Mad1 kinetochore recruitment by Mps1-mediated phosphorylation of Bub1 signals the spindle checkpoint

The spindle checkpoint is a conserved signaling pathway that ensures genomic integrity by preventing cell division when chromosomes are not correctly attached to the spindle. Checkpoint activation depends on the hierarchical recruitment of checkpoint proteins to generate a catalytic platform at the kinetochore. Although Mad1 kinetochore localization is the key regulatory downstream event in this cascade, its receptor and mechanism of recruitment have not been conclusively identified. Here, we demonstrate that Mad1 kinetochore association in budding yeast is mediated by phosphorylation of a region within the Bub1 checkpoint protein by the conserved protein kinase Mps1. Tethering this region of Bub1 to kinetochores bypasses the checkpoint requirement for Mps1-mediated kinetochore recruitment of upstream checkpoint proteins. The Mad1 interaction with Bub1 and kinetochores can be reconstituted in the presence of Mps1 and Mad2. Together, this work reveals a critical mechanism that determines kinetochore activation of the spindle checkpoint.     

Gyrification from constrained cortical expansion

The exterior of the mammalian brain—the cerebral cortex—has a conserved layered structure whose thickness varies little across species. However, selection pressures over evolutionary time scales have led to cortices that have a large surface area to volume ratio in some organisms, with the result that the brain is strongly convoluted into sulci and gyri. Here we show that the gyrification can arise as a nonlinear consequence of a simple mechanical instability driven by tangential expansion of the gray matter constrained by the white matter. A physical mimic of the process using a layered swelling gel captures the essence of the mechanism, and numerical simulations of the brain treated as a soft solid lead to the formation of cusped sulci and smooth gyri similar to those in the brain. The resulting gyrification patterns are a function of relative cortical expansion and relative thickness (compared with brain size), and are consistent with observations of a wide range of brains, ranging from smooth to highly convoluted. Furthermore, this dependence on two simple geometric parameters that characterize the brain also allows us to qualitatively explain how variations in these parameters lead to anatomical anomalies in such situations as polymicrogyria, pachygyria, and lissencephalia.The mammalian brain is functionally and anatomically complex. Over the years, accumulating evidence (1, 2) shows that there are strong anatomical correlates of its information-processing ability; indeed the iconic convoluted shape of the human brain is itself used as a symbol of its functional complexity. This convoluted (gyrified) shape is associated with the rapid expansion of the cerebral cortex. Understanding the evolutionary and developmental origins of the cortical expansion (1–6) and their mechanistic role in gyrification is thus an important question that needs to be answered to decipher the functional complexity of the brain.Historically there have been three broad hypotheses about the origin of sulci and gyri. The first is that gyri rise above sulci by growing more (7), requiring the pattern of sulci and gyri to be laid down before the cortex folds, presumably by a chemical morphogen. There is no evidence for this mechanism. The second hypothesis considers that the outer gray matter consists of neurons, and the inner white matter is largely long thin axons that connect the neurons to each other and to other parts of the nervous system and proposes that these axons pull mechanically, drawing together highly interconnected regions of gray matter to form gyri (8–10). However, recent experimental evidence (11) shows that axonal tension when present is weak and arises deep in the white matter and is thus insufficient to explain the strongly deformed gyri and sulci. The third hypothesis is that the gray matter simply grows more than the white matter, an experimentally confirmed fact, leading to a mechanical buckling that shapes the cortex (11–14). Evidence for this hypothesis has recently been provided by observations of mechanical stresses in developing ferret brains (11), which were found to be in patterns irreconcilable with the axonal tension hypothesis. In addition, experiments show that sulci and gyri can be induced in usually smooth-brained mice by genetic manipulations that promote cortical expansion (15, 16), suggesting that gyrification results from an unregulated and unpatterned growth of the cortex relative to sublayers.Nevertheless, there is as yet no explicit biologically and physically plausible model that can convincingly reproduce individual sulci and gyri, let alone the complex patterns of sulci and gyri found in the brain. Early attempts to mechanically model brain folding (13) were rooted in the physics of wrinkling and assumed a thin stiff layer of gray matter that grows relative to a thick soft substrate of white matter. This model falls short in two ways. First, the gray matter is neither thin nor stiff relative to the white matter (17, 18). Second, this model predicts smooth sinusoidal wrinkling patterns, sketched in Fig. 1A, whereas even lightly folded brains have smooth gyri but cusped sulci. More complicated mechanical models including, e.g., elasto-plasticity and stress-related growth (14, 19, 20), lead to varying morphologies, but all produced simple smooth convolutions rather than cusped sulci.Open in a separate windowFig. 1.Wrinkling and sulcification in a layered material subject to differential growth. (A) If the growing gray matter is much stiffer than the white matter it will wrinkle in a smooth sinusoidal way. (B) If the gray matter is much softer than the white matter its surface will invaginate to form cusped folds. (C) If the two layers have similar moduli the gray matter will both wrinkle and cusp giving gyri and sulci. Physical realizations of A, B, and C, based on differential swelling of a bilayer gel (Materials and Methods), confirm this picture and are shown in D, E, and F, respectively.A fundamentally different mechanical instability that occurs on the surface of a uniformly compressed soft solid (21, 22) has recently been exposed and clarified, theoretically, computationally, and experimentally (23–26). This sulcification instability arises under sufficient compression leading to the folding of the soft surface to form cusped sulci via a strongly subcritical transition. In Fig. 1B, we show a geometry dual to that associated with wrinkling: A soft layer of gray matter grows on a stiff white-matter substrate. Unlike wrinkling, this instability can produce the cusped centers of sulci, but the flat bottom of the gray matter is not seen in the brain. This is a consequence of the assumption that the gray matter is much softer than the white matter—in reality the two have very similar stiffnesses (17, 18). We are thus led to the final simple alternate, sketched in Fig. 1C, where the stiffnesses of the gray and white matter are assumed to be identical. Such a system is subject to a cusp-forming sulcification instability discussed earlier, and can lead to an emergent pattern very reminiscent of sulci and gyri in the brain.     

Artifactually high coherences result from using spherical spline computation of scalp current density.

Coherence computed from common reference montages inextricably confounds true coherence with power and phase at the recording and reference electrodes. Direct measurement of coherence requires reference-free EEG data, such as data from EEG scalp current densities (SCDs), which estimate the potential gradient perpendicular to the scalp. Perrin et al. (1989) presented a method for computing SCDs by taking the Laplacian of the scalp potential surface generated by spherical spline interpolation. When this method of computing SCDs was applied to EEG data gathered from young adults, very high values were observed for inter-electrode coherences computed from the spherical spline derived SCD data but not from coherences computed from the common reference data. These high coherences prompted further examination of the properties of the spherical spline function and of spherical spline derived SCDs. Simulated data were constructed, and coherence was computed on the simulated data and on the SCDs derived from the spherical spline procedure and from the Hjorth (1980) procedure. The results of those simulations are presented, which demonstrate that a major artifact is introduced by using the spherical spline procedure. This artifact results from the spline weighting matrix used to derive the SCDs and strongly inflates the inter-electrode coherences of the SCD transformed data.     

Effect of photic stimulation on human visual cortex lactate and phosphates using 1H and 31P magnetic resonance spectroscopy.

Previous animal and human studies showed that photic stimulation (PS) increased cerebral blood flow and glucose uptake much more than oxygen consumption, suggesting selective activation of anaerobic glycolysis. In the present studies, image-guided 1H and 31P magnetic resonance spectroscopy (MRS) was used to monitor the changes in lactate and high-energy phosphate concentrations produced by PS of visual cortex in six normal volunteers. PS initially produced a significant rise (to 250% of control, p less than 0.01) in visual cortex lactate during the first 6.4 min of PS, followed by a significant decline (p = 0.01) as PS continued. The PCr/Pi ratios decreased significantly from control values during the first 12.8 min of PS (p less than 0.05), and the pH was slightly increased. The positive P100 deflection of the visual evoked potential recorded between 100 and 172 ms after the strobe was significantly decreased from control at 12.8 min of PS (p less than 0.05). The finding that PS caused decreased PCr/Pi is consistent with the view that increased brain activity stimulated ATPase, causing a rise in ADP that shifted the creatine kinase reaction in the direction of ATP synthesis. The rise in lactate together with an increase in pH suggest that intracellular alkalosis, caused by the shift of creatine kinase, selectively stimulated glycolysis.     

Poor sleep is related to lower general health,increased stress and increased confusion in elite Gaelic athletes

Objectives: Persistent poor sleep is associated with a range of adverse health outcomes. Sleep is considered the main method of recovery in athletes; however, studies report that a significant number of athletes are getting insufficient sleep. The purpose of this study was to assess the sleep profiles of elite Gaelic athletes and to compare wellbeing in those with poor sleep and those with good sleep.

Methods: 69 elite Gaelic athletes completed questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), Subjective Health Complaints Inventory (SHC), Nordic Musculoskeletal Questionnaire (NMQ), stress subscale of the Depression Anxiety Stress Scale (DASS), the tension-anxiety, anger-hostility and confusion-bewilderment subscales of the Profile of Mood States (POMS) as well as the catastrophising subscale of the Coping Strategies Questionnaire (CSQ). Participants were categorised into poor sleepers (PSQI ≥5) and good sleepers (PSQI <5) and outcome measures of health and wellbeing were analysed between the two groups.

Results: 47.8% of athletes were poor sleepers. Self-reported sleep duration was 7.5 ± 0.6 h per night. 63.7% of poor sleepers took >30 min to fall asleep, compared to 5.6% of good sleepers. Poor sleepers had significantly lower general health (SHC) (p = 0.029), increased stress (DASS) (p = 0.035) and increased confusion (POMS-subscale) (p = 0.005). There was no significant difference between groups for number of painful body parts (NMQ) (p = 0.052), catastrophising (CSQ) (p = 0.287), overall mood (POMS) (p = 0.059), or POMS subscales of anger (p = 0.346) or tension (p = 0.593).

Conclusion: Nearly 50% of elite Gaelic athletes report poor sleep. There is a significant relationship between poor sleep and lower general health, increased stress and increased confusion, and these factors may interact with each other. Monitoring of and interventions to enhance sleep may be required to improve athletes’ wellbeing.     

Solid organ donation after death in the United States: Data‐driven messaging to encourage potential donors

US deceased donor solid organ transplantation (dd‐SOT) depends upon an individual's/family's altruistic willingness to donate organs after death; however, there is a shortage of deceased organ donors in the United States. Informing individuals of their own lifetime risk of needing dd‐SOT could reframe the decision‐making around organ donation after death. Using United Network for Organ Sharing (UNOS) data (2007‐2016), this cross‐sectional study identified (1) deceased organ donors, (2) individuals waitlisted for dd‐SOT (liver, kidney, pancreas, heart, lung, intestine), and (3) dd‐SOT recipients. Using US population projections, life tables, and mortality estimates, we quantified probabilities (Pr) of (1) becoming deceased organ donors, (2) needing dd‐SOT, and (3) receiving dd‐SOT. Lifetime Pr (per 100 000 US population) for males and females of becoming deceased organ donors were 212 and 146, respectively, and of needing dd‐SOT were 1323 and 803, respectively. Lifetime Pr of receiving dd‐SOT was 50% for males, 48% for females. Over a lifetime, males were 6.2 and females 5.5 times more likely to need dd‐SOT than to become deceased organ donors. Organ donation is traditionally contextualized in terms of charity toward others. Our analyses yield a new tool, in the form of quantifying an individual's own likelihood of needing dd‐SOT, which may assist with reframing motivations toward deceased donor organ donation.