Insulin-Like Growth Factor-I Accelerates the Cell Cycle by Decreasing G1 Phase Length and Increases Cell Cycle Reentry in the Embryonic Cerebral Cortex

Neurogenesis in the developing cerebral cortex of mice occurs in the dorsal telencephalon between embryonic day 11 (E11) and E17, during which time the majority of cortical projection neurons and some glia are produced from proliferating neuroepithelial cells in the ventricular zone. The number of cells produced by this process is governed by several factors, including cell cycle kinetics and the proportion of daughter cells exiting the cell cycle after a given round of cell division. Th

Insulin-like growth factor-I (IGF-I) inhibits neuronal apoptosis in the developing cerebral cortex in vivo

Increased expression of insulin-like growth factor-I (IGF-I) in embryonic neural progenitors in vivo has been shown to accelerate neuron proliferation in the neocortex. In the present study, the in vivo actions of (IGF-I) on naturally occurring neuron death in the cerebral cortex were investigated during embryonic and early postnatal development in a line of transgenic (Tg) mice that overexpress IGF-I in the brain, directed by nestin genomic regulatory elements, beginning at least as early as embryonic day (E) 13. The areal density of apoptotic cells (NA, cells/mm2) at E16 in the telencephalic wall of Tg and littermate control embryos was determined by immunostaining with an antibody specific for activated caspase-3. Stereological analyses were conducted to measure the numerical density (NV, cells/mm3) and total number of immunoreactive apoptotic cells in the cerebral cortex of nestin/IGF-I Tg and control mice at postnatal days (P) 0 and 5. The volume of cerebral cortex and both the NV and total number of all cortical neurons also were determined in both cerebral hemispheres at P0, P5 and P270. Apoptotic cells were rare in the embryonic telencephalic wall at E16. However, the overall NA of apoptotic cells was found to be significantly less by 46% in Tg embryos. The volume of the cerebral cortex was significantly greater in Tg mice at P0 (30%), P5 (13%) and P270 (26%). The total number of cortical neurons in Tg mice was significantly increased at P0 (29%), P5 (29%) and P270 (31%), although the NV of cortical neurons did not differ significantly between Tg and control mice at any age. Transgenic mice at P0 and P5 exhibited significant decreases in the NV of apoptotic cells in the cerebral cortex (31% and 39%, respectively). The vast majority of these apoptotic cells (>90%) were judged to be neurons by their morphological appearance. Increased expression of IGF-I inhibits naturally occurring (i.e. apoptotic) neuron death during early postnatal development of the cerebral cortex to a degree that sustains a persistent increase in total neuron number even in the adult animal

Improving predictions of critical shear stress in gravel bed rivers: Identifying the onset of sediment transport and quantifying sediment structure

Understanding when gravel moves in river beds is essential for a range of different applications but is still surprisingly hard to predict. Here we consider how our ability to predict critical shear stress (τ c ) is being improved by recent advances in two areas: (1) identifying the onset of bedload transport; and (2) quantifying grain‐scale gravel bed structure. This paper addresses these areas through both an in‐depth review and a comparison of new datasets of gravel structure collected using three different methods. We focus on advances in these two areas because of the need to understand how the conditions for sediment entrainment vary spatially and temporally, and because spatial and temporal changes in grain‐scale structure are likely to be a major driver of changes in τ c . We use data collected from a small gravel‐bed stream using direct field‐based measurements, terrestrial laser scanning (TLS) and computed tomography (CT) scanning, which is the first time that these methods have been directly compared. Using each method, we measure structure‐relevant metrics including grain size distribution, grain protrusion and fine matrix content. We find that all three methods produce consistent measures of grain size, but that there is less agreement between measurements of grain protrusion and fine matrix content

Multi-modal characterization and simulation of human epileptic circuitry

Temporal lobe epilepsy is the fourth most common neurological disorder with about 40% of patients not responding to pharmacological treatment. Increased cellular loss in the hippocampus is linked to disease severity and pathological phenotypes such as heightened seizure propensity. While the hippocampus is the target of therapeutic interventions such as temporal lobe resection, the impact of the disease at the cellular level remains unclear in humans. Here we show that properties of hippocampal granule cells change with disease progression as measured in living, resected hippocampal tissue excised from epilepsy patients. We show that granule cells increase excitability and shorten response latency while also enlarging in cellular volume, surface area and spine density. Single-cell RNA sequencing combined with simulations ascribe the observed electrophysiological changes to gradual modification in three key ion channel conductances: BK, Cav2.2 and Kir2.1. In a bio-realistic computational network model, we show that the changes related to disease progression bring the circuit into a more excitable state. In turn, we observe that by reversing these changes in the three key conductances produces a less excitable, early disease-like state. These results provide mechanistic understanding of epilepsy in humans and will inform future therapies such as viral gene delivery to reverse the course of the disorder

Reduced T2* Values in Soleus Muscle of Patients with Type 2 Diabetes Mellitus

Tissue water transverse relaxation times (T2) are highly sensitive to fluid and lipid accumulations in skeletal muscles whereas the related T2* is sensitive to changes in tissue oxygenation in addition to factors affecting T2. Diabetes mellitus (DM) affects muscles of lower extremities progressively by impairing blood flow at the macrovascular and microvascular levels. This study is to investigate whether T2 and T2* are sensitive enough to detect abnormalities in skeletal muscles of diabetic patients in the resting state. T2 and T2* values in calf muscle of 18 patients with type 2 DM (T2DM), 22 young healthy controls (YHC), and 7 age-matched older healthy controls (OHC) were measured at 3T using multi-TE spin echo and gradient echo sequences. Regional lipid levels of the soleus muscle were also measured using the Dixon method in a subset of the subjects. Correlations between T2, T2*, lipid levels, glycated hemoglobin (HbA1c) and presence of diabetes were evaluated. We found that T2 values were significantly higher in calf muscles of T2DM subjects, as were T2* values in anterior tibialis, and gastrocnemius muscles of T2DM participants. However, soleus T2* values of the T2DM subjects were significantly lower than those of the older, age-matched HC cohort $(22.9\pm 0.5 vs 26.7\pm 0.4 ms, p<0.01)$. The soleus T2* values in the T2DM cohort were inversely correlated with the presence of diabetes (t = −3.46, p<0.001) and with an increase in HbA1c, but not with body mass index or regional lipid levels. Although multiple factors may contribute to changes in T2* values, the lowered T2* value observed in the T2DM soleus muscle is most consistent with a combination of high oxygen consumption and poor regional perfusion. This finding is consistent with results of previous perfusion studies and suggests that the soleus in individuals with T2DM is likely under tissue oxygenation stress

Metal and dust evolution in ALMA REBELS galaxies: insights for future JWST observations

ALMA observations revealed the presence of significant amounts of dust in the first Gyr of Cosmic time. However, the metal and dust buildup picture remains very uncertain due to the lack of constraints on metallicity. JWST has started to reveal the metal content of high-redshift targets, which may lead to firmer constraints on high-redshift dusty galaxies evolution. In this work, we use detailed chemical and dust evolution models to explore the evolution of galaxies within the ALMA REBELS survey, testing different metallicity scenarios that could be inferred from JWST observations. In the models, we track the buildup of stellar mass by using non-parametric SFHs for REBELS galaxies. Different scenarios for metal and dust evolution are simulated by allowing different prescriptions for gas flows and dust processes. The model outputs are compared with measured dust scaling relations, by employing metallicity-dependent calibrations for the gas mass based on the [CII]158micron line. Independently of the galaxies metal content, we found no need for extreme dust prescriptions to explain the dust masses revealed by ALMA. However, different levels of metal enrichment will lead to different dominant dust production mechanisms, with stardust production dominant over other ISM dust processes only in the metal-poor case. This points out how metallicity measurements from JWST will significantly improve our understanding of the dust buildup in high-redshift galaxies. We also show that models struggle to reproduce observables such as dust-to-gas and dust-to-stellar ratios simultaneously, possibly indicating an overestimation of the gas mass through current calibrations, especially at high metallicities.Comment: 16 pages + appendices, 9 Figures, 1 Table. Resubmitted to MNRAS after moderate revisio

The ALMA REBELS Survey: Dust Continuum Detections at z > 6.5

We report 18 dust continuum detections ($\geq 3.3\sigma$) at $\sim88{\rm \mu m}$ and $158{\rm \mu m}$ out of 49 ultraviolet(UV)-bright galaxies ($M_{\rm UV} 6.5$, observed by the Cycle-7 ALMA Large Program, REBELS and its pilot programs. This has more than tripled the number of dust continuum detections known at $z>6.5$. Out of these 18 detections, 12 are reported for the first time as part of REBELS. In addition, 15 of the dust continuum detected galaxies also show a [CII]$_{\rm 158{\rm \mu m}}$ emission line, providing us with accurate redshifts. We anticipate more line emission detections from six targets (including three continuum detected targets) where observations are still ongoing. The dust continuum detected sources in our sample tend to have a redder UV spectral slope than the ones without a dust continuum detection. We estimate that all of the sources have an infrared (IR) luminosity ($L_{\rm IR}$) in a range of $3-8 \times 10^{11} L_\odot$, except for one with $L_{\rm IR} = 1.5^{+0.8}_{-0.5} \times 10^{12}\,L_{\odot}$. Their fraction of obscured star formation is significant at $\gtrsim 50\%$. Some of the dust continuum detected galaxies show spatial offsets ($\sim 0.5-1.5''$) between the rest-UV and far-IR emission peaks. These separations appear to have an increasing trend against an indicator that suggests spatially decoupled phases of obscured and unobscured star formation. REBELS offers the best available statistical constraints on obscured star formation in UV-bright, massive galaxies at $z > 6.5$.Comment: 17 pages, 9 figures, submitted to MNRA