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Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.

Brain structure scaffolds intrinsic function, supporting cognition and behavioral flexibility. Here, the authors show how macroscale organization of cortical microstructure and resting-state function uncouple in transmodal cortex of humans and macaques.

Which combination of current genome sequencing and assembly approaches results in high-quality, complete diploid genome assemblies is determined.

Transcription factor Foxp3 is essential for the development and function of regulatory T cells, but it does not act in isolation. Benoist and colleagues identify a quintet of factors that facilitate transcriptional regulation by Foxp3.

The acidophilic fungus Acrodontium crateriforme is present in traps of the carnivorous plant Drosera spatulata and promotes prey digestion.

Understanding the pathology in the lungs of patients with COVID-19 might provide clues as to the susceptibility of patients and how the SARS-CoV-2 virus can be fatal. Here the authors analyze cadaveric pulmonary tissue and show one group with high viral load, early death, inflammation and inflammatory damage, and another with low viral load, longer duration of disease, and more M2-like polarization and fibrotic lung damage.

A broadly neutralizing antibody (bnAb) response is required to combat SARS-CoV-2 variants of concern (VOCs). The authors isolated and characterized a large panel of sarbecovirus bnAbs from vaccinated individuals who had recovered from COVID-19, finding that many of these antibodies were able to neutralize all VOCs, including Omicron, and demonstrate prophylaxis in mice infected with diverse sarbecoviruses.

From 1980 to 2018, the levels of total and non-high-density lipoprotein cholesterol increased in low- and middle-income countries, especially in east and southeast Asia, and decreased in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe.

Swanton and colleagues present a clonal expression signature, ORACLE, which, in combination with clinicopathological and molecular risk factors, can predict survival of patients with lung adenocarcinoma, and they prospectively validate its prognostic value.

A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.

Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.

A surface electromyography biosensing system that is based on a screen-printed, conformal electrode array and has in-sensor adaptive learning capabilities can classify human gestures in real time and with high accuracy.

Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment.

Heart contraction, which is decreased in disease, is determined by Ca²⁺binding to troponin C. Here, the authors combine a protein engineering approach with gene therapy to modulate heart contractility in mice with the use of rationally designed Troponin C variants, suggesting a new therapy for diseased hearts.

The complexity of the brain adds another level of difficulty to our understanding of how the brain develops, matures and functions. Both structural and molecular components define brain functional connectivity, and its alteration may result in developmental, behavioral and social deficits. Uncovering the roots and mechanisms behind neurodevelopmental disorders, such as fragile X syndrome or autism, is the goal of several lines of research. Despite the challenges associated with studying these diseases, new advances are linking pathological genetic changes with mechanisms in the brain. In Bench to Bedside, Guoping Feng and Jonathan Ting peruse a study that uncovers how fragile X syndrome–causing gene mutations unleash a translation break that finally leads to overexpression of synaptic proteins that alter the proper transmission of signals at the synapse. Furthermore, changes in the brain during the development of a person can also provide information about when and where the diseased brain loses functional connectivity. In Bedside to Bench, Jeffrey Neul proposes that studying the functional networks in people with autism and other neurodevelopmental disorders, and correlating changes with functional connectivity in animal models of these diseases, will uncover the mechanisms of normal and abnormal development and suggest possible treatment strategies.

Functional MRI studies across ages show that the classic homunculus of the motor cortex in humans is in fact discontinuous, alternating with action control-linked regions termed the somato-cognitive action network.

The combination of hot and dry conditions reduces crop yields through heat and drought stresses. The heat sensitivity of crops depends on the local strength of couplings between temperature and moisture, but how future climate will impact the temperature–moisture couplings remains unknown. On the basis of historical patterns and a suite of climate models, this study projects that climate change will modify the couplings and probably worsen the impacts of warming on some of the world’s most important crops.

Wu et al. report that a stiff extracellular matrix stimulates the release of exosomes from cancer cells under the control of Akt and Rab8. These exosomes in turn promote tumour growth.

CAR T cells targeting PSMA and engineered to be resistant to immunosuppressive TGFβ signaling exhibit dose-dependent toxicity and expansion following infusion, with some transient antitumor activity, in patients with metastatic castration-resistant prostate cancer

Analyses of expression profiles from whole blood of 31,684 individuals identify cis-expression quantitative trait loci (eQTL) effects for 88% of genes and trans-eQTL effects for 37% of trait-associated variants.

Amphipols, bicelles and nanodiscs are used to study intact membrane protein complexes by mass spectrometry, with better preservation of oligomeric complexes than traditional detergent micelles.

Previous studies identified an association between the 2q35 locus and breast cancer. Here, the authors show that a SNP at 2q35, rs4442975, is associated with oestrogen receptor positive disease and suggest that this effect is mediated through the downregulation of a known breast cancer gene, IGFBP5.

Delivering genes to and across the brain vasculature efficiently and specifically across species remains challenging. Here, the authors show that endothelial-specific AAVs with serotype flexibility enable redosing and transform the brain vasculature into an in vivo biofactory in genetically diverse rodents. In primates, these vectors cross the blood-brain-barrier and show broad tropism.

Major histocompatibility complex (MHC) loss of heterozygosity, allele-specific mutation and measurement of expression and repression (MHC Hammer) detects disruption to human leukocyte antigens due to mutations, loss of heterogeneity, altered gene expression or alternative splicing. Applied to lung and breast cancer datasets, the tool shows that these aberrations are common across cancer and can have clinical implications.

Single-nucleus and spatial, whole-transcriptome profiling of 43 pancreatic adenocarcinomas provides a refined molecular and cellular classification, highlighting a new neoadjuvant treatment-associated neural-like progenitor tumor cell state.

A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.

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.

Polygenic risk scores predict the likelihood that an individual will develop a certain cancer, however these are often specific for a given population. Here, the authors show that a risk score developed to assess the risk of breast cancer in European women can also predict risk in Asian populations.

Efficient repair of demyelinated CNS lesions involves the resolution of inflammation and induction of remyelination. Berghoff et al. show that sterol synthesis in microglia is key to both processes, which can be supported by squalene therapy.

The BRAIN Initiative Cell Census Network has constructed a multimodal cell census and atlas of the mammalian primary motor cortex in a landmark effort towards understanding brain cell-type diversity, neural circuit organization and brain function.

Roger Milne and colleagues conduct a genome-wide association study for estrogen receptor (ER)-negative breast cancer combined with BRCA1 mutation carriers in a large cohort. They identify ten new risk variants and find high genetic correlation between breast cancer risk for BRCA1 mutation carriers and risk of ER-negative breast cancer in the general population.

An additive manufacturing strategy is used to produce dual-phase nanolamellar high-entropy alloys that show a combination of enhanced high yield strength and high tensile ductility.

The specific high-sensitivity enzymatic reporter unlocking (SHERLOCK) assay detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA with high sensitivity and specificity in hundreds of nasopharyngeal and throat swab samples collected at Siriraj Hospital in Thailand.

Using machine learning, this study shows that self-reported experience of task states maps onto ‘brain space’, i.e., features of different task states identified in fMRI.

An examination of motor cortex in humans, marmosets and mice reveals a generally conserved cellular makeup that is likely to extend to many mammalian species, but also differences in gene expression, DNA methylation and chromatin state that lead to species-dependent specializations.

The molecular mechanisms that regulate senescence are incompletely understood. Here the authors couple high-throughput mapping of disease-associated functional SNPs (fSNPs) with proteomics analysis of fSNP-binding proteins to identify the transcription factor CUX1 as an activator of p16 expression and a regulator of senescence.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

A randomized trial in patients hospitalized with COVID-19 showed no benefit and potentially increased harm associated with the use of convalescent plasma, with subgroup analyses suggesting that the antibody profile in donor plasma is critical in determining clinical outcomes.

Association analysis identifies 65 new breast cancer risk loci, predicts target genes for known risk loci and demonstrates a strong overlap with somatic driver genes in breast tumours.

Genetic deletion or transcriptional silencing of HERV-H elements in human pluripotent stem cells (hPSCs) eliminates nearby topologically associating domain boundaries, while de novo insertion of HERV-H elements can introduce new ones. Mutations of specific HERV-H elements can impact hPSC differentiation.

Uropathogenic Escherichia coli infection induces epigenetic remodelling and trained immune responses in bladder epithelial stem cells that affect susceptibility to recurrent infection.

How spatial organisation in the brain affects function is not well understood. Here, the authors show that function changes gradually across sensory cortex, more rapidly across association cortex, and that these changes are related to variation in intracortical myelination.

Individuals with malignant hyperthermia susceptibility (MHS) suffer from lifethreatening responses to heat. Here the authors demonstrate that adaptive thermogenesis from brown adipose tissue contributes to this heat sensitivity in a preclinical mouse model of MHS

Coronary heart disease is the leading cause of death worldwide with multiple environmental and genetic risk factors. Here the authors integrate genomic, epigenomic and transcriptomic mapping to elucidate causal variation and mechanisms of known genetic associations.

Postmortem studies indicate reduced synaptic density in schizophrenia. Sellgren et al. show increased synaptic pruning in patient-derived cell models and provide evidence that C4 risk variants increase engulfment, while minocycline decreases it.

Using optogenetics and multi-electrode recording in behaving mice, the authors find that briefly driving the thalamic reticular nucleus (TRN) switches thalamocortical firing mode and generates neocortical spindles, which have been implicated in memory and disease. These findings provide causal support for the idea that the TRN is involved in state regulation and introduce a new model for addressing the role of spindles in behavior.