A distinct role for recombination repair factors in an early cellular response to transcription-replication conflicts

Transcription–replication (T–R) conflicts are profound threats to genome integrity. However, whilst much is known about the existence of T–R conflicts, our understanding of the genetic and temporal nature of how cells respond to them is poorly established. Here, we address this by characterizing the early cellular response to transient T–R conflicts (TRe). This response specifically requires the DNA recombination repair proteins BLM and BRCA2 as well as a non-canonical monoubiquitylation-independent function of FANCD2. A hallmark of the TRe response is the rapid co-localization of these three DNA repair factors at sites of T–R collisions. We find that the TRe response relies on basal activity of the ATR kinase, yet it does not lead to hyperactivation of this key checkpoint protein. Furthermore, specific abrogation of the TRe response leads to DNA damage in mitosis, and promotes chromosome instability and cell death. Collectively our findings identify a new role for these well-established tumor suppressor proteins at an early stage of the cellular response to conflicts between DNA transcription and replication

X-ray diffraction analysis and in vitro characterization of the UAM2 protein from Oryza sativa

The role of seemingly non-enzymatic proteins in complexes interconverting UDP-arabinopyranose and UDP-arabinofuranose (UDP-arabinosemutases; UAMs) in the plant cytosol remains unknown. To shed light on their function, crystallographic and functional studies of the seemingly non-enzymatic UAM2 protein from Oryza sativa (OsUAM2) were undertaken. Here, X-ray diffraction data are reported, as well as analysis of the oligomeric state in the crystal and in solution. OsUAM2 crystallizes readily but forms highly radiation-sensitive crystals with limited diffraction power, requiring careful low-dose vector data acquisition. Using size-exclusion chromatography, it is shown that the protein is monomeric in solution. Finally, limited proteolysis was employed to demonstrate DTT-enhanced proteolytic digestion, indicating the existence of at least one intramolecular disulfide bridge or, alternatively, a requirement for a structural metal ion

Brain serotonin 4 receptor binding is inversely associated with verbal memory recall

BACKGROUND: We have previously identified an inverse relationship between cerebral serotonin 4 receptor (5‐HT (4)R) binding and nonaffective episodic memory in healthy individuals. Here, we investigate in a novel sample if the association is related to affective components of memory, by examining the association between cerebral 5‐HT (4)R binding and affective verbal memory recall. METHODS: Twenty‐four healthy volunteers were scanned with the 5‐HT (4)R radioligand [(11)C]SB207145 and positron emission tomography, and were tested with the Verbal Affective Memory Test‐24. The association between 5‐HT (4)R binding and affective verbal memory was evaluated using a linear latent variable structural equation model. RESULTS: We observed a significant inverse association across all regions between 5‐HT (4)R binding and affective verbal memory performances for positive (p = 5.5 × 10(−4)) and neutral (p = .004) word recall, and an inverse but nonsignificant association for negative (p = .07) word recall. Differences in the associations with 5‐HT (4)R binding between word categories (i.e., positive, negative, and neutral) did not reach statistical significance. CONCLUSION: Our findings replicate our previous observation of a negative association between 5‐HT (4)R binding and memory performance in an independent cohort and provide novel evidence linking 5‐HT (4)R binding, as a biomarker for synaptic 5‐HT levels, to the mnestic processing of positive and neutral word stimuli in healthy humans

Brain reactivity during aggressive response in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator

Premenstrual dysphoric disorder (PMDD) is a psychiatric condition characterized by late luteal phase affective, cognitive, and physical impairment. The disorder causes significant suffering in about 5% of women in their reproductive age. Altered sensitivity of cognitive-affective brain circuits to progesterone and its downstream metabolite allopregnanolone is suggested to underlie PMDD symptomatology. Core mood symptoms include irritability and anger, with aggression being the behavioral outcome of these symptoms. The present study sought to investigate the neural correlates of reactive aggression during the premenstrual phase in women with PMDD, randomized to a selective progesterone receptor modulator (SPRM) or placebo. Self-reports on the Daily Record of Severity of Problems were used to assess PMDD symptoms and gonadal hormone levels were measured by liquid chromatography tandem mass spectrometry. Functional magnetic resonance imaging was performed in 30 women with PMDD, while performing the point subtraction aggression paradigm. Overall, a high SPRM treatment response rate was attained (93%), in comparison with placebo (53.3%). Women with PMDD randomized to SPRM treatment had enhanced brain reactivity in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex during the aggressive response condition. The fronto-cingulate reactivity during aggressive responses depended on treatment, with a negative relationship between brain reactivity and task-related aggressiveness found in the placebo but not the SPRM group. The findings contribute to define the role of progesterone in PMDD symptomatology, suggesting a beneficial effect of progesterone receptor antagonism, and consequent anovulation, on top-down emotion regulation, i.e., greater fronto-cingulate activity in response to provocation stimuli.publishedVersio

The <i>Arabidopsis</i> Golgi-localized GDP-L-fucose transporter is required for plant development

Indexación: Web of Science.Nucleotide sugar transport across Golgi membranes is essential for the luminal biosynthesis of glycan structures. Here we identify GDP-fucose transporter 1 (GFT1), an Arabidopsis nucleotide sugar transporter that translocates GDP-L-fucose into the Golgi lumen. Using proteo-liposome-based transport assays, we show that GFT preferentially transports GDP-L-fucose over other nucleotide sugars in vitro, while GFT1-silenced plants are almost devoid of L-fucose in cell wall-derived xyloglucan and rhamnogalacturonan II. Furthermore, these lines display reduced L-fucose content in N-glycan structures accompanied by severe developmental growth defects. We conclude that GFT1 is the major nucleotide sugar transporter for import of GDP-L-fucose into the Golgi and is required for proper plant growth and development.http://www.nature.com/articles/ncomms1211

Pediatric Emergencies in Helicopter Emergency Medical Services:A National Population-Based Cohort Study From Denmark

Study objective: To examine the diagnostic pattern, level of severity of illness or injuries, and mortality among children for whom a physician-staffed helicopter emergency medical service (HEMS) was dispatched. Methods: Population-based cohort study including patients aged less than 16 years treated by the Danish national HEMS from October 1, 2014, to September 30, 2018. Diagnoses were retrieved from inhospital medical records, and the severity of illness or injuries was assessed by a severity score on scene, administration of advanced out-of-hospital care, need for intensive care in a hospital, and mortality. Results: In total, 651 HEMS missions included pediatric patients aged less than 1 year (9.2%), 1 to 2 years (29.0%), 3 to 7 years (28.3%), and 8 to 15 years (33.5%). A third of the patients had critical emergencies (29.6%), and for 20.1% of the patients, 1 or more out-of-hospital interventions were performed: intubation, mechanical chest compressions, intraosseous vascular access, blood transfusion, chest tube insertion, and/or ultrasound examination. Among the 525 patients with hospital follow-up, the most frequent hospital diagnoses were injuries (32.2%), burns (11.2%), and respiratory diseases (7.8%). Within 24 hours of the mission, 18.1% of patients required intensive care. Twenty-nine patients (5.1%, 95% confidence interval [CI] 3.6 to 7.3) died either on or within 1 day of the mission, and the cumulative 30-day mortality was 35 of 565 (6.2%, 95% CI 4.5 to 8.5) (N¼565 first-time missions). Conclusion: On Danish physician-staffed HEMS missions, 1 in 5 pediatric patients required advanced out-of-hospital care. Among hospitalized patients, nearly one-fifth of the patients required immediate intensive care and 6.2% died within 30 days of the mission.publishedVersio

Neuroticism Associates with Cerebral in Vivo Serotonin Transporter Binding Differently in Males and Females

Background: Neuroticism is a major risk factor for affective disorders. This personality trait has been hypothesized to associate with synaptic availability of the serotonin transporter, which critically controls serotonergic tone in the brain. However, earlier studies linking neuroticism and serotonin transporter have failed to produce converging findings. Because sex affects both the serotonergic system and the risk that neuroticism poses to the individual, sex may modify the association between neuroticism and serotonin transporter, but this question has not been investigated by previous studies. Methods: Here, we combined data from 4 different positron emission tomography imaging centers to address whether neuroticism is related to serotonin transporter binding in vivo. The data set included serotonin transporter binding potential values from the thalamus and striatum and personality scores from 91 healthy males and 56 healthy females. We specifically tested if the association between neuroticism and serotonin transporter is different in females and males. Results: We found that neuroticism and thalamic serotonin transporter binding potentials were associated in both males and females, but with opposite directionality. Higher neuroticism associated with higher serotonin transporter binding potential in males (standardized beta 0.292, P = .008), whereas in females, higher neuroticism associated with lower serotonin transporter binding potential (standardized beta -0.288, P = .014). Conclusions: The finding is in agreement with recent studies showing that the serotonergic system is involved in affective disorders differently in males and females and suggests that contribution of thalamic serotonin transporter to the risk of affective disorders depends on sex.Peer reviewe