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The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease, but it is not deterministic. Here, the authors show that common genetic variation changes how APOE-ε4 influences cognition.

McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.

Alkenes are essential functional groups in organic chemistry, featuring well-defined geometries and bond orders of 2. In this study, cubene and 1,7-quadricyclene are calculated to possess unusual hyperpyramidalized geometries and low alkene bond orders near 1.5. Their resultant high reactivities ultimately permit access to intricate scaffolds and new chemical space.

The strained C₆H₆ isomer 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes which demonstrate their potential for selective chemical transformations and provide an unconventional entryway to complex scaffolds.

Asymmetric nickel catalysis is used to intercept transient cyclic allene intermediates to achieve stereocontrol.

Transamidation reactions are kinetically and thermodynamically challenging because of the stability of the amide starting materials. Here, the authors show a two-step process—activation of a secondary amide, followed by nickel-catalysed C–N bond cleavage—that allows mild and high yielding transamidation.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

QR Chem is a free resource that enables teachers and researchers to link audiences directly to three-dimensional renderings of molecules.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.

Although π-bonds are typically associated with having well-defined arrangements of atoms, ring constraints can lead to geometric distortion, resulting in heightened reactivity. These effects can be leveraged to enable synthetic transformations. This Review features processes wherein geometric distortion is leveraged to provide rapid access to structurally complex products.

The LHCb experiment at CERN has observed significant asymmetries between the decay rates of the beauty baryon and its CP-conjugated antibaryon, thus demonstrating CP violation in baryon decays.

Six-membered cyclic 1,2,3-trienes are geometrically distorted, short-lived intermediates that have high reactivity. Now, azacyclic 1,2,3-trienes can be generated and trapped, allowing for the synthesis of annulated pyridones.

Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

A new synthetic method provides a coveted motif, the bicyclo[2.1.1]hexane scaffold, using the uncommon coupling of two strained diradicaloid fragments: transiently generated cyclic allenes and bicyclo[1.1.0]butanes.

Chem Kids is a science camp where children ages 10 to 12 years old learn the notoriously difficult subject of organic chemistry.

Ten years after the discovery of the Higgs boson, the ATLAS  experiment at CERN probes its kinematic properties with a significantly larger dataset from 2015–2018 and provides further insights on its interaction with other known particles.

Although enzymes are able to cleave amide bonds in nature, it is difficult to selectively break the carbon–nitrogen bond of an amide using synthetic chemistry; now the activation and cleavage of these bonds using nickel catalysts is used to convert amides to esters.

Fungal siderophores are biosynthesised by nonribosomal peptide synthetases (NRPSs) with highly unusual domain architectures. Here, the authors characterise cryptic programming events occurring within SidC NRPS, responsible for ferricrocin biosynthesis in Aspergillus nidulans.

Accurate, phased assemblies are a key tool in understanding the human genome, particularly in highly polymorphic regions like the medically important MHC. Here the authors provide an assembly-based benchmark for this difficult-to-characterize region.

Strained cyclic allenes are short-lived intermediates that confine a functional group with a preferred linear geometry, an allene, into a small ring, inducing strain-driven reactivity. Now, 2,3-azacyclic and 2,3-oxacyclic allenes are generated and trapped using cycloaddition reactions, generating complex heterocycles that bear a large fraction of sp³-hybridized atoms.

Experienced chemists know that chemistry is all around them. Helping students to see the connections between real life and concepts of organic chemistry is the driving force behind the development of a set of online resources pioneered at UCLA.

A genome-wide association study of critically ill patients with COVID-19 identifies genetic signals that relate to important host antiviral defence mechanisms and mediators of inflammatory organ damage that may be targeted by repurposing drug treatments.

Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

Amides have historically been considered stable and unreactive functional groups because of resonance stabilization. Here, it is demonstrated that Boc-activated amides can be employed in Suzuki–Miyaura couplings using non-precious-metal catalysis. The overall reaction is complementary to the widely employed Weinreb ketone synthesis.

Organometallic complexes have numerous applications in chemistry and biology, but diversification of their structures is synthetically challenging. Here, the authors report a versatile platform for on-the-complex annulation reactions using transient aryne intermediates to access pi-extended polypyridyl complexes.

The in situ trapping of pyridynes is an efficient method for the generation of a variety of substituted pyridines but, until now, the method has been hampered by a lack of regiocontrol. Here, proximal halide and sulfamate substituents are shown to perturb pyridyne distortion and thus govern regioselectivities in pyridyne reactions.

Diluting phosphorescent and thermally activated delayed fluorescence emitter molecules in solid-state host matrices has proven to be a useful strategy to hinder self-quenching mechanisms, but host materials must meet several criteria to enable energy efficient and stable OLEDs. Here, the authors report the synthesis of a series of 1,3,5-oxadiazines from a one-pot interrupted Fischer indolization, and demonstrate that they possess highly desirable characteristics as host materials in deep-blue OLED devices.

Strained organic compounds have long fascinated the chemistry community. Heterocyclic allenes are particularly interesting strained intermediates, but their use in synthetic chemistry is rather scarce. Now, an experimental and computational study of azacyclic allenes demonstrates that heteroatom-containing cyclic allenes can be harnessed for the construction of complex molecular scaffolds, including those that bear multiple stereogenic centres.

The total synthesis of tubingensin B — an indole diterpenoid that bears a daunting chemical structure — has now been achieved. The design and evolution of this succinct total synthesis underscores the utility of long-avoided aryne intermediates for the introduction of structural motifs that have conventionally been viewed as challenging.

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

An integrative genomic analysis of several hundred endometrial carcinomas shows that a minority of tumour samples carry copy number alterations or TP53 mutations and many contain key cancer-related gene mutations, such as those involved in canonical pathways and chromatin remodelling; a reclassification of endometrial tumours into four distinct types is proposed, which may have an effect on patient treatment regimes.

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

Simple methods to incorporate deuterium into organic compounds are highly sought after as deuteration can enable mechanistic studies or improve the metabolic stability of pharmaceuticals. Now, a catalytic hydrogen–deuterium exchange reaction using deuterated water allows convenient access to deuterated aldehyde building blocks.

Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.