Molecular basis for the regulation of human glycogen synthase by phosphorylation and glucose-6-phosphate

\ua9 2022, The Author(s). Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity is inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which is relieved by allosteric activation of glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0–4.0 \uc5 resolution of phosphorylated human GYS1, in complex with a minimal interacting region of glycogenin, in the inhibited, activated and catalytically competent states. Phosphorylations of specific terminal residues are sensed by different arginine clusters, locking the GYS1 tetramer in an inhibited state via intersubunit interactions. The Glc6P activator promotes conformational change by disrupting these interactions and increases the flexibility of GYS1, such that it is poised to adopt a catalytically competent state when the sugar donor UDP-glucose (UDP-glc) binds. We also identify an inhibited-like conformation that has not transitioned into the activated state, in which the locking interaction of phosphorylation with the arginine cluster impedes subsequent conformational changes due to Glc6P binding. Our results address longstanding questions regarding the mechanism of human GYS1 regulation

Sequence learning in Associative Neuronal-Astrocytic Network

The neuronal paradigm of studying the brain has left us with limitations in both our understanding of how neurons process information to achieve biological intelligence and how such knowledge may be translated into artificial intelligence and its most brain-derived branch, neuromorphic computing. Overturning our fundamental assumptions of how the brain works, the recent exploration of astrocytes is revealing that these long-neglected brain cells dynamically regulate learning by interacting with neuronal activity at the synaptic level. Following recent experimental evidence, we designed an associative, Hopfield-type, neuronal-astrocytic network and analyzed the dynamics of the interaction between neurons and astrocytes. We show that astrocytes were sufficient to trigger transitions between learned memories in the neuronal component of the network. Further, we mathematically derived the timing of the transitions that was governed by the dynamics of the calcium-dependent slow-currents in the astrocytic processes. Overall, we provide a brain-morphic mechanism for sequence learning that is inspired by, and aligns with, recent experimental findings. To evaluate our model, we emulated astrocytic atrophy and showed that memory recall becomes significantly impaired after a critical point of affected astrocytes was reached. This brain-inspired and brain-validated approach supports our ongoing efforts to incorporate non-neuronal computing elements in neuromorphic information processing.Comment: 8 pages, 5 figure

The Effect of Transposable Element Insertions on Gene Expression Evolution in Rodents

Background:Many genomes contain a substantial number of transposable elements (TEs), a few of which are known to be involved in regulating gene expression. However, recent observations suggest that TEs may have played a very important role in the evolution of gene expression because many conserved non-genic sequences, some of which are know to be involved in gene regulation, resemble TEs. Results:Here we investigate whether new TE insertions affect gene expression profiles by testing whether gene expression divergence between mouse and rat is correlated to the numbers of new transposable elements inserted near genes. We show that expression divergence is significantly correlated to the number of new LTR and SINE elements, but not to the numbers of LINEs. We also show that expression divergence is not significantly correlated to the numbers of ancestral TEs in most cases, which suggests that the correlations between expression divergence and the numbers of new TEs are causal in nature. We quantify the effect and estimate that TE insertion has accounted for ~20% (95% confidence interval: 12% to 26%) of all expression profile divergence in rodents. Conclusions:We conclude that TE insertions may have had a major impact on the evolution of gene expression levels in rodents

Future possibilities in the prevention of breast cancer: Breast cancer prevention trials

The available results from breast cancer chemoprevention trials are reviewed. Four trials using tamoxifen have been performed, of which three have reported efficacy results. A fifth trial using raloxifene has also been reported. The largest tamoxifen trial showed approximately 50% reduction in breast cancer incidence in the short term, but the two smaller trials did not find any reduction. Greater agreement exists for side effects; incidences of thromboembolic disease and endometrial cancers are raised approximately threefold when tamoxifen is used for 5 years. The possible reasons for the discrepancy in breast cancer reduction are explored. A review of trial parameters does not clearly explain this difference, and a meta-analysis indicates that all results are compatible with a 40% reduction in short-term incidence. Several important questions remain regarding the clinical implications of this result, including the effect on mortality, the appropriate risk groups for chemoprevention and the long-term effects on incidence. Continued follow up of these trials is crucial for resolving these issues

Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation

The force-dependent interaction between talin and vinculin plays a crucial role in the initiation and growth of focal adhesions. Here we use magnetic tweezers to characterise the mechano-sensitive compact N-terminal region of the talin rod, and show that the three helical bundles R1-R3 in this region unfold in three distinct steps consistent with the domains unfolding independently. Mechanical stretching of talin R1-R3 enhances its binding to vinculin and vinculin binding inhibits talin refolding after force is released. Mutations that stabilize R3 identify it as the initial mechano-sensing domain in talin, unfolding at ~5 pN, suggesting that 5 pN is the force threshold for vinculin binding and adhesion progression

Regional differences in APD restitution can initiate wavebreak and re-entry in cardiac tissue: A computational study

Background Regional differences in action potential duration (APD) restitution in the heart favour arrhythmias, but the mechanism is not well understood. Methods We simulated a 150 × 150 mm 2D sheet of cardiac ventricular tissue using a simplified computational model. We investigated wavebreak and re-entry initiated by an S1S2S3 stimulus protocol in tissue sheets with two regions, each with different APD restitution. The two regions had a different APD at short diastolic interval (DI), but similar APD at long DI. Simulations were performed twice; once with both regions having steep (slope > 1), and once with both regions having flat (slope < 1) APD restitution. Results Wavebreak and re-entry were readily initiated using the S1S2S3 protocol in tissue sheets with two regions having different APD restitution properties. Initiation occurred irrespective of whether the APD restitution slopes were steep or flat. With steep APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms with S1S2 of 250 ms, to 75 ms (S1S2 180 ms). With flat APD restitution, the range of S2S3 intervals resulting in wavebreak increased from 1 ms (S1S2 250 ms), to 21 ms (S1S2 340 ms) and then 11 ms (S1S2 400 ms). Conclusion Regional differences in APD restitution are an arrhythmogenic substrate that can be concealed at normal heart rates. A premature stimulus produces regional differences in repolarisation, and a further premature stimulus can then result in wavebreak and initiate re-entry. This mechanism for initiating re-entry is independent of the steepness of the APD restitution curve

No observed effect of homologous recombination on influenza C virus evolution

The occurrence of homologous recombination in influenza viruses has been under some debate recently. To determine the extent of homologous recombination in influenza C virus, recombination analyses of all available gene sequences of influenza C virus were carried out. No recombination signal was found. With the previous evidence in influenza A and B viruses, it seems that homologous recombination has minimal or no effect on influenza virus evolution

The effect of ultrasound pretreatment on some selected physicochemical properties of black cumin (Nigella Sativa)

Background In the present study, the effects of ultrasound pretreatment parameters including irradiation time and power on the quantity of the extracted phenolic compounds quantity as well as on some selected physicochemical properties of the extracted oils including oil extraction efficiency, acidity and peroxide values, color, and refractive index of the extracted oil of black cumin seeds with the use of cold press have been studied. Methods For each parameter, three different levels (30, 60, and 90 W) for the ultrasound power and (30, 45, and 60 min) and for the ultrasound irradiation time were studied. Each experiment was performed in three replications. Results The achieved results revealed that, with enhancements in the applied ultrasound power, the oil extraction efficiency, acidity value, total phenolic content, peroxide value, and color parameters increased significantly (P 0.05). Conclusions In summary, it could be mentioned that the application of ultrasound pretreatment in the oil extraction might improve the oil extraction efficiency, the extracted oil’s quality, and the extracted phenolic compounds content.info:eu-repo/semantics/publishedVersio

Thunderclap headache triggered by micturition: responsive to nimodipine

Primary thunderclap headache (TCH) is a rare condition, of which the onset can be triggered by coughing, exercise, and sexual activity. Micturition is a recognized trigger of secondary TCH with pheochromocytoma in bladder, but not of primary TCH. We describe a patient with an apparent primary TCH, which repeatedly occurred immediately after micturition until she achieved a therapeutic dosage of nimodipine

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/