MAGI-1 Modulates AMPA Receptor Synaptic Localization and Behavioral Plasticity in Response to Prior Experience

It is well established that the efficacy of synaptic connections can be rapidly modified by neural activity, yet how the environment and prior experience modulate such synaptic and behavioral plasticity is only beginning to be understood. Here we show in C. elegans that the broadly conserved scaffolding molecule MAGI-1 is required for the plasticity observed in a glutamatergic circuit. This mechanosensory circuit mediates reversals in locomotion in response to touch stimulation, and the AMPA-type receptor (AMPAR) subunits GLR-1 and GLR-2, which are required for reversal behavior, are localized to ventral cord synapses in this circuit. We find that animals modulate GLR-1 and GLR-2 localization in response to prior mechanosensory stimulation; a specific isoform of MAGI-1 (MAGI-1L) is critical for this modulation. We show that MAGI-1L interacts with AMPARs through the intracellular domain of the GLR-2 subunit, which is required for the modulation of AMPAR synaptic localization by mechanical stimulation. In addition, mutations that prevent the ubiquitination of GLR-1 prevent the decrease in AMPAR localization observed in previously stimulated magi-1 mutants. Finally, we find that previously-stimulated animals later habituate to subsequent mechanostimulation more rapidly compared to animals initially reared without mechanical stimulation; MAGI-1L, GLR-1, and GLR-2 are required for this change in habituation kinetics. Our findings demonstrate that prior experience can cause long-term alterations in both behavioral plasticity and AMPAR localization at synapses in an intact animal, and indicate a new, direct role for MAGI/S-SCAM proteins in modulating AMPAR localization and function in the wake of variable sensory experience.     

Electron-impact induced fragmentations and structures of benzeneboronates of acyclic tetraols

The isomeric 4,4′-bi-2-phenyl-1,3,2-dioxaborolanes and 2,7-diphenyl-1,3,6,8-tetraoxa-2,7-diborabicyclo[4.4.0]decanes have been distinguished by their electron-impact induced fragmentation. The bisbenzeneboronates of erythritol, L-threitol, 1-deoxy-D-arabinitol, 1-deoxy-D-lyxitol, 1-deoxy-D-ribitol, 1-deoxy-D-xylitol, 1,6-dideoxygalactitol, and 1,6-dideoxy-L-mannitol are likely to be mixtures of structural isomers.     

Loss to Clinic and Five-Year Mortality among HIV-Infected Antiretroviral Therapy Initiators

Missing outcome data due to loss to follow-up occurs frequently in clinical cohort studies of HIV-infected patients. Censoring patients when they become lost can produce inaccurate results if the risk of the outcome among the censored patients differs from the risk of the outcome among patients remaining under observation. We examine whether patients who are considered lost to follow up are at increased risk of mortality compared to those who remain under observation. Patients from the US Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) who newly initiated combination antiretroviral therapy between January 1, 1998 and December 31, 2009 and survived for at least one year were included in the study. Mortality information was available for all participants regardless of continued observation in the CNICS. We compare mortality between patients retained in the cohort and those lost-to-clinic, as commonly defined by a 12-month gap in care. Patients who were considered lost-to-clinic had modestly elevated mortality compared to patients who remained under observation after 5 years (risk ratio (RR): 1.2; 95% CI: 0.9, 1.5). Results were similar after redefining loss-to-clinic as 6 months (RR: 1.0; 95% CI: 0.8, 1.3) or 18 months (RR: 1.2; 95% CI: 0.8, 1.6) without a documented clinic visit. The small increase in mortality associated with becoming lost to clinic suggests that these patients were not lost to care, rather they likely transitioned to care at a facility outside the study. The modestly higher mortality among patients who were lost-to-clinic implies that when we necessarily censor these patients in studies of time-varying exposures, we are likely to incur at most a modest selection bias.     

Patient dosimetry and a novel approach to establishing Diagnostic Reference Levels in dental radiology

Diagnostic Reference Levels provide a method of ensuring that patient doses in medical procedures are kept at acceptable levels. Their application in dentistry can provide an indication of current dose levels and can assist in potentially significant dose reduction in Ireland given the number of patients screened annually.This study involved retrospective analyses of entrance surface dose and dose-width-product measurements obtained in Irish Dental Practices for both Intra-Oral and Panoramic units respectively, followed by comparisons with Monte-Carlo generated computer models of these procedures. Analysis was performed on data from 33 Intra-Oral units for an Adult Mandibular Molar entrance surface dose, 198 readings for a proposed mGy/mAs reference level and 50 Panoramic machines for a dose-width product investigation.The third quartile value of the entrance surface dose for a standard Adult Mandibular Molar Intra-Oral radiograph is (2.40 ± 0.92)mGy, compared to a computer-modelled value of 2.60 mGy. The third quartile mGy/mAs value for Intra-Oral procedures is (1.03 ± 0.38)mGy/mAs, compared to a computer-modelled value of 0.75 mGy/mAs. The third quartile dose width product for an Adult Panoramic radiograph is (59.89 ± 20.97)mGymm, compared to a computer-modeled value of 62.40 mGymm.It is proposed to introduce Diagnostic Reference Levels of 2.4 mGy for an Adult Mandibular Molar Intra-Oral radiograph and 60 mGymm for an Adult Panoramic radiograph. The use of a new reference quantity in Intra-Oral radiology is also suggested. This has a value of 1 mGy/mAs and may be introduced alongside established procedures. These levels can be taken as guides to acceptable doses, but it should be noted that further reductions are practical under ALARA principles.     

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.     

Life on Mars

Abstract

There is evidence that at one time Mars had liquid water habitats on its surface. Studies of microbial communities in cold and dry environments on the Earth provide a basis for discussion of the possible nature of any life that may have existed on Mars during that time. Of particular relevance are the cyanobacterial communities found in hypolithic and endolithic habitats in deserts. Microbial mats found under ice-covered lakes provide an additional possible Martian system. Results obtained from these field studies can be used to guide the search for fossil evidence of life on Mars. It is possible that in the future life will be reintroduced on Mars in an effort to restore that planet to habitable conditions. In this case the organisms under study as exemplars of past life may provide the hardy stock of pioneering Martian organisms. These first organisms must be followed by plants. The feasibility of reviving Mars will depend on the ability of plants to grow in an abundance of CO₂ but at extremely low pressures, temperatures, O₂, and N₂ levels. On Mars, biology was, and is, destiny.