Molecular environment and thermal X-ray spectroscopy of the semicircular young composite supernova remnant 3C 396

We have investigated the molecular environment of the semicircular composite supernova remnant (SNR) 3C396 and performed a Chandra spatially resolved thermal X-ray spectroscopic study of this young SNR. With our CO millimeter observations, we find that the molecular clouds (MCs) at V(LSR)~84km/s can better explain the multiwavelength properties of the remnant than the V(LSR)=67-72km/s MCs that are suggested by Lee et al. (2009). At around 84km/s, the western boundary of the SNR is perfectly confined by the western molecular wall. The CO emission fades out from west to east, indicating that the eastern region is of low gas density. In particular, an intruding finger/pillar-like MC, which may be shocked at the tip, can well explain the X-ray and radio enhancement in the southwest and some infrared filaments there. The SNR-MC interaction is also favored by the relatively elevated 12CO J=2-1/J=1-0 line ratios in the southwestern "pillar tip" and the molecular patch on the northwestern boundary. The redshifted 12CO (J=1-0 and J=2-1) wings (86-90km/s) of an eastern 81km/s molecular patch may be the kinematic evidence for shock-MC interaction. We suggest that the 69km/s MCs are in the foreground based on HI self-absorption while the 84km/s MCs at a distance of 6.2 kpc (the tangent point) are in physical contact with SNR 3C396. The X-ray spectral analysis suggests an SNR age of ~3kyr. The metal enrichment of the X-ray emitting gas in the north and south implies a 13-15Msun B1-B2 progenitor star.Comment: 17 amulateapj pages, including 11 figures and 3 tables. Accepted to ApJ. Version 2: minor correction

Nociceptive interneurons control modular motor pathways to promote escape behavior in Drosophila.

Rapid and efficient escape behaviors in response to noxious sensory stimuli are essential for protection and survival. Yet, how noxious stimuli are transformed to coordinated escape behaviors remains poorly understood. In Drosophila larvae, noxious stimuli trigger sequential body bending and corkscrew-like rolling behavior. We identified a population of interneurons in the nerve cord of Drosophila, termed Down-and-Back (DnB) neurons, that are activated by noxious heat, promote nociceptive behavior, and are required for robust escape responses to noxious stimuli. Electron microscopic circuit reconstruction shows that DnBs are targets of nociceptive and mechanosensory neurons, are directly presynaptic to pre-motor circuits, and link indirectly to Goro rolling command-like neurons. DnB activation promotes activity in Goro neurons, and coincident inactivation of Goro neurons prevents the rolling sequence but leaves intact body bending motor responses. Thus, activity from nociceptors to DnB interneurons coordinates modular elements of nociceptive escape behavior

Nociceptive interneurons control modular motor pathways to promote escape behavior in Drosophila

Rapid and efficient escape behaviors in response to noxious sensory stimuli are essential for protection and survival. Yet, how noxious stimuli are transformed to coordinated escape behaviors remains poorly understood. In Drosophila larvae, noxious stimuli trigger sequential body bending and corkscrew-like rolling behavior. We identified a population of interneurons in the nerve cord of Drosophila, termed Down-and-Back (DnB) neurons, that are activated by noxious heat, promote nociceptive behavior, and are required for robust escape responses to noxious stimuli. Electron microscopic circuit reconstruction shows that DnBs are targets of nociceptive and mechanosensory neurons, are directly presynaptic to pre-motor circuits, and link indirectly to Goro rolling command-like neurons. DnB activation promotes activity in Goro neurons, and coincident inactivation of Goro neurons prevents the rolling sequence but leaves intact body bending motor responses. Thus, activity from nociceptors to DnB interneurons coordinates modular elements of nociceptive escape behavior

Is oral lipid-based delivery for drug targeting to the brain feasible?

This review outlines the feasibility of oral lipid-based targeted delivery of drugs to the brain, including permeation of the central nervous system's (CNS) protective blood–brain barrier (BBB). The structure of the BBB and disruption caused by varying disease states highlights the need for disease-specific approaches to alter permeation. Disruption during disease state, and the effects of certain molecules on the barrier, demonstrate the possibility of exploiting such BBB disruption for drug delivery. Many administration methods can be used to target the brain, but oral administration is considered ideal for chronic, long-term illnesses. Several lipids that have been shown to facilitate drug delivery into the brain after systemic administration, but could also be delivered orally, are discussed, including oleic acid, triolein, alkylglycerol, and conjugates of linoleic and myristic acids. Current data reveal the potential for the use of such lipids as part of oral formulations for delivery to the brain by reaching sufficient plasma levels after administration to increase the permeability of the BBB. However, gaps in the literature remain regarding the concentrations and form of most lipids required to produce the desired effects. The use of lipids via oral delivery for brain targeting has not been investigated thoroughly enough to determine with certainty if similar permeability-enhancing effects would be observed as for parenteral administration. In conclusion, further research to fill research gaps is needed, but the limited evidence suggests that oral lipid-based drug delivery for brain targeting is potentially feasible

Metastatic Lymph Node 64 (MLN64) expression in gastric cancer, the clinical and molecular implications in drug resistance

Background/Aim: Metastatic Lymph Node 64 (MLN64) is often co-amplified with ERBB2 (HER2) and plays a role in the progression of breast and prostate cancers. The present study explored the expression of MLN64 in clinical gastric cancer in association with the ERBB family and its impact on drug resistance in patients. Materials and Methods: Two independent gastric cancer cohorts (n=324; n=87) were used to explore the expression profile of MLN64 in con-junction with ERBB family members in clinical gastric cancer and its association with neoad-juvant chemotherapy responses. Gastric cancer AGS and HCG27 cells with MLN64 knock-down were generated to determine the function of MLN64 in cell behavioral changes. Results: Gastric tumor tissues expressed significantly increased levels of MLN64 compared with normal tissues (p<0.01); however, MLN64 alone was a weak prognostic indicator. An integrated co-expression of MLN64, ERBB4, and NRG4 was a significant factor in assessing overall survival in both cohorts. MLN64 was a profound indicator of patient response to neoadjuvant chemotherapy. In vitro studies indicated a significant contribution of MLN64 to the response of gastric cancer cells to chemodrugs and Her-2 inhibitors. MLN64 knockdown also contributed to the adhesiveness and migration and suggested a possible mechanism mediated by the in-teraction between MLN64 and ERBBs. Conclusion: MLN64 is an indicator for patient response to neoadjuvant chemotherapies in gastric cancer. Together with the expression pattern of ERBB4, it makes is a poor prognostic factor in gastric cancer patients

Sortase anchored proteins of Streptococcus uberis play major roles in the pathogenesis of bovine mastitis in dairy cattle

Streptococcus uberis, strain 0140J, contains a single copy sortase A (srtA), encoding a transamidase capable of covalently anchoring specific proteins to peptidoglycan. Unlike the wild-type, an isogenic mutant carrying an inactivating ISS1 insertion within srtA was only able to infect the bovine mammary gland in a transient fashion. For the first 24 h post challenge, the srtA mutant colonised at a similar rate and number to the wild type strain, but unlike the wild type did not subsequently colonise in higher numbers. Similar levels of host cell infiltration were detected in response to infection with both strains, but only in those mammary quarters infected with the wild type strain were clinical signs of disease evident. Mutants that failed to express individual sortase substrate proteins (sub0135, sub0145, sub0207, sub0241, sub0826, sub0888, sub1095, sub1154, sub1370, and sub1730) were isolated and their virulence determined in the same challenge model. This revealed that mutants lacking sub0145, sub1095 and sub1154 were attenuated in cattle. These data demonstrate that a number of sortase anchored proteins each play a distinct, non-redundant and important role in pathogenesis of S. uberis infection within the lactating bovine mammary gland

A cytosolic invertase is required for normal growth and cell development in the model legume, Lotus japonicus

Neutral/alkaline invertases are a subgroup, confined to plants and cyanobacteria, of a diverse family of enzymes. A family of seven closely-related genes, LjINV1–LjINV7, is described here and their expression in the model legume, Lotus japonicus, is examined. LjINV1 previously identified as encoding a nodule-enhanced isoform is the predominant isoform present in all parts of the plant. Mutants for two isoforms, LjINV1 and LjINV2, were isolated using TILLING. A premature stop codon allele of LjINV2 had no effect on enzyme activity nor did it show a visible phenotype. For LjINV1, premature stop codon and missense mutations were obtained and the phenotype of the mutants examined. Recovery of homozygous mutants was problematic, but their phenotype showed a severe reduction in growth of the root and the shoot, a change in cellular development, and impaired flowering. The cellular organization of both roots and leaves was altered; leaves were smaller and thicker with extra layers of cells and roots showed an extended and broader zone of cell division. Moreover, anthers contained no pollen. Both heterozygotes and homozygous mutants showed decreased amounts of enzyme activity in nodules and shoot tips. Shoot tips also contained up to a 9-fold increased level of sucrose. However, mutants were capable of forming functional root nodules. LjINV1 is therefore crucial to whole plant development, but is clearly not essential for nodule formation or function

Tumor Therapy Applying Membrane-bound Form of Cytokines

Tumor therapy using cytokines has been developed for last two decades. Several recombinant cytokines and tumor cell vaccines produced by cytokine gene transfer have been in clinical trials, but several side effects hamper routine clinical applications. Many cytokines are originally expressed as membrane-bound form and then processed to secretory form exerting paracrine effects. Though functional differences of these two types of cytokines are elusive yet, the membrane-bound form of cytokine may exert its effects on restricted target cells as a juxtacrine, which are in physical contacts. With the efforts to improve antitumor activities of cytokines in cancer patients, developing new strategies to alleviate life-threatening side effects became an inevitable goal of tumor immunologists. Among these, tumor cell vaccines expressing cytokines as membrane-bound form on tumor cell surface have been developed by genetic engineering techniques with the hope of selective stimulation of the target cells that are in cell-to-cell contacts. In this review, recent progress of tumor cell vaccines expressing membrane-bound form of cytokines will be discussed

PRPF8-mediated dysregulation of hBrr2 helicase disrupts human spliceosome kinetics and 5´-splice-site selection causing tissue-specific defects.

The carboxy-terminus of the spliceosomal protein PRPF8, which regulates the RNA helicase Brr2, is a hotspot for mutations causing retinitis pigmentosa-type 13, with unclear role in human splicing and tissue-specificity mechanism. We used patient induced pluripotent stem cells-derived cells, carrying the heterozygous PRPF8 c.6926 A > C (p.H2309P) mutation to demonstrate retinal-specific endophenotypes comprising photoreceptor loss, apical-basal polarity and ciliary defects. Comprehensive molecular, transcriptomic, and proteomic analyses revealed a role of the PRPF8/Brr2 regulation in 5'-splice site (5'SS) selection by spliceosomes, for which disruption impaired alternative splicing and weak/suboptimal 5'SS selection, and enhanced cryptic splicing, predominantly in ciliary and retinal-specific transcripts. Altered splicing efficiency, nuclear speckles organisation, and PRPF8 interaction with U6 snRNA, caused accumulation of active spliceosomes and poly(A)+ mRNAs in unique splicing clusters located at the nuclear periphery of photoreceptors. Collectively these elucidate the role of PRPF8/Brr2 regulatory mechanisms in splicing and the molecular basis of retinal disease, informing therapeutic approaches