechanism of Hydroxyapatite Crystal Dissolution in Weak Acid Buffers Using the Rotating Disk Method

The dissolution rates of synthetic hydroxyapatite pellets under sink conditions were measured using the rotating disk method. The experimental data were analyzed by means of a physical model that yielded an ionic activity product of KHAP = a10Ca2+ a6 PO4 3- a2OH- = 1 × 10-124.5±1.0 that was found to govern the dissolution reaction. Also, a surface resistance factor of k' equal to about 174 sec/cm was deduced from the data.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67157/2/10.1177_00220345760550033201.pd

Simulating (electro)hydrodynamic effects in colloidal dispersions: smoothed profile method

Previously, we have proposed a direct simulation scheme for colloidal dispersions in a Newtonian solvent [Phys.Rev.E 71,036707 (2005)]. An improved formulation called the ``Smoothed Profile (SP) method'' is presented here in which simultaneous time-marching is used for the host fluid and colloids. The SP method is a direct numerical simulation of particulate flows and provides a coupling scheme between the continuum fluid dynamics and rigid-body dynamics through utilization of a smoothed profile for the colloidal particles. Moreover, the improved formulation includes an extension to incorporate multi-component fluids, allowing systems such as charged colloids in electrolyte solutions to be studied. The dynamics of the colloidal dispersions are solved with the same computational cost as required for solving non-particulate flows. Numerical results which assess the hydrodynamic interactions of colloidal dispersions are presented to validate the SP method. The SP method is not restricted to particular constitutive models of the host fluids and can hence be applied to colloidal dispersions in complex fluids

Facts, Values and Quanta

Quantum mechanics is a fundamentally probabilistic theory (at least so far as the empirical predictions are concerned). It follows that, if one wants to properly understand quantum mechanics, it is essential to clearly understand the meaning of probability statements. The interpretation of probability has excited nearly as much philosophical controversy as the interpretation of quantum mechanics. 20th century physicists have mostly adopted a frequentist conception. In this paper it is argued that we ought, instead, to adopt a logical or Bayesian conception. The paper includes a comparison of the orthodox and Bayesian theories of statistical inference. It concludes with a few remarks concerning the implications for the concept of physical reality.Comment: 30 pages, AMS Late

Colonization of vancomycin-resistant Enterococcus faecium in human-derived colonic epithelium: Unraveling the transcriptional dynamics of host-enterococcal interactions

Enterococcus faecium is an opportunistic pathogen able to colonize the intestines of hospitalized patients. This initial colonization is an important step in the downstream pathogenesis, which includes outgrowth of the intestinal microbiota and potential infection of the host. The impact of intestinal overgrowth on host-enterococcal interactions is not well understood. We therefore applied a RNAseq approach in order to unravel the transcriptional dynamics of E. faecium upon co-culturing with human derived colonic epithelium. Co-cultures of colonic epithelium with a hospital-associated vancomycin resistant (vanA-type) E. faecium (VRE) showed that VRE resided on top of the colonic epithelium when analyzed by microscopy. RNAseq revealed that exposure to the colonic epithelium resulted in upregulation of 238 VRE genes compared to the control condition, including genes implicated in pili expression, conjugation (plasmid_2), genes related to sugar uptake, and biofilm formation (chromosome). In total, 260 were downregulated, including the vanA operon located on plasmid_3. Pathway analysis revealed an overall switch in metabolism to amino acid scavenging and reduction. In summary, our study demonstrates that co-culturing of VRE with human colonic epithelium promotes an elaborate gene response in VRE, enhancing our insight in host-E. faecium interactions, which might facilitate the design of novel anti-infectivity strategies