The JWST Advanced Deep Extragalactic Survey: Discovery of an Extreme Galaxy Overdensity at z = 5.4 with JWST/NIRCam in GOODS-S

Abstract We report the discovery of an extreme galaxy overdensity at z = 5.4 in the GOODS-S field using James Webb Space Telescope (JWST)/NIRCam imaging from JADES and JEMS alongside JWST/NIRCam wide-field slitless spectroscopy from FRESCO. We identified potential members of the overdensity using Hubble Space Telescope+JWST photometry spanning λ = 0.4–5.0 μm. These data provide accurate and well-constrained photometric redshifts down to m ≈ 29–30 mag. We subsequently confirmed N = 81 galaxies at 5.2 &lt; z &lt; 5.5 using JWST slitless spectroscopy over λ = 3.9–5.0 μm through a targeted line search for Hα around the best-fit photometric redshift. We verified that N = 42 of these galaxies reside in the field, while N = 39 galaxies reside in a density around ∼10 times that of a random volume. Stellar populations for these galaxies were inferred from the photometry and used to construct the star-forming main sequence, where protocluster members appeared more massive and exhibited earlier star formation (and thus older stellar populations) when compared to their field galaxy counterparts. We estimate the total halo mass of this large-scale structure to be 12.6 ≲ log 10 M halo / M ⊙ ≲ 12.8 using an empirical stellar mass to halo mass relation, which is likely an underestimate as a result of incompleteness. Our discovery demonstrates the power of JWST at constraining dark matter halo assembly and galaxy formation at very early cosmic times.</jats:p

Targeting beta-amyloid pathology in Alzheimer's disease with Abeta immunotherapy

More than 10 clinical trials of Abeta immunotherapy are currently underway in patients with Alzheimer's disease (AD). The aim is to identify safe approaches for the efficacious antibody-mediated removal of brain beta-amyloid or its neurotoxic oligomeric precursors consisting of aggregated amyloid beta-peptide (Abeta). Initial experimental and neuro-pathological evidence for clearance of brain beta-amyloid in response to Abeta immunotherapy is associated with structural and functional rescue of neurons, as well as initial signs of clinical stabilization and reduced rates of dementia progression. For the next steps in the future improvement of Abeta immunotherapy, major challenges in pharmacokinetics, safety, and tolerability need to be addressed. These include the low penetrations rates of IgG molecules through the blood-brain barrier, possible reductions in brain volume, the possibility of autoimmune disease related to unwanted cross-reactivity with endogenous antigens on physiological structures, micro-hemorrhages related to cross-reaction with pre-existing vascular amyloid pathology, possible relocalization of Abeta from beta-amyloid plaques to brain blood vessels resulting in increased amyloid angiopathy, and the lacking activity of Abeta antibodies on pre-existing neurofibrillary tangle pathology, as well as the lacking molecular identification of the forms of Abeta to be therapeutically targeted. The solutions to these problems will be guided by the fine lines between tolerance and immunity against physiological and pathological structures, respectively, as well as by the understanding of the pathogenic transition of soluble Abeta into toxic oligomeric aggregation intermediates in the dynamic equilibrium of beta-amyloid fibril assembly. Provided that the ongoing and planned clinical trials address these issues in a timely manner, there is a good chance for Abeta immunotherapy to be one of the first disease-modifying therapies of Alzheimer's disease to be introduced into clinical practice

Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin- kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001). CONCLUSIONS In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients