General relativistic Sagnac formula revised

The Sagnac effect is a time or phase shift observed between two beams of light traveling in opposite directions in a rotating interferometer. We show that the standard description of this effect within the framework of general relativity misses the effect of deflection of light due to rotational inertial forces. We derive the necessary modification and demonstrate it through a detailed analysis of the square Sagnac interferometer rotating about its symmetry axis in Minkowski space-time. The role of the time shift in a Sagnac interferometer in the synchronization procedure of remote clocks as well as its analogy with the Aharanov-Bohm effect are revised.Comment: 11 pages, 3 figure

Total synthesis and biological mode of action of largazole: A potent class I histone deacetylase inhibitor

The efficient total synthesis of the recently described natural substance largazole (1) and its active metabolite largazole thiol (2) is described. The synthesis required eight linear steps and proceeded in 37% overall yield. It is demonstrated that largazole is a pro-drug that is activated by removal of the octanoyl residue from the 3-hydroxy-7-mercaptohept-4-enoic acid moiety to generate the active metabolite 2, which is an extraordinarily potent Class I histone deacetylase inhibitor. Synthetic largazole and 2 have been evaluated side-by-side with FK228 and SAHA for inhibition of HDACs 1, 2, 3, and 6. Largazole and largazole thiol were further assayed for cytotoxic activity against a panel of chemoresistant melanoma cell lines, and it was found that largazole is substantially more cytotoxic than largazole thiol; this difference is attributed to differences in the cell permeability of the two substances

Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole

The peptide isosteres (10 and 11) of the naturally occurring and potent histone deacetylase (HDAC) Inhibitors FK228 and largazole have been synthesized and evaluated side-by-side with FK228, largazole, and SAHA for inhibition of the class I HDACs 1, 2, 3, and 6

GOODS-ALMA: Optically dark ALMA galaxies shed light on a cluster in formation at z = 3.5

Thanks to its outstanding angular resolution, the Atacama Large Millimeter/submillimeter Array (ALMA) has recently unambiguously identified a population of optically dark galaxies with redshifts greater than z = 3, which play an important role in the cosmic star formation in massive galaxies. In this paper we study the properties of the six optically dark galaxies detected in the 69 arcmin2 GOODS-ALMA 1.1 mm continuum survey. While none of them are listed in the deepest H-band based CANDELS catalog in the GOODS-South field down to H = 28.16 AB, we were able to de-blend two of them from their bright neighbor and measure an H-band flux for them. We present the spectroscopic scan follow-up of five of the six sources with ALMA band 4. All are detected in the 2 mm continuum with signal-to-noise ratios higher than eight. One emission line is detected in AGS4 (νobs = 151.44 GHz with an S/N = 8.58) and AGS17 (νobs = 154.78 GHz with an S/N = 10.23), which we interpret in both cases as being due to the CO(6–5) line at zspecAGS4 = 3.556 and zspecAGS17 = 3.467, respectively. These redshifts match both the probability distribution of the photometric redshifts derived from the UV to near-infrared spectral energy distributions (SEDs) and the far-infrared SEDs for typical dust temperatures of galaxies at these redshifts. We present evidence that nearly 70% (4/6 of galaxies) of the optically dark galaxies belong to the same overdensity of galaxies at z ∼ 3.5. overdensity The most massive one, AGS24 (M⋆ = 1011.32−0.19+0.02 M⊙), is the most massive galaxy without an active galactic nucleus at z > 3 in the GOODS-ALMA field. It falls in the very center of the peak of the galaxy surface density, which suggests that the surrounding overdensity is a proto-cluster in the process of virialization and that AGS24 is the candidate progenitor of the future brightest cluster galaxy

Paternal mosaicism for a novel PBX1 mutation associated with recurrent perinatal death: Phenotypic expansion of the PBX1-related syndrome

First published:06 March 2020Autosomal dominant (de novo) mutations in PBX1 are known to cause congenital abnormalities of the kidney and urinary tract (CAKUT), with or without extra-renal abnormalities. Using trio exome sequencing, we identified a PBX1 p.(Arg107Trp) mutation in a deceased one-day-old neonate presenting with CAKUT, asplenia, and severe bilateral diaphragmatic thinning and eventration. Further investigation by droplet digital PCR revealed that the mutation had occurred post-zygotically in the father, with different variant allele frequencies of the mosaic PBX1 mutation in blood (10%) and sperm (20%). Interestingly, the father had subclinical hydronephrosis in childhood. With an expected recurrence risk of one in five, chorionic villus sampling and prenatal diagnosis for the PBX1 mutation identified recurrence in a subsequent pregnancy. The family opted to continue the pregnancy and the second affected sibling was stillborn at 35 weeks, presenting with similar severe bilateral diaphragmatic eventration, microsplenia, and complete sex reversal (46, XY female). This study highlights the importance of follow-up studies for presumed de novo and low-level mosaic variants and broadens the phenotypic spectrum of developmental abnormalities caused by PBX1 mutations.Tristan S.E. Hardy … Andreas W. Schreiber … Nick Manton, Lynette Moore … Christopher P. Barnett … Hamish S. Scott … et al

GOODS-ALMA: The slow downfall of star formation in z = 2–3 massive galaxies

We investigate the properties of a sample of 35 galaxies, detected with the Atacama Large Millimeter/Submillimeter Array (ALMA) at 1.1 mm in the GOODS-ALMA field (area of 69 arcmin2, resolution = 0.60″, rms ≃ 0.18 mJy beam−1). Using the ultraviolet-to-radio deep multiwavelength coverage of the GOODS–South field, we fit the spectral energy distributions of these galaxies to derive their key physical properties. The galaxies detected by ALMA are among the most massive at z = 2−4 (M⋆, med = 8.5 × 1010 M⊙) and they are either starburst or located in the upper part of the galaxy star-forming main sequence. A significant portion of our galaxy population (∼40%), located at z ∼ 2.5 − 3, exhibits abnormally low gas fractions. The sizes of these galaxies, measured with ALMA, are compatible with the trend between the rest-frame 5000 Å size and stellar mass observed for z ∼ 2 elliptical galaxies, suggesting that they are building compact bulges. We show that there is a strong link between star formation surface density (at 1.1 mm) and gas depletion time: The more compact a galaxy’s star-forming region is, the shorter its lifetime will be (without gas replenishment). The identified compact sources associated with relatively short depletion timescales (∼100 Myr) are the ideal candidates to be the progenitors of compact elliptical galaxies at z ∼ 2

GOODS-ALMA: Using IRAC and VLA to probe fainter millimeter galaxies

In this paper, we extend the source detection in the GOODS-ALMA field (69 arcmin2, 1σ ≃ 0.18 mJy beam−1) to deeper levels than presented in our previous work. Using positional information at 3.6 and 4.5 μm (from Spitzer-IRAC) as well as the Very Large Array (VLA) at 3 GHz, we explore the presence of galaxies detected at 1.1 mm with ALMA below our original blind detection limit of 4.8-σ, at which the number of spurious sources starts to dominate over that of real sources. In order to ensure the most reliable counterpart association possible, we have investigated the astrometry differences between different instruments in the GOODS–South field. In addition to a global offset between the Atacama Large Millimeter/submillimeter Array (ALMA) and the Hubble Space Telescope (HST) already discussed in previous studies, we have highlighted a local offset between ALMA and the HST that was artificially introduced in the process of building the mosaic of the GOODS–South image. We created a distortion map that can be used to correct for these astrometric issues. In this Supplementary Catalog, we find a total of 16 galaxies, including two galaxies with no counterpart in HST images (also known as optically dark galaxies), down to a 5σ limiting depth of H = 28.2 AB (HST/WFC3 F160W). This brings the total sample of GOODS-ALMA 1.1 mm sources to 35 galaxies. Galaxies in the new sample cover a wider dynamic range in redshift (z = 0.65−4.73), are on average twice as large (1.3 vs 0.65 kpc), and have lower stellar masses (M⋆SC = 7.6 × 1010 M⊙ vs M⋆MC = 1.2 × 1011 M⊙). Although exhibiting larger physical sizes, these galaxies still have far-infrared sizes that are significantly more compact than inferred from their optical emission

Pseudodiastrophic dysplasia expands the known phenotypic spectrum of defects in proteoglycan biosynthesis

Background: Pseudodiastrophic dysplasia (PDD) is a severe skeletal dysplasia associated with prenatal manifestation and early lethality. Clinically, PDD is classified as a 'dysplasia with multiple joint dislocations'; however, the molecular aetiology of the disorder is currently unknown. Methods: Whole exome sequencing (WES) was performed on three patients from two unrelated families, clinically diagnosed with PDD, in order to identify the underlying genetic cause. The functional effects of the identified variants were characterised using primary cells and human cell-based overexpression assays. Results: WES resulted in the identification of biallelic variants in the established skeletal dysplasia genes, B3GAT3 (family 1) and CANT1 (family 2). Mutations in these genes have previously been reported to cause 'multiple joint dislocations, short stature, and craniofacial dysmorphism with or without congenital heart defects' ('JDSCD'; B3GAT3) and Desbuquois dysplasia 1 (CANT1), disorders in the same nosological group as PDD. Follow-up of the B3GAT3 variants demonstrated significantly reduced B3GAT3/GlcAT-I expression. Downstream in vitro functional analysis revealed abolished biosynthesis of glycosaminoglycan side chains on proteoglycans. Functional evaluation of the CANT1 variant showed impaired nucleotidase activity, which results in inhibition of glycosaminoglycan synthesis through accumulation of uridine diphosphate. Conclusion: For the families described in this study, the PDD phenotype was caused by mutations in the known skeletal dysplasia genes B3GAT3 and CANT1, demonstrating the advantage of genomic analyses in delineating the molecular diagnosis of skeletal dysplasias. This finding expands the phenotypic spectrum of B3GAT3-related and CANT1-related skeletal dysplasias to include PDD and highlights the significant phenotypic overlap of conditions within the proteoglycan biosynthesis pathway.Alicia B Byrne, Shuji Mizumoto, Peer Arts, Patrick Yap, Jinghua Feng, Andreas W Schreiber, Milena Babic, Sarah L King-Smith, Christopher P Barnett, Lynette Moore, Kazuyuki Sugahara, Hatice Mutlu-Albayrak, Gen Nishimura, Jan E Liebelt, Shuhei Yamada, Ravi Savarirayan, Hamish S Scot

Moments of isovector quark distributions from lattice QCD

We present a complete analysis of the chiral extrapolation of lattice moments of all twist-2 isovector quark distributions, including corrections from Nπ and Δπ loops. Even though the Δ resonance formally gives rise to higher order non-analytic structure, the coefficients of the higher order terms for the helicity and transversity moments are large and cancel much of the curvature generated by the wave function renormalization. The net effect is that, whereas the unpolarized moments exhibit considerable curvature, the polarized moments show little deviation from linearity as the chiral limit is approached