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Abstract Symptoms of the Post-COVID-19 Condition are often non-specific making it a challenge to distinguish them from symptoms due to other medical conditions. In this study, we compare the proportion of emergency department patients who developed symptoms consistent with the World Health Organization’s Post-COVID-19 Condition clinical case definition between those who tested positive for Severe Acute Respiratory Syndrome Coronavirus-2 infection and time-matched patients who tested negative. Our results show that over one-third of emergency department patients with a proven acute infection meet Post-COVID-19 Condition criteria 3 months post-index visit. However, one in five test-negative patients who claim never having been infected also report symptoms consistent with Post-COVID-19 Condition highlighting the lack of specificity of the clinical case definition. Testing for SARS-CoV-2 during the acute phase of a suspected infection should continue until specific biomarkers of Post-COVID-19 Condition become available for diagnosis and treatment.

Abstract Novel chimeric antigen receptor (CAR) T-cell approaches are needed to improve therapeutic efficacy in solid tumors. High-risk neuroblastoma is an aggressive pediatric solid tumor that expresses cell-surface GPC2 and GD2 with a tumor microenvironment infiltrated by CD16a-expressing innate immune cells. Here we engineer T-cells to express a GPC2-directed CAR and simultaneously secrete a bispecific innate immune cell engager (BiCE) targeting both GD2 and CD16a. In vitro, GPC2.CAR-GD2.BiCE T-cells induce GPC2-dependent cytotoxicity and secrete GD2.BiCE that promotes GD2-dependent activation of antitumor innate immunity. In vivo, GPC2.CAR-GD2.BiCE T-cells locally deliver GD2.BiCE and increase intratumor retention of NK-cells. In mice bearing neuroblastoma patient-derived xenografts and reconstituted with human CD16a-expressing immune cells, GD2.BiCEs enhance GPC2.CAR antitumor efficacy. A CAR.BiCE strategy should be considered for tumor histologies where antigen escape limits CAR efficacy, especially for solid tumors like neuroblastoma that are infiltrated by innate immune cells.

Abstract The global energy budget is pivotal to understanding planetary evolution and climate behaviors. Assessing the energy budget of giant planets, particularly those with large seasonal cycles, however, remains a challenge without long-term observations. Evolution models of Saturn cannot explain its estimated Bond albedo and internal heat flux, mainly because previous estimates were based on limited observations. Here, we analyze the long-term observations recorded by the Cassini spacecraft and find notably higher Bond albedo (0.41 ± 0.02) and internal heat flux (2.84 ± 0.20 Wm−2) values than previous estimates. Furthermore, Saturn’s global energy budget is not in a steady state and exhibits significant dynamical imbalances. The global radiant energy deficit at the top of the atmosphere, indicative of the planetary cooling of Saturn, reveals remarkable seasonal fluctuations with a magnitude of 16.0 ± 4.2%. Further analysis of the energy budget of the upper atmosphere including the internal heat suggests seasonal energy imbalances at both global and hemispheric scales, contributing to the development of giant convective storms on Saturn. Similar seasonal variabilities of planetary cooling and energy imbalance exist in other giant planets within and beyond the Solar System, a prospect currently overlooked in existing evolutional and atmospheric models.

Abstract Class B G protein-coupled receptors can form dimeric complexes important for high potency biological effects. Here, we apply pharmacological, biochemical, and biophysical techniques to cells and membranes expressing the prototypic secretin receptor (SecR) to gain insights into secretin binding to homo-dimeric and monomeric SecR. Spatial proximity between peptide and receptor residues, probed by disulfide bond formation, demonstrates that the secretin N-terminus moves from adjacent to extracellular loop 3 (ECL3) at wild type SecR toward ECL2 in non-dimerizing mutants. Analysis of fluorescent secretin analogs demonstrates stable engagement of the secretin C-terminal region within the receptor extracellular domain (ECD) for both dimeric and monomeric receptors, while the mid-region exhibits lower mobility while docked at the monomer. Moreover, decoupling of G protein interaction reduces mobility of the peptide mid-region at wild type receptor to levels similar to the mutant, whereas it has no further impact on the monomer. These data support a model of peptide engagement whereby the ability of SecR to dimerize promotes higher conformational dynamics of the peptide-bound receptor ECD and ECLs that likely facilitates more efficient G protein recruitment and activation, consistent with the higher observed functional potency of secretin at wild type SecR relative to the monomeric mutant receptor.

Abstract Dupilumab, an IL4R-blocking antibody, has shown clinical efficacy for atopic dermatitis (AD) treatment. In addition to conjunctivitis/blepharitis, the de novo appearance of head/neck dermatitis is now recognized as a distinct side effect, occurring in up to 10% of patients. Histopathological features distinct from AD suggest a drug effect, but exact underlying mechanisms remain unknown. We profiled punch biopsies from dupilumab-associated head and neck dermatitis (DAHND) by using single-cell RNA sequencing and compared data with untreated AD and healthy control skin. We show that dupilumab treatment was accompanied by normalization of IL-4/IL-13 downstream activity markers such as CCL13, CCL17, CCL18 and CCL26. By contrast, we found strong increases in type 22-associated markers (IL22, AHR) especially in oligoclonally expanded T cells, accompanied by enhanced keratinocyte activation and IL-22 receptor upregulation. Taken together, we demonstrate that dupilumab effectively dampens conventional type 2 inflammation in DAHND lesions, with concomitant hyperactivation of IL22-associated responses.

Abstract Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.

Abstract Polarons and spin-orbit (SO) coupling are distinct quantum effects that play a critical role in charge transport and spin-orbitronics. Polarons originate from strong electron-phonon interaction and are ubiquitous in polarizable materials featuring electron localization, in particular 3d transition metal oxides (TMOs). On the other hand, the relativistic coupling between the spin and orbital angular momentum is notable in lattices with heavy atoms and develops in 5d TMOs, where electrons are spatially delocalized. Here we combine ab initio calculations and magnetic measurements to show that these two seemingly mutually exclusive interactions are entangled in the electron-doped SO-coupled Mott insulator Ba2Na1−xCa x OsO6 (0

Abstract Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

Abstract Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this study, we employ a clonality-supervised deep learning methodology to dissect key pathological features implicated in mycosis fungoides, the most common cutaneous T-cell lymphoma. Our investigations unveil the prominence of the IL-32β–major histocompatibility complex (MHC)-I axis as a critical determinant in tumor T-cell immune evasion within the skin microenvironment. In patients’ skin, we find MHC-I to detrimentally impact the functionality of natural killer (NK) cells, diminishing antibody-dependent cellular cytotoxicity and promoting resistance of tumor skin T-cells to cell-surface targeting therapies. Through murine experiments in female mice, we demonstrate that disruption of the MHC-I interaction with NK cell inhibitory Ly49 receptors restores NK cell anti-tumor activity and targeted T-cell lymphoma elimination in vivo. These findings underscore the significance of attenuating the MHC-I-dependent immunosuppressive networks within skin tumors. Overall, our study introduces a strategy to reinvigorate NK cell-mediated anti-tumor responses to overcome treatment resistance to existing cell-surface targeted therapies for skin lymphoma.

Abstract Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous CALR mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.

Abstract Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.

Abstract The M4 muscarinic acetylcholine receptor (M4 mAChR) has emerged as a drug target of high therapeutic interest due to its expression in regions of the brain involved in the regulation of psychosis, cognition, and addiction. The mAChR agonist, xanomeline, has provided significant improvement in the Positive and Negative Symptom Scale (PANSS) scores in a Phase II clinical trial for the treatment of patients suffering from schizophrenia. Here we report the active state cryo-EM structure of xanomeline bound to the human M4 mAChR in complex with the heterotrimeric Gi1 transducer protein. Unexpectedly, two molecules of xanomeline were found to concomitantly bind to the monomeric M4 mAChR, with one molecule bound in the orthosteric (acetylcholine-binding) site and a second molecule in an extracellular vestibular allosteric site. Molecular dynamic simulations supports the structural findings, and pharmacological validation confirmed that xanomeline acts as a dual orthosteric and allosteric ligand at the human M4 mAChR. These findings provide a basis for further understanding xanomeline’s complex pharmacology and highlight the myriad of ways through which clinically relevant ligands can bind to and regulate GPCRs.

Abstract Representing the most attractive and successful druggable receptors of the proteome, GPCRs regulate a myriad of physiological and pathophysiological functions. Although over half of present pharmaceuticals target GPCRs, the advancement of drug discovery is hampered by a lack of adequate screening tools, the majority of which are limited to probing agonist-induced G-protein and β-arrestin-2-mediated events as a measure of receptor activation. Here, we develop Tango-Trio, a comprehensive cell-based high-throughput platform comprising cumate-inducible expression of transducers, capable of the parallelized profiling of both basal and agonist-dependent GPCR activities. We capture the functional diversity of GPCRs, reporting β-arrestin-1/2 couplings, selectivities, and receptor internalization signatures across the GPCRome. Moreover, we present the construction of cumate-induced basal activation curves at approximately 200 receptors, including over 50 orphans. Overall, Tango-Trio’s robustness is well-suited for the functional characterization and screening of GPCRs, especially for parallel interrogation, and is a valuable addition to the pharmacological toolbox.

Previously, peptide selectivity in the VPAC receptor family of GPCRs was poorly understood. Here, authors combine cryo-EM and MD data to understand binding and selectivity of VPAC1R and PAC1R peptide agonists that can guide future drug development.

Gut microbiota composition is altered in patients with alcohol use disorder, and fecal microbiota transplant reduced alcohol craving in patients with alcohol use disorder and liver cirrhosis in a phase 1 clinical trial. Here the authors used stool samples collected in the trial to report that this phenotype is transmissible via microbial transfer to germ free mice, as assessed by reduced ethanol acceptance, intake and preference.

Sleep and wakefulness is stabilized by a population of orexin-expressing neurons. In this study, the authors demonstrate how these neurons drive arousal by silencing sleep-promoting neurons in the ventrolateral preoptic nucleus.

The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.

Spaces with negative curvature are difficult to realise and investigate experimentally, but they can be emulated with synthetic matter. Here, the authors show how to do this using an electric circuit network, and present a method to characterize and verify the hyperbolic nature of the implemented model.

The glucagon-like peptide-1 receptor (GLP-1R) can be targeted in the treatment of diabetes, obesity and other metabolic disorders. Here, the authors assess the molecular mechanisms of peptide agonists binding to GLP-1R and the responses elucidated by these ligands, including distinct kinetics of G protein activation.

There is a long-standing interest in the development of patterning process for porous materials. Here, the authors report a solvent-free bottom-up approach for the patterning of zeolitic imidazolate frameworks; well-resolved patterns with features down to the scale of 100 nm can be achieved.

How the immune responses induced by SARS-CoV-2 and human coronavirus (hCoV) crosstalk is still unclear. Here the authors profile the humoral responses of prepandemic and SARS-CoV-2-infected donors to find that higher hCoV antibody titers are associated with SARS-CoV-2 negativity, and with reduced hospitalization in SARS-CoV-2 positive patients.

Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.

Arctic lakes are strong and increasing sources of atmospheric methane, but extreme conditions and limited observations hinder robust understanding. Here the authors show that microbes in the middle of Arctic lakes have elevated methane producing potential, and are poised to release even more in the future.

Human metaplastic breast cancers (MpBC) are a rare, aggressive subclass of triple-negative breast cancers. Here, the authors show over-expression of histone reader TRIM24 is sufficient to generate tumors with a molecular signature of metabolic dysfunction and EMT in a mouse model of human MpBC.

DNA from tumour cells can be detected in the blood of cancer patients. Here, the authors show that cell free DNA fragmentation patterns can identify lung cancer patients and when this information is further interrogated it can be used to predict lung cancer histological subtype.

T cells derived from stem cells can be harnessed for regenerative medicine and cancer immunotherapy, but current technologies limit production and translation. Here, the authors present a serum-free, stromal-cell free DLL4-coated microbead method for the scalable production of T-lineage cells from multiple sources of stem cells.

There is a need to optimise cryo-EM data acquisition approaches to improve the resolution of GPCR cryo-EM structures to better than 2.5 Å, in order to use them for structure-based drug design purposes. Here, the authors present a systematic analysis of the main cryo-EM experimental parameters using three GPCRs as test cases, which is also of interest for the cryo-EM structure determination of other small membrane proteins.

Vibrational energy transfer (VET) is essential for protein function as it is responsible for efficient energy dissipation in reaction sites and is linked to pathways of allosteric communication. Here authors equipped a tryptophan zipper with a VET injector and a VET sensor for femtosecond pump probe experiments to map the VET.

HCCAA is a dominantly inherited disease which causes brain hemorrhages as a result of mutant cystatin C aggregation in carriers. Here, the authors show that n- acetyl cysteine can prevent aggregation of mutant protein in a cell model system and reverse protein deposition in the skin of mutation-carrying subjects.

Cell groups in the hypothalamic suprachiasmatic clock contribute to the genesis of circadian rhythms. The authors identified two populations of vasoactive intestinal polypeptide-expressing neurons in the suprachiasmatic nucleus which regulate locomotor circadian rhythm in mice.

The class B secretin GPCR (SecR) has broad physiological effects, with target potential for treatment of metabolic and cardiovascular disease. Here, authors present a cryo-EM structure and biochemical studies of secretin binding to the SecR:Gs complex which show that interactions between peptide and receptor were dynamic.

Predicting the fate of carbon in peatlands relies on assumptions of behaviour in response to temperature. Here, the authors show that the temperature dependency of respiratory carbon losses shift strongly over day-night cycles, an overlooked facet causing bias in peatland carbon cycle simulations.

Hydroxyglutarate synthase (HglS) converts 2-oxoadipate to D-2- hydroxyglutarate during lysine catabolism in bacteria. Here the authors use structural and biochemical approaches to show that HglS acts via successive decarboxylation and intramolecular hydroxylation and that homologous enzymes catalyze the final step of lysine catabolism in plants.

Dorsal raphe 5HT(DRSert) neurons regulate arousal from hypercapnia by their projections to the neurons in the external lateral parabrachial nucleus (PBel) that are glutamatergic and also express calcitonin gene related peptide (PBelCGRP). The DRSert input to the PBel modulates the arousal system to rising levels of blood CO2, and may be mediated by 5HT2a receptors on the PBelCGRP neurons.

Associations of copy number variations (CNVs) with complex traits are challenging to study because of their low frequency. Here, the authors analyse SNP array and array comparative genomic hybridization data of 100,028 individuals and report their associations with immune-related, cardiometabolic and neuropsychiatric diseases as well as cancer.

Telecommunication, navigation and remote sensing services are highly dependent on how well satellites provide global coverage. Here the authors show a pair of four-satellite low-cost longer-life constellations that provide nearly continuous global coverage to support Earth observation.

Whether topological semimetal states can emerge in two-dimensional magnetic materials remains less understood. Here, Niu and Hanke et al. propose the concepts of mixed Weyl and nodal-line semimetallic phases by including the magnetization direction into the topological analysis in two-dimensional ferromagnets.

Allosteric GPCR modulators can achieve exquisite subtype selectivity, but the underlying mechanism is unclear. Using molecular dynamics simulations, the authors here identify a previously undetected dynamic pocket in muscarinic GPCRs that is critical for subtype selectivity of allosteric modulators.

The halogen bond is well known for its ability to assemble supramolecules. Here, using NMR experiments, the authors reveal the role of these bonds in dynamic processes, finding that the halogen bond directly catalyzes dynamical rotation in solid cocrystals by reducing the associated energy barrier.

Most cyanobacteria are oxygenic photoautotrophs, and fermenters under dark anoxic conditions. Here, the authors analyse genomic sequences of related uncultivated bacteria, inferring their metabolic potential, and supporting that their common ancestor was an anaerobe capable of fermentation and H2 metabolism.

Testing the association between genetic variants and a range of phenotypes can assist drug development. Here, in a phenome-wide association study in up to 697,815 individuals, Diogo et al. identify genotype–phenotype associations predicting efficacy, alternative indications or adverse drug effects.

Amphibians have seen large population declines, but the key drivers are hard to establish. Here, Miller et al. investigate trends of occupancy for 81 species of amphibians across North America and find greater sensitivity to water availability during breeding and winter conditions than mean climate.

Disease risk variants can exert their influence on phenotypes by altering epigenome function. Here, Pelikan et al. show that variants inducing allelic imbalance in histone marks in lymphoblastoid cell lines from lupus patients are enriched in autoimmune disease haplotypes and influence gene expression.

White matter properties correlate with cognitive performance in a number of domains. Here the authors show that altering a child’s educational environment though a targeted intervention program induces rapid, large-scale changes in the white matter, and that these changes track the learning process.

The bone marrow microenvironment modulates haematopoiesis, stem cell maintenance and differentiation. Here, the authors use 3D microscopy to map the topography of haematopoietic stem cell niche stromal components.

Hyperemesis gravidarum (HG) is a severe form of nausea and vomiting associated with unfavourable outcomes during pregnancy. Here, Fejzo et al. perform genome-wide scans for HG and pregnancy nausea and vomiting and identify genetic associations at two loci implicating the genes GDF15 and IGFBP7.

Supramammillary nucleus (SuM) neurons have been studied in the context of REM sleep but their possible role in mediating wakefulness is not known. Here the authors elucidate the distinct functional contributions of three subpopulations in the SuM on electrographical and behavioral arousal in mice using genetically targeted approaches.