Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer neuropathology, inefficient or ineffective neural processing, and increased risk for Alzheimer’s disease (AD). Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging. Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed a fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged .048 to .0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD.

Simultaneous recordings of upper lip, lower lip, and jaw movements concomitant with intramuscular electromyography were obtained from five subjects during the production of VCV tokens where V = /i/, /ε/, and /æ/ and C = /p/, /b/, and /m/. The temporal sequencing of muscle activity from major elevators and depressors of the lips and jaw was determined and incorporated into a preliminary description of the motor control of the bilabial gesture. Magnitudes of articulator displacement and velocity and electromyographic data revealed a trend among the bilabial consonants so that the voiceless stop /p/ was produced with the highest level of preocclusion activity, and the nasal consonant /m/, with the highest level of postocclusion activity. Production of the three stop cognates involved a complementary contribution of aerodynamic and neuromuscular forces in the achievement of the necessary upper articulatory maneuvers. A left-to-right coarticulation effect for jaw depression whereby the EMG level related to V 2 was reduced as V 1 lowered was shown to span the medial stop consonant. A right-to-left coarticulation effect was observed in one speaker whereby jaw elevation was inversely related to the openness of V 2 . Such an anticipatory maneuver was contradictory to more immediate phonetic goals and necessitated neuromuscular compensatory adjustments of the lower lip.

To ensure faithful chromosome segregation, cells use the spindle assembly checkpoint (SAC), which can be activated in aneuploid cancer cells. Targeting the components of SAC machinery required for the growth of aneuploid cells may offer a cancer cell specific therapeutic approach. In this study, the effects of inhibiting Monopolar spindle 1, MPS1 (TTK), an essential SAC kinase, on the radiosensitization of glioblastoma (GBM) cells was analyzed. Clonogenic survival was used to determine the effects of the MPS1 inhibitor, NMS-P715 on radiosensitivity in multiple model systems including: GBM cell lines, a normal astrocyte and a normal fibroblast cell line. DNA double strand breaks (DSBs) were evaluated using γH2AX foci and cell death was measured by mitotic catastrophe evaluation. Transcriptome analysis was performed via unbiased microarray expression profiling. Tumor xenografts grown from GBM cells were used in tumor growth delay studies. Inhibition of MPS1 activity resulted in reduced GBM cell proliferation. Further, NMS-P715 enhanced the radiosensitivity of GBM cells by decreased repair of DSBs and induction of post-radiation mitotic catastrophe. MNS-P715 in combination with fractionated doses of radiation significantly enhanced the tumor growth delay. Molecular profiling of MPS1 silenced GBM cells showed an altered expression of transcripts associated with DNA damage, repair and replication including the DNA-dependent protein kinase (PRKDC/DNAPK). Next, inhibition of MPS1 blocked two important DNA repair pathways. In conclusion, these results not only highlight a role for MPS1 kinase in DNA repair and as prognostic marker but also indicate it as a viable option in glioblastoma therapy.

Protein Phosphatase 2A (PP2A) is a tumor suppressor whose function is lost in many cancers. An emerging, though counterintuitive, therapeutic approach is inhibition of PP2A to drive damaged cells through the cell cycle, sensitizing them to radiation therapy. We investigated the effects of PP2A inhibition on U251 glioblastoma cells following radiation treatment in vitro and in a xenograft mouse model in vivo. Radiation therapy alone augmented PP2A activity, though this was significantly attenuated with combination LB100 treatment. LB100 treatment yielded a radiation dose enhancement factor of 1.45 and increased the rate of post-radiation mitotic catastrophe at 72 and 96 hours. Glioblastoma cells treated with combination LB100 and radiation therapy maintained increased γ-H2AX expression at 24 hours, diminishing cellular repair of radiation-induced DNA double-strand breaks. Combination therapy significantly enhanced tumor growth delay and mouse survival and decreased p53 expression 3.68-fold, compared to radiation therapy alone. LB100 treatment effectively inhibited PP2A activity and enhanced U251 glioblastoma radiosensitivity in vitro and in vivo. Combination treatment with LB100 and radiation significantly delayed tumor growth, prolonging survival. The mechanism of radiosensitization appears to be related to increased mitotic catastrophe, decreased capacity for repair of DNA double-strand breaks, and diminished p53 DNA damage response pathway activity.

This paper describes an experimental investigation of dipole−dipole interactions between molecules in an orientationally ordered environment. Measurements are reported of the dielectric properties of a series of anisotropic solutions of two structurally similar dipolar solutes (1-cyano-2-fluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene (CP1) and 1,2-difluoro-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]benzene (CP3)) dissolved in a nonpolar nematic liquid crystal solvent (1-[trans-4-ethylcyclohexyl]-2-[4-ethyl-2-fluorobiphenyl]ethane (I22)). The solvent provides an orienting medium for the solute molecules, and by varying the temperature the degree of orientational order of the solutions is changed. The measurements have been made on aligned thin films of the liquid crystalline solutions for different concentrations and over a range of frequencies from 1 kHz to 10 MHz. All solutions exhibited a low-frequency relaxation associated with end-over-end reorientation of the polar solutes in the ordered environment. The results indicate that the dipolar interactions in CP1 solutions are qualitatively different from those for CP3 solutions. In particular, the dielectric properties of CP1 solutions can be interpreted by assuming that solute molecules are locally ordered antiferroelectrically, while for CP3 solutions the local order appears to be ferroelectric. Analysis of both the low-frequency permittivities and the dielectric loss supports the interpretation. The results can be fitted to an association model which enables the proportion of parallel and antiparallel species to be determined.