A Chromosomal Deletion and New Frameshift Mutation Cause ARSACS in an African-American

Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is a rare, progressive, neurodegenerative disease characterized by ataxia, spasticity and polyneuropathy. First described in the French-Canadian population of Quebec in 1978, ARSACS has since been identified in multiple patients worldwide. In this clinical case report, we describe the evaluation of an 11-years-old African-American male who presented to neuromuscular clinic for assessment of a gait abnormality. He had a history of gross motor delay since early childhood, frequent falls and a below average IQ. Chromosomal microarray revealed a 1.422 megabase loss in the 13q12.12 region, which includes the SACS gene. Next Generation Sequencing then showed a novel, predicted to be pathogenic missense mutation (c.11824dup) of this gene. His clinical presentation and neurological imaging further confirmed the diagnosis of ARSACS. To our knowledge, this is the first reported case of this disease in the African-American population of the United States. This case report further highlights the growing trend of identifying genetic diseases previously restricted to single, ethnically isolated regions in many different ethnic groups worldwide

A Neutron Star with a Massive Progenitor in Westerlund 1

We report the discovery of an X-ray pulsar in the young, massive Galactic star cluster Westerlund 1. We detected a coherent signal from the brightest X-ray source in the cluster, CXO J164710.2-455216, during two Chandra observations on 2005 May 22 and June 18. The period of the pulsar is 10.6107(1) s. We place an upper limit to the period derivative of Pdot<2e-10 s/s, which implies that the spin-down luminosity is Edot<3e33 erg/s. The X-ray luminosity of the pulsar is L_X = 3(+10,-2)e33 (D/5 kpc)^2 erg/s, and the spectrum can be described by a kT = 0.61+/-0.02 keV blackbody with a radius of R_bb = 0.27+/-0.03 (D/5 kpc}) km. Deep infrared observations reveal no counterpart with K1 Msun. Taken together, the properties of the pulsar indicate that it is a magnetar. The rarity of slow X-ray pulsars and the position of CXO J164710.2-455216 only 1.6' from the core of Westerlund 1 indicates that it is a member of the cluster with >99.97% confidence. Westerlund 1 contains 07V stars with initial masses M_i=35 Msun and >50 post-main-sequence stars that indicate the cluster is 4+/-1 Myr old. Therefore, the progenitor to this pulsar had an initial mass M_i>40 Msun. This is the most secure result among a handful of observational limits to the masses of the progenitors to neutron stars.Comment: 4 pages, 5 figures. Final version to match ApJL (added one figure since v2

LOGISTICS IN CONTESTED ENVIRONMENTS

This report examines the transport and delivery of logistics in contested environments within the context of great-power competition (GPC). Across the Department of Defense (DOD), it is believed that GPC will strain our current supply lines beyond their capacity to maintain required warfighting capability. Current DOD efforts are underway to determine an appropriate range of platforms, platform quantities, and delivery tactics to meet the projected logistics demand in future conflicts. This report explores the effectiveness of various platforms and delivery methods through analysis in developed survivability, circulation, and network optimization models. Among other factors, platforms are discriminated by their radar cross-section (RCS), noise level, speed, cargo capacity, and self-defense capability. To maximize supply delivered and minimize the cost of losses, the results of this analysis indicate preference for utilization of well-defended convoys on supply routes where bulk supply is appropriate and smaller, and widely dispersed assets on shorter, more contested routes with less demand. Sensitivity analysis on these results indicates system survivability can be improved by applying RCS and noise-reduction measures to logistics assets.Director, Warfare Integration (OPNAV N9I)Major, Israel Defence ForcesCivilian, Singapore Technologies Engineering Ltd, SingaporeCommander, Republic of Singapore NavyCommander, United States NavyCaptain, Singapore ArmyLieutenant, United States NavyLieutenant, United States NavyMajor, Republic of Singapore Air ForceCaptain, United States Marine CorpsLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyLieutenant, United States NavyCaptain, Singapore ArmyLieutenant Junior Grade, United States NavyCaptain, Singapore ArmyLieutenant Colonel, Republic of Singapore Air ForceApproved for public release. distribution is unlimite

Epitaxial Growth and Processing of Compound Semiconductors

Contains an introduction and reports on six research projects.Defense Advanced Research Projects Agency/U.S. Navy - Office of Naval Research University Research Initiative Subcontract N00014-92-J-1893Joint Services Electronics Program Grant DAAH04-95-1-0038National Center for Integrated Photonics Technology Contract 542-381National Science Foundation Grant DMR 92-02957MIT Lincoln Laboratory Contract BX-6085National Center for Integrated Photonics Technology Subcontract 542-383U.S. Air Force - Office of Scientific Research Grant F49620-96-1-0126U.S. Navy - Office of Naval Research Grant N00014-91-J-1956National Science Foundation Grant DMR 94-0033

Phasevarions Mediate Random Switching of Gene Expression in Pathogenic Neisseria

Many host-adapted bacterial pathogens contain DNA methyltransferases (mod genes) that are subject to phase-variable expression (high-frequency reversible ON/OFF switching of gene expression). In Haemophilus influenzae, the random switching of the modA gene controls expression of a phase-variable regulon of genes (a “phasevarion”), via differential methylation of the genome in the modA ON and OFF states. Phase-variable mod genes are also present in Neisseria meningitidis and Neisseria gonorrhoeae, suggesting that phasevarions may occur in these important human pathogens. Phylogenetic studies on phase-variable mod genes associated with type III restriction modification (R-M) systems revealed that these organisms have two distinct mod genes—modA and modB. There are also distinct alleles of modA (abundant: modA11, 12, 13; minor: modA4, 15, 18) and modB (modB1, 2). These alleles differ only in their DNA recognition domain. ModA11 was only found in N. meningitidis and modA13 only in N. gonorrhoeae. The recognition site for the modA13 methyltransferase in N. gonorrhoeae strain FA1090 was identified as 5′-AGAAA-3′. Mutant strains lacking the modA11, 12 or 13 genes were made in N. meningitidis and N. gonorrhoeae and their phenotype analyzed in comparison to a corresponding mod ON wild-type strain. Microarray analysis revealed that in all three modA alleles multiple genes were either upregulated or downregulated, some of which were virulence-associated. For example, in N. meningitidis MC58 (modA11), differentially expressed genes included those encoding the candidate vaccine antigens lactoferrin binding proteins A and B. Functional studies using N. gonorrhoeae FA1090 and the clinical isolate O1G1370 confirmed that modA13 ON and OFF strains have distinct phenotypes in antimicrobial resistance, in a primary human cervical epithelial cell model of infection, and in biofilm formation. This study, in conjunction with our previous work in H. influenzae, indicates that phasevarions may be a common strategy used by host-adapted bacterial pathogens to randomly switch between “differentiated” cell types

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Square Kilometre Array Developments

NRC publication: Ye

Could Mexico become the new 'China'? Policy drivers of competitiveness and productivity

Over the last decade, Mexico's unit labour costs decreased relative to other emerging markets', especially compared to China's. This decrease boosted Mexico's trade competitiveness, particularly in the manufacturing sector. However, Mexico's increasing competitiveness masks one of the country's fundamental concerns, which is the absence of productivity improvements. The aim of this paper is two-fold: first, we examine the evolution of total factor productivity in Mexico's manufacturing sector, as compared to China's. Firm-level data is employed to analyse the distribution and characteristics of productivity across Mexico's regions. Second, using regional data for the period 2005-2012, we study the policy impediments behind sluggish productivity improvements, particularly to determine how labour informality may have contributed. The study takes advantage of Mexico's heterogeneity across regions in terms of productivity, market regulation, financial constraints and firm size to identify economic policies that can help to boost productivity in the future

Diffuse, Nonthermal X-Ray Emission from the Galactic Star Cluster Westerlund 1

We present the diffuse X-ray emission identified in Chandra observations of the young, massive Galactic star cluster Westerlund 1. After removing pointlike X-ray sources down to a completeness limit of ≈ ergs s−1, we identify ergs s−1 (2–8 keV) of diffuse emission. The spatial distribution of the emission can be described as a slightly elliptical Lorentzian core with a half-width at half-maximum along the major axis of , similar to the distribution of point sources in the cluster, plus a 5 halo of extended emission. The spectrum of the diffuse emission is dominated by a hard continuum component that can be described as a keV thermal plasma that has a low iron abundance (0.3 solar) or as nonthermal emission that could be stellar light that is inverse Compton scattered by MeV electrons. Only 5% of the flux is produced by a keV plasma. The low luminosity of the thermal emission and the lack of a 6.7 keV iron line suggest that 40,000 unresolved stars with masses between 0.3 and 2 M are present in the cluster, fewer than previously estimated. Moreover, the flux in the diffuse emission is a factor of several lower than would be expected from a supersonically expanding cluster wind, and there is no evidence for thermal remnants produced by supernovae. Less than 10−5 of the mechanical luminosity of the cluster is dissipated as 2–8 keV X-rays, leaving a large amount of energy that either is radiated at other wavelengths, is dissipated beyond the bounds of our image, or escapes into the intergalactic medium

Imaging Novel Ruthenium bipyridine-based Nanophotoswitches in Retina

Nanophotoswitches (NPSs) offer a new tool for optical stimulation of neuronal activity, in vitro and also potentially in vivo. Our group previously reported a ruthenium bipyridine (Rubpy)-based NPS that inserts into the plasma membrane and upon visible illumination generates an electrical dipole, triggering action potentials in adrenal chromaffin cells. We have recently demonstrated that after intravitreal injection of this NPS into the eyes of blind rats, illumination of the eye elicited electrical activity in the contralateral superior colliculus. To better understand the site of action of the NPS in retina, we examined the distribution of the molecules in different retinal layers after intravitreal injection. Methods: Rubpy molecules can be visualized by their luminescence (610 nm) upon visible wavelength illumination (460 nm). To resolve the luminescence from different retinal layers, a rapid-scan twophoton imaging system (LaVison) was used (Ti:Sapphire laser tuned to 900 nm). Intravitreal injection (1 mM, 4 μL Rubpy-based NPSs in BSS), followed by eye removal and retina isolation 2-5 hrs after, was performed on young RCS rats. Luminescence images of the wholemount retina were captured by an EM-CCD camera (Andor). Results: At 2 hrs after intravitreal injection and with continuous superfusion of Ames medium, luminescence was confined near the injection site. Luminescence was observed localized to surface membranes of axons and somata of retinal ganglion cells (RGC), demonstrating the impermeability of the cell membrane to the NPS molecules. The outer retina did not show significant luminescence. After 3 additional hours, luminescence was more diffused within the RGC layer and still did not extend to the outer retina. Conclusions: This study shows marked staining of RGC layer by intravitreally injected Rubpy-based NPS molecules, consistent with the hypothesis that the photoactivated NPS molecules induce electrical activity in the superior colliculus by acting on the RGCs that deliver electrical signals to the visual pathway outside the eyes. Distinct from other nano-scale optical cellular modulating approaches using optogenetics or azobenzene-based photoswitches, the NPS approach obviates the need for gene manipulation or toxic UV illumination, highlighting its potential in generating high-acuity prosthetic vision in patients blinded by retinal degenerative diseases