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The inner \\(\\sim\\)200 pc region of the Galaxy contains a 4 million M\\(_{\\odot}\\) supermassive black hole (SMBH), significant quantities of molecular gas, and star formation and cosmic ray energy densities that are roughly two orders of magnitude higher than the corresponding levels in the Galactic disk. At a distance of only 8.2 kpc, the region presents astronomers with a unique opportunity to study a diverse range of energetic astrophysical phenomena, from stellar objects in extreme environments, to the SMBH and star-formation driven feedback processes that are known to influence the evolution of galaxies as a whole. We present a new survey of the Galactic center conducted with the South African MeerKAT radio telescope. Radio imaging offers a view that is unaffected by the large quantities of dust that obscure the region at other wavelengths, and a scene of striking complexity is revealed. We produce total intensity and spectral index mosaics of the region from 20 pointings (144 hours on-target in total), covering 6.5 square degrees with an angular resolution of 4\\(\"\\),at a central frequency of 1.28 GHz. Many new features are revealed for the first time due to a combination of MeerKAT's high sensitivity, exceptional \\(u,v\\)-plane coverage, and geographical vantage point. We highlight some initial survey results, including new supernova remnant candidates, many new non-thermal filament complexes, and enhanced views of the Radio Arc Bubble, Sgr A and Sgr B regions. This project is a SARAO public legacy survey, and the image products are made available with this article.

We present the SARAO MeerKAT Galactic Plane Survey (SMGPS), a 1.3 GHz continuum survey of almost half of the Galactic Plane (251\\deg \\(\\le l \\le\\) 358\\deg and 2\\deg \\(\\le l \\le\\) 61\\deg at \\(|b| \\le 1.5\\deg \\)). SMGPS is the largest, most sensitive and highest angular resolution 1 GHz survey of the Plane yet carried out, with an angular resolution of 8\" and a broadband RMS sensitivity of \\(\\sim\\)10--20 \\(\\mu\\) Jy/beam. Here we describe the first publicly available data release from SMGPS which comprises data cubes of frequency-resolved images over 908--1656 MHz, power law fits to the images, and broadband zeroth moment integrated intensity images. A thorough assessment of the data quality and guidance for future usage of the data products are given. Finally, we discuss the tremendous potential of SMGPS by showcasing highlights of the Galactic and extragalactic science that it permits. These highlights include the discovery of a new population of non-thermal radio filaments; identification of new candidate supernova remnants, pulsar wind nebulae and planetary nebulae; improved radio/mid-IR classification of rare Luminous Blue Variables and discovery of associated extended radio nebulae; new radio stars identified by Bayesian cross-matching techniques; the realisation that many of the largest radio-quiet WISE HII region candidates are not true HII regions; and a large sample of previously undiscovered background HI galaxies in the Zone of Avoidance.

We present the confusion-limited 1.28 GHz MeerKAT DEEP2 image covering one \\(\\approx 68'\\) FWHM primary beam area with \\(7.6''\\) FWHM resolution and \\(0.55 \\pm 0.01\\) \\(\\mu\\)Jy/beam rms noise. Its J2000 center position \\(\\alpha=04^h 13^m 26.4^s\\), \\(\\delta=-80^\\circ 00' 00''\\) was selected to minimize artifacts caused by bright sources. We introduce the new 64-element MeerKAT array and describe commissioning observations to measure the primary beam attenuation pattern, estimate telescope pointing errors, and pinpoint \\((u,v)\\) coordinate errors caused by offsets in frequency or time. We constructed a 1.4 GHz differential source count by combining a power-law count fit to the DEEP2 confusion \\(P(D)\\) distribution from \\(0.25\\) to \\(10\\) \\(\\mu\\)Jy with counts of individual DEEP2 sources between \\(10\\) \\(\\mu\\)Jy and \\(2.5\\) mJy. Most sources fainter than \\(S \\sim 100\\) \\(\\mu\\)Jy are distant star-forming galaxies obeying the FIR/radio correlation, and sources stronger than \\(0.25\\) \\(\\mu\\)Jy account for \\(\\sim93\\%\\) of the radio background produced by star-forming galaxies. For the first time, the DEEP2 source count has reached the depth needed to reveal the majority of the star formation history of the universe. A pure luminosity evolution of the 1.4 GHz local luminosity function consistent with the Madau & Dickinson (2014) model for the evolution of star-forming galaxies based on UV and infrared data underpredicts our 1.4 GHz source count in the range \\(-5 \\lesssim \\log[S(\\mathrm{Jy})] \\lesssim -4\\).

The Galactic Centre contains a supermassive black hole with a mass of 4 million suns within an environment that differs markedly from that of the Galactic disk. While the black hole is essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings. Also, while the levels of star formation in the Galactic Centre have been approximately constant over the last few hundred Myr, there is evidence of elevated short-duration bursts, strongly influenced by interaction of the black hole with the enhanced gas density present within the ring-like Central Molecular Zone at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200 pc region is characterized by large amounts of warm molecular gas, a high cosmic ray ionization rate, unusual gas chemistry, enhanced synchrotron emission, and a multitude of radio-emitting magnetised filaments, the origin of which has not been established. Here we report radio imaging that reveals bipolar bubbles spanning 1 degree x 3 degrees (140 parsecs x 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 x 10^52 ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.

In this new edition of the acclaimed Dementia: Presentations, Differential Diagnosis, and Nosology, V. Olga B. Emery, Ph.D., and Thomas E. Oxman, M.D., bring together a distinguished group of medical authorities—including many who have done seminal research in this field—to discuss the spectrum of dementing disorders and explain their overlap, presentations, and differential diagnosis. The chapters present original data as well as material from the authors' clinical experiences. Current classification systems are evaluated and modified to better account for common presentations of dementia. Thoroughly revised, updated, and expanded, the second edition includes new material on neuroimaging, genetics, the role of inflammation in Alzheimer disease, retrophylogenesis in Alzheimer memory, and on AIDS dementia. In addition, each chapter includes a new section entitled describing clinical applications.

Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4–24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis. Chemically modified mRNA is a new approach for therapeutic protein expression that could be applied to angiogenesis. Here the authors show in a phase 1 clinical trial that a modified mRNA encoding VEGF-A is well tolerated in patients with type 2 diabetes.

Broadly-neutralizing antibodies (bNAbs) against HIV-1 Env can protect from infection. We characterize Ab1303 and Ab1573, heterologously-neutralizing CD4-binding site (CD4bs) antibodies, isolated from sequentially-immunized macaques. Ab1303/Ab1573 binding is observed only when Env trimers are not constrained in the closed, prefusion conformation. Fab-Env cryo-EM structures show that both antibodies recognize the CD4bs on Env trimer with an ‘occluded-open’ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4. The occluded-open Env trimer conformation includes outwardly-rotated gp120 subunits, but unlike CD4-bound Envs, does not exhibit V1V2 displacement, 4-stranded gp120 bridging sheet, or co-receptor binding site exposure. Inter-protomer distances within trimers measured by double electron-electron resonance spectroscopy suggest an equilibrium between occluded-open and closed Env conformations, consistent with Ab1303/Ab1573 binding stabilizing an existing conformation. Studies of Ab1303/Ab1573 demonstrate that CD4bs neutralizing antibodies that bind open Env trimers can be raised by immunization, thereby informing immunogen design and antibody therapeutic efforts. Neutralizing antibodies (bNAbs) against HIV-1 are exclusively directed against the viral envelope protein (Env) and mainly target Env in a closed, prefusion state. Here, Yang et al. structurally characterize two heterologously-neutralizing CD4-binding site (CD4bs) antibodies isolated from sequentially immunized macaques, and show that these antibodies recognize the CD4bs on Env trimers in an „occluded-open‟ conformation between closed, as targeted by bNAbs, and fully-open, as recognized by CD4.

Background Preterm birth (PTB) is a leading cause of child morbidity and mortality. Evidence suggests an increased risk with both maternal underweight and obesity, with some studies suggesting underweight might be a greater factor in spontaneous PTB (SPTB) and that the relationship might vary by parity. Previous studies have largely explored established body mass index (BMI) categories. Our aim was to compare associations of maternal pre-pregnancy BMI with any PTB, SPTB and medically indicated PTB (MPTB) among nulliparous and parous women across populations with differing characteristics, and to identify the optimal BMI with lowest risk for these outcomes. Methods We used three UK datasets, two USA datasets and one each from South Australia, Norway and Denmark, together including just under 29 million pregnancies resulting in a live birth or stillbirth after 24 completed weeks gestation. Fractional polynomial multivariable logistic regression was used to examine the relationship of maternal BMI with any PTB, SPTB and MPTB, among nulliparous and parous women separately. The results were combined using a random effects meta-analysis. The estimated BMI at which risk was lowest was calculated via differentiation and a 95% confidence interval (CI) obtained using bootstrapping. Results We found non-linear associations between BMI and all three outcomes, across all datasets. The adjusted risk of any PTB and MPTB was elevated at both low and high BMIs, whereas the risk of SPTB was increased at lower levels of BMI but remained low or increased only slightly with higher BMI. In the meta-analysed data, the lowest risk of any PTB was at a BMI of 22.5 kg/m 2 (95% CI 21.5, 23.5) among nulliparous women and 25.9 kg/m 2 (95% CI 24.1, 31.7) among multiparous women, with values of 20.4 kg/m 2 (20.0, 21.1) and 22.2 kg/m 2 (21.1, 24.3), respectively, for MPTB; for SPTB, the risk remained roughly largely constant above a BMI of around 25–30 kg/m 2 regardless of parity. Conclusions Consistency of findings across different populations, despite differences between them in terms of the time period covered, the BMI distribution, missing data and control for key confounders, suggests that severe under- and overweight may play a role in PTB risk.

Transition metal-catalysed C–H activation has emerged as an increasingly powerful platform for molecular syntheses, enabling applications to natural product syntheses, late-stage modification, pharmaceutical industries and material sciences, among others. This Primer summarizes representative best practices for the experimental set-up and data deposition for C–H activation, as well as discussing key developments including recent advances in asymmetric, photoinduced and electrocatalytic C–H activation. Likewise, strategies for applications of C–H activation towards the assembly of structurally complex (bio)polymers and drugs in academia and industry are discussed. In addition, current limitations in C–H activation and possible approaches for overcoming these shortcomings are reviewed.This Primer provides an overview of the best practices for C–H activation as well as key advances in asymmetric, photoinduced and electrocatalytic-mediated catalysis for this synthetic platform. An overview of how C–H activation facilitates the synthesis of molecules such as structurally complex (bio)polymers and drugs is provided along with the current challenges and priorities for the next decade.

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.