Homozygous ARHGEF2 mutation causes intellectual disability and midbrain- hindbrain malformation

Abstract Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain- hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder. Author summary During brain development, localized gene expression is crucial for the formation and function of specific brain regions. Various groups of proteins are known to regulate segmentation through controlled gene expression, among them, the Rho GTPase regulator family. In this study, we identified a frameshift mutation in the Rho guanine nucleotide exchange factor 2 gene (ARHGEF2) in two children presenting with intellectual disability, mild microcephaly, and a midbrain- hindbrain malformation. This phenotype is also observed in Arhgef2 mutant mice, highlighting the importance of ARHGEF2 across development of distinct mammalian species. We show that loss of Arhgef2 affects neurogenesis and also cell migration. In addition, we extended the current knowledge of ARHGEF2 expression and its role in early central nervous system development, with special reference to the formation of the precerebellar system. In addition to extensive literature on ARHGEF2, we now provide evidence for its significant role in neuronal migration in brain development and link the gene to human neurodevelopmental disease

Biological Activity and Implications of the Metalloproteinases in Diabetic Foot Ulcers

Inadequate metabolic control predisposes diabetic patient to a series of complications on account of diabetes mellitus (DM). Among the most common complications of DM is neuropathy, which causes microvascular damage by hyperglycemia in the lower extremities which arrives characterized by a delayed closing. The global prevalence of diabetic neuropathy (DN) was 66% of people with diabetes in 2015, representing the principal cause of total or partial lower extremities amputation, with 22.6% of the patients with DN. Matrix metalloproteinases (MMPs) are involved in healing. The function that these mainly play is the degradation during inflammation that has as consequence the elimination of the extracellular matrix (ECM), the disintegration of the capillary membrane to give way to angiogenesis and cellular migration for the remodeling of damaged tissue. The imbalance in MMPs may increase the chronicity of a wound, what leads to chronic foot ulcers and amputation. This chapter focuses on the role of MMPs in diabetic wound healing

Search for very-high-energy emission from Gamma-ray Bursts using the first 18 months of data from the HAWC Gamma-ray Observatory

The High Altitude Water Cherenkov (HAWC) Gamma-ray Observatory is an extensive air shower detector operating in central Mexico, which has recently completed its first two years of full operations. If for a burst like GRB 130427A at a redshift of 0.34 and a high-energy component following a power law with index -1.66, the high-energy component is extended to higher energies with no cut-off other than from extragalactic background light attenuation, HAWC would observe gamma rays with a peak energy of $\sim$300 GeV. This paper reports the results of HAWC observations of 64 gamma-ray bursts (GRBs) detected by $\mathit{Swift}$ and $\mathit{Fermi}$, including three GRBs that were also detected by the Large Area Telescope ($\mathit{Fermi}$-LAT). An ON/OFF analysis method is employed, searching on the time scale given by the observed light curve at keV-MeV energies and also on extended time scales. For all GRBs and time scales, no statistically significant excess of counts is found and upper limits on the number of gamma rays and the gamma-ray flux are calculated. GRB 170206A, the third brightest short GRB detected by the Gamma-ray Burst Monitor on board the $\mathit{Fermi}$ satellite ($\mathit{Fermi}$-GBM) and also detected by the LAT, occurred very close to zenith. The LAT measurements can neither exclude the presence of a synchrotron self-Compton (SSC) component nor constrain its spectrum. Instead, the HAWC upper limits constrain the expected cut-off in an additional high-energy component to be less than $100~\rm{GeV}$ for reasonable assumptions about the energetics and redshift of the burst.Comment: 19 pages, 6 figures, published in Ap

All-particle cosmic ray energy spectrum measured by the HAWC experiment from 10 to 500 TeV

We report on the measurement of the all-particle cosmic ray energy spectrum with the High Altitude Water Cherenkov (HAWC) Observatory in the energy range 10 to 500 TeV. HAWC is a ground based air-shower array deployed on the slopes of Volcan Sierra Negra in the state of Puebla, Mexico, and is sensitive to gamma rays and cosmic rays at TeV energies. The data used in this work were taken from 234 days between June 2016 to February 2017. The primary cosmic-ray energy is determined with a maximum likelihood approach using the particle density as a function of distance to the shower core. Introducing quality cuts to isolate events with shower cores landing on the array, the reconstructed energy distribution is unfolded iteratively. The measured all-particle spectrum is consistent with a broken power law with an index of $-2.49\pm0.01$ prior to a break at $(45.7\pm0.1$) TeV, followed by an index of $-2.71\pm0.01$. The spectrum also respresents a single measurement that spans the energy range between direct detection and ground based experiments. As a verification of the detector response, the energy scale and angular resolution are validated by observation of the cosmic ray Moon shadow's dependence on energy.Comment: 16 pages, 11 figures, 4 tables, submission to Physical Review

Constraining the pˉ/p\bar{p}/p Ratio in TeV Cosmic Rays with Observations of the Moon Shadow by HAWC

An indirect measurement of the antiproton flux in cosmic rays is possible as the particles undergo deflection by the geomagnetic field. This effect can be measured by studying the deficit in the flux, or shadow, created by the Moon as it absorbs cosmic rays that are headed towards the Earth. The shadow is displaced from the actual position of the Moon due to geomagnetic deflection, which is a function of the energy and charge of the cosmic rays. The displacement provides a natural tool for momentum/charge discrimination that can be used to study the composition of cosmic rays. Using 33 months of data comprising more than 80 billion cosmic rays measured by the High Altitude Water Cherenkov (HAWC) observatory, we have analyzed the Moon shadow to search for TeV antiprotons in cosmic rays. We present our first upper limits on the $\bar{p}/p$ fraction, which in the absence of any direct measurements, provide the tightest available constraints of $\sim1\%$ on the antiproton fraction for energies between 1 and 10 TeV.Comment: 10 pages, 5 figures. Accepted by Physical Review

Interdigital cell death in the embryonic limb is associated with depletion of Reelin in the extracellular matrix

Interdigital cell death is a physiological regression process responsible for sculpturing the digits in the embryonic vertebrate limb. Changes in the intensity of this degenerative process account for the different patterns of interdigital webbing among vertebrate species. Here, we show that Reelin is present in the extracellular matrix of the interdigital mesoderm of chick and mouse embryos during the developmental stages of digit formation. Reelin is a large extracellular glycoprotein which has important functions in the developing nervous system, including neuronal survival; however, the significance of Reelin in other systems has received very little attention. We show that reelin expression becomes intensely downregulated in both the chick and mouse interdigits preceding the establishment of the areas of interdigital cell death. Furthermore, fibroblast growth factors, which are cell survival signals for the interdigital mesoderm, intensely upregulated reelin expression, while BMPs, which are proapototic signals, downregulate its expression in the interdigit. Gene silencing experiments of reelin gene or its intracellular effector Dab-1 confirmed the implication of Reelin signaling as a survival factor for the limb undifferentiated mesoderm. We found that Reelin activates canonical survival pathways in the limb mesoderm involving protein kinase B and focal adhesion kinase. Our findings support that Reelin plays a role in interdigital cell death, and suggests that anoikis (apoptosis secondary to loss of cell adhesion) may be involved in this process