Even a little sleepiness influences neural activation and clinical reasoning in novices.

BACKGROUND AND AIMS: Sleepiness influences alertness and cognitive functioning and impacts many aspects of medical care, including clinical reasoning. However, dual processing theory suggests that sleepiness will impact clinical reasoning differently in different individual, depending on their level of experience with the given condition. Our aim, therefore, was to examine the association between clinical reasoning, neuroanatomical activation, and sleepiness in senior medical students. METHODS: Our methodology replicated an earlier study but with novices rather than board-certified physicians. Eighteen final-year medical students answered validated multiple-choice questions (MCQs) during an fMRI scan. Each MCQ was projected in three phases: reading, answering, and reflection (modified think aloud). Echo-planar imaging (EPI) scans gave a time series that reflected blood oxygenation level dependent (BOLD) signal in each location (voxel) within the brain. Sleep data were collected via self-report (Epworth Sleepiness Scale) and actigraphy. These data were correlated with answer accuracy using Pearson correlation. RESULTS: Analysis revealed an increased BOLD signal in the right dorsomedial prefrontal cortex (P < .05) during reflection (Phase 3) associated with increased self-reported sleepiness (ESS) immediately before scanning. Covariate analysis also revealed that increased BOLD signal in the right supramarginal gyrus (P < .05) when reflecting (Phase 3) was associated with increased correct answer response time. Both patterns indicate effortful analytic (System 2) reasoning. CONCLUSION: Our findings that novices use System 2 thinking for clinical reasoning and even a little (perceived) sleepiness influences their clinical reasoning ability to suggest that the parameters for safe working may be different for novices (eg, junior doctors) and experienced physicians.

Glycosylphosphatidylinositol-anchored proteins as chaperones and co-receptors for FERONIA receptor kinase signaling in Arabidopsis.

The Arabidopsis receptor kinase FERONIA (FER) is a multifunctional regulator for plant growth and reproduction. Here we report that the female gametophyte-expressed glycosylphosphatidylinositol-anchored protein (GPI-AP) LORELEI and the seedling-expressed LRE-like GPI-AP1 (LLG1) bind to the extracellular juxtamembrane region of FER and show that this interaction is pivotal for FER function. LLG1 interacts with FER in the endoplasmic reticulum and on the cell surface, and loss of LLG1 function induces cytoplasmic retention of FER, consistent with transport of FER from the endoplasmic reticulum to the plasma membrane in a complex with LLG1. We further demonstrate that LLG1 is a component of the FER-regulated RHO GTPase signaling complex and that fer and llg1 mutants display indistinguishable growth, developmental and signaling phenotypes, analogous to how lre and fer share similar reproductive defects. Together our results support LLG1/LRE acting as a chaperone and co-receptor for FER and elucidate a mechanism by which GPI-APs enable the signaling capacity of a cell surface receptor.

A novel trial of topotecan, ifosfamide, and carboplatin (TIC) in children with recurrent solid tumors.

BACKGROUND: Ifosfamide, carboplatin, and etoposide (ICE) in children with refractory or recurrent solid tumors and lymphomas has resulted in good overall response rates (ORR). Etoposide, a topoisomerase-II inhibitor, however, has been associated with a significant increase in secondary leukemia. The rationale for substituting topotecan, a topoisomerase-I inhibitor, for etoposide in this regimen, a topoisomerase-II inhibitor, includes its limited toxicity profile and decreased leukemogenicity. Furthermore, topotecan in combination with both alkylators and platinating agents are additive and/or synergistic against a variety of solid tumors. PROCEDURE: Patients with relapsed/refractory solid tumors received ifosfamide (9 g/m2 ) and carboplatin (area under the curve: 3 mg/ml/min). Topotecan was also administered at 0.5 mg/m2 /day × 3 days (N = 12) and in a small cohort (N = 3) at 0.75 mg/m2 /day. RESULTS: Fifteen patients were entered onto study. Two patients developed seizures/encephalitis secondary to ifosfamide. One patient had dose-limiting thrombocytopenia secondary to TIC that resolved with supportive care. Patients received a median of three cycles (1-3) of TIC. Of the 14 evaluable patients for response, 4/14 had a complete response (CR), 2/14 had a partial response (PR), and 1/14 patients had stable disease (SD). The ORR (CR + PR) was 43%. CONCLUSION: TIC chemotherapy is feasible and tolerable in children and adolescents with refractory/recurrent solid tumors and lymphomas and results in a 43% excellent ORR in this poor-risk group of patients. A larger cohort of patients, especially in Wilms tumor and central nervous system (CNS) tumors, should be studied in the future to attempt to confirm these preliminary findings. Pediatr Blood Cancer 2015;62:274-278. © 2014 Wiley Periodicals, Inc.

Reactive oxygen species mediate pollen tube rupture to release sperm for fertilization in Arabidopsis.

In flowering plants, sperm are transported inside pollen tubes to the female gametophyte for fertilization. The female gametophyte induces rupture of the penetrating pollen tube, resulting in sperm release and rendering them available for fertilization. Here we utilize the Arabidopsis FERONIA (FER) receptor kinase mutants, whose female gametophytes fail to induce pollen tube rupture, to decipher the molecular mechanism of this critical male-female interactive step. We show that FER controls the production of high levels of reactive oxygen species at the entrance to the female gametophyte to induce pollen tube rupture and sperm release. Pollen tube growth assays in vitro and in the pistil demonstrate that hydroxyl free radicals are likely the most reactive oxygen molecules, and they induce pollen tube rupture in a Ca(2+)-dependent process involving Ca(2+) channel activation. Our results provide evidence for a RHO GTPase-based signalling mechanism to mediate sperm release for fertilization in plants.