Mol Cancer. 2023 Mar 17;22(1):53. doi: 10.1186/s12943-023-01757-3.

ABSTRACT

Endometrial cancer (EC) is one of the most common gynecologic cancers and its incidence is rising globally. Although advanced EC has a poor prognosis; diagnosing EC at an earlier stage could improve long-term patient outcomes. However, there is no consensus on the early detection strategies for EC and the current diagnostic practices such as transvaginal ultrasound, hysteroscopy and endometrial biopsy are invasive, costly and low in specificity. Thus, accurate and less invasive screening tests that detect EC in women with early stages of the disease are needed. Current research has revolutionized novel EC early detection methodologies in many aspects. This review aims to comprehensively characterizes minimally invasive screening techniques that can be applied to EC in the future, and fully demonstrate their potential in the early detection of EC.

PMID:36932368 | DOI:10.1186/s12943-023-01757-3

Nat Methods. 2023 Mar 17. doi: 10.1038/s41592-023-01844-9. Online ahead of print.

NO ABSTRACT

PMID:36932185 | DOI:10.1038/s41592-023-01844-9

Leukemia. 2023 Mar 17. doi: 10.1038/s41375-023-01849-5. Online ahead of print.

ABSTRACT

Clinical effect of donor-derived natural killer cell infusion (DNKI) after HLA-haploidentical hematopoietic cell transplantation (HCT) was evaluated in high-risk myeloid malignancy in phase 2, randomized trial. Seventy-six evaluable patients (aged 21-70 years) were randomized to receive DNKI (N = 40) or not (N = 36) after haploidentical HCT. For the HCT conditioning, busulfan, fludarabine, and anti-thymocyte globulin were administered. DNKI was given twice 13 and 20 days after HCT. Four patients in the DNKI group failed to receive DNKI. In the remaining 36 patients, median DNKI doses were 1.0 × 108/kg and 1.4 × 108/kg on days 13 and 20, respectively. Intention-to-treat analysis showed a lower disease progression for the DNKI group (30-month cumulative incidence, 35% vs 61%, P = 0.040; subdistribution hazard ratio, 0.50). Furthermore, at 3 months after HCT, the DNKI patients showed a 1.8- and 2.6-fold higher median absolute blood count of NK and T cells, respectively. scRNA-sequencing analysis in seven study patients showed that there was a marked increase in memory-like NK cells in DNKI patients which, in turn, expanded the CD8+ effector-memory T cells. In high-risk myeloid malignancy, DNKI after haploidentical HCT reduced disease progression. This enhanced graft-vs-leukemia effect may be related to the DNKI-induced, post-HCT expansion of NK and T cells. Clinical trial number: NCT02477787.

PMID:36932165 | DOI:10.1038/s41375-023-01849-5

Nat Commun. 2023 Mar 17;14(1):1489. doi: 10.1038/s41467-023-37193-6.

ABSTRACT

Pulmonary fibrosis (PF) is characterized by profound scarring and poor survival. We investigated the association of leukocyte telomere length (LTL) with chronological age and mortality across racially diverse PF cohorts. LTL measurements among participants with PF stratified by race/ethnicity were assessed in relation to age and all-cause mortality, and compared to controls. Generalized linear models were used to evaluate the age-LTL relationship, Cox proportional hazards models were used for hazard ratio estimation, and the Cochran-Armitage test was used to assess quartiles of LTL. Standardized LTL shortened with increasing chronological age; this association in controls was strengthened in PF (R = -0.28; P < 0.0001). In PF, age- and sex-adjusted LTL below the median consistently predicted worse mortality across all racial groups (White, HR = 2.21, 95% CI = 1.79-2.72; Black, HR = 2.22, 95% CI = 1.05-4.66; Hispanic, HR = 3.40, 95% CI = 1.88-6.14; and Asian, HR = 2.11, 95% CI = 0.55-8.23). LTL associates uniformly with chronological age and is a biomarker predictive of mortality in PF across racial groups.

PMID:36932145 | DOI:10.1038/s41467-023-37193-6

Nat Commun. 2023 Mar 17;14(1):1485. doi: 10.1038/s41467-023-37151-2.

ABSTRACT

Turnover numbers characterize a key property of enzymes, and their usage in constraint-based metabolic modeling is expected to increase the prediction accuracy of diverse cellular phenotypes. In vivo turnover numbers can be obtained by integrating reaction rate and enzyme abundance measurements from individual experiments. Yet, their contribution to improving predictions of condition-specific cellular phenotypes remains elusive. Here, we show that available in vitro and in vivo turnover numbers lead to poor prediction of condition-specific growth rates with protein-constrained models of Escherichia coli and Saccharomyces cerevisiae, particularly when protein abundances are considered. We demonstrate that correction of turnover numbers by simultaneous consideration of proteomics and physiological data leads to improved predictions of condition-specific growth rates. Moreover, the obtained estimates are more precise than corresponding in vitro turnover numbers. Therefore, our approach provides the means to correct turnover numbers and paves the way towards cataloguing kcatomes of other organisms.

PMID:36932067 | DOI:10.1038/s41467-023-37151-2

J Ind Microbiol Biotechnol. 2023 Mar 17:kuad005. doi: 10.1093/jimb/kuad005. Online ahead of print.

ABSTRACT

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a large class of secondary metabolites that have garnered scientific attention due to their complex scaffolds with potential roles in medicine, agriculture, and chemical ecology. RiPPs derive from the cleavage of ribosomally-synthesized proteins and the additional modifications, catalyzed by various enzymes to alter the peptide backbone or side chains. Of these enzymes, cytochromes P450 are a superfamily of heme-thiolate proteins involved in many metabolic pathways, including RiPP biosyntheses. In this review, we focus our discussion on cytochromes P450 involved in RiPP pathways and the unique chemical transformations they mediate. Previous studies have revealed a wealth of cytochromes P450 distributed across all domains of life. While the number of characterized cytochromes P450 involved in RiPP biosyntheses is relatively small, they catalyze various enzymatic reactions such as C-C or C-N bond formation. Formation of some RiPPs is catalyzed by more than one cytochrome P450, enabling structural diversity. With the continuous improvement of the bioinformatic tools for RiPP prediction and advancement in synthetic biology techniques, it is expected that further cytochrome P450-mediated RiPP biosynthetic pathways will be discovered.

PMID:36931895 | DOI:10.1093/jimb/kuad005

Dev Cell. 2023 Mar 14:S1534-5807(23)00075-8. doi: 10.1016/j.devcel.2023.02.016. Online ahead of print.

ABSTRACT

Interstitial fluid (IF) accumulation between embryonic cells is thought to be important for embryo patterning and morphogenesis. Here, we identify a positive mechanical feedback loop between cell migration and IF relocalization and find that it promotes embryonic axis formation during zebrafish gastrulation. We show that anterior axial mesendoderm (prechordal plate [ppl]) cells, moving in between the yolk cell and deep cell tissue to extend the embryonic axis, compress the overlying deep cell layer, thereby causing IF to flow from the deep cell layer to the boundary between the yolk cell and the deep cell layer, directly ahead of the advancing ppl. This IF relocalization, in turn, facilitates ppl cell protrusion formation and migration by opening up the space into which the ppl moves and, thereby, the ability of the ppl to trigger IF relocalization by pushing against the overlying deep cell layer. Thus, embryonic axis formation relies on a hydraulic feedback loop between cell migration and IF relocalization.

PMID:36931269 | DOI:10.1016/j.devcel.2023.02.016

Cell Chem Biol. 2023 Mar 16;30(3):231-233. doi: 10.1016/j.chembiol.2023.02.009.

ABSTRACT

In this issue of Cell Chemical Biology, Bonazzi et al. demonstrate that pharmacologically degrading the transcription factor Helios (IKZF2) results in destabilization of regulatory T cells, which normally restrain anti-tumor immunity. These results highlight how molecular glue degraders can selectively target previously undruggable proteins with potential applications in the clinic.

PMID:36931248 | DOI:10.1016/j.chembiol.2023.02.009

Biomater Adv. 2023 Mar 8;148:213370. doi: 10.1016/j.bioadv.2023.213370. Online ahead of print.

ABSTRACT

Tissue engineered cartilage for external ear reconstruction of congenital deformities, such as microtia or resulting from trauma, remains a significant challenge for plastic and reconstructive surgeons. Current strategies involve harvesting autologous costal cartilage or expanding autologous chondrocytes ex vivo. However, these procedures often lead to donor site morbidity and a cell source with limited expansion capacity. Stromal stem cells such as perivascular stem cells (pericytes) offer an attractive alternative cell source, as they can be isolated from many human tissues, readily expanded in vitro and possess chondrogenic differentiation potential. Here, we successfully isolate CD146+ pericytes from the microtia remnant from patients undergoing reconstructive surgery (Microtia pericytes; MPs). Then we investigate their chondrogenic potential using the polymer poly(ethyl acrylate) (PEA) to unfold the extracellular matrix protein fibronectin (FN). FN unfolding exposes key growth factor (GF) and integrin binding sites on the molecule, allowing tethering of the chondrogenic GF transforming growth factor beta 1 (TGFβ1). This system leads to solid-phase, matrix-bound, GF presentation in a more physiological-like manner than that of typical chondrogenic induction media (CM) formulations that tend to lead to off-target effects. This simple and controlled material-based approach demonstrates similar chondrogenic potential to CM, while minimising proclivity toward hypertrophy, without the need for complex induction media formulations.

PMID:36931082 | DOI:10.1016/j.bioadv.2023.213370

Sci Immunol. 2023 Mar 17;8(81):eadc9417. doi: 10.1126/sciimmunol.adc9417. Epub 2023 Mar 17.

ABSTRACT

IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1+ sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body's thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1+ sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.

PMID:36930731 | DOI:10.1126/sciimmunol.adc9417

Proc Natl Acad Sci U S A. 2023 Mar 21;120(12):e2217383120. doi: 10.1073/pnas.2217383120. Epub 2023 Mar 17.

ABSTRACT

This year marks the 25th anniversary of the coinage of the term metabolome [S. G. Oliver et al., Trends Biotech. 16, 373-378 (1998)]. As the field rapidly advances, it is important to take stock of the progress which has been made to best inform the disciplines future. While a medical-centric perspective on metabolomics has recently been published [M. Giera et al., Cell Metab. 34, 21-34 (2022)], this largely ignores the pioneering contributions made by the plant and microbial science communities. In this perspective, we provide a contemporary overview of all fields in which metabolomics is employed with particular emphasis on both methodological and application breakthroughs made in plant and microbial sciences that have shaped this evolving research discipline from the very early days of its establishment. This will not cover all types of metabolomics assays currently employed but will focus mainly on those utilizing mass spectrometry-based measurements since they are currently by far the most prominent. Having established the historical context of metabolomics, we will address the key challenges currently facing metabolomics and offer potential approaches by which these can be faced. Most salient among these is the fact that the vast majority of mass features are as yet not annotated with high confidence; what we may refer to as definitive identification. We discuss the potential of both standard compound libraries and artificial intelligence technologies to address this challenge and the use of natural variance-based approaches such as genome-wide association studies in attempt to assign specific functions to the myriad of structurally similar and complex specialized metabolites. We conclude by stating our contention that as these challenges are epic and that they will need far greater cooperative efforts from biologists, chemists, and computer scientists with an interest in all kingdoms of life than have been made to date. Ultimately, a better linkage of metabolome and genome data will likely also be needed particularly considering the Earth BioGenome Project.

PMID:36930598 | DOI:10.1073/pnas.2217383120

Elife. 2023 Mar 17;12:e81780. doi: 10.7554/eLife.81780.

ABSTRACT

Across species, the optokinetic reflex (OKR) stabilizes vision during self-motion. OKR occurs when ON direction-selective retinal ganglion cells (oDSGCs) detect slow, global image motion on the retina. How oDSGC activity is integrated centrally to generate behavior remains unknown. Here, we discover mechanisms that contribute to motion encoding in vertically tuned oDSGCs and leverage these findings to empirically define signal transformation between retinal output and vertical OKR behavior. We demonstrate that motion encoding in vertically tuned oDSGCs is contrast-sensitive and asymmetric for oDSGC types that prefer opposite directions. These phenomena arise from the interplay between spike threshold nonlinearities and differences in synaptic input weights, including shifts in the balance of excitation and inhibition. In behaving mice, these neurophysiological observations, along with a central subtraction of oDSGC outputs, accurately predict the trajectories of vertical OKR across stimulus conditions. Thus, asymmetric tuning across competing sensory channels can critically shape behavior.

PMID:36930180 | DOI:10.7554/eLife.81780

Bioinformatics. 2023 Mar 17:btad132. doi: 10.1093/bioinformatics/btad132. Online ahead of print.

ABSTRACT

MOTIVATION: Advances in RNA sequencing technologies have achieved an unprecedented accuracy in the quantification of mRNA isoforms, but our knowledge of isoform-specific functions has lagged behind. There is a need to understand the functional consequences of differential splicing, which could be supported by the generation of accurate and comprehensive isoform-specific Gene Ontology (GO) annotations.

RESULTS: We present Isopret (Isoform Interpretation), a method that uses expectation-maximization to infer isoform specific functions based on the relationship between sequence and functional isoform similarity. We predicted isoform-specific functional annotations for 85,617 isoforms of 17,900 protein-coding human genes spanning a range of 17,430 distinct GO terms. Comparison with a gold-standard corpus of manually annotated human isoform functions showed that isopret significantly outperforms state-of-the-art competing methods. We provide experimental evidence that functionally related isoforms predicted by isopret show a higher degree of domain sharing and expression correlation than functionally related genes. We also show that isoform sequence similarity correlates better with inferred isoform function than with gene level function.

AVAILABILITY AND IMPLEMENTATION: Source code, documentation, and resource files are freely available under a GNU3 license at https://github.com/TheJacksonLaboratory/isopretEM and https://zenodo.org/record/7594321.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID:36929917 | DOI:10.1093/bioinformatics/btad132

Elife. 2023 Mar 17;12:e68531. doi: 10.7554/eLife.68531. Online ahead of print.

ABSTRACT

Seizure generation, propagation, and termination occur through spatiotemporal brain networks. In this paper, we demonstrate the significance of large-scale brain interactions in high-frequency (80-200 Hz) for identification of the epileptogenic zone (EZ) and seizure evolution. To incorporate the continuity of neural dynamics, here we have modeled brain connectivity constructed from stereoelectroencephalography (SEEG) data during seizures using multilayer networks. After introducing a new measure of brain connectivity for temporal networks, named multilayer eigenvector centrality (mlEVC), we applied a consensus hierarchical clustering on the developed model to identify the epileptogenic zone (EZ) as a cluster of nodes with distinctive brain connectivity in the ictal period. Our algorithm could successfully predict electrodes inside the resected volume as EZ for 88% of participants, who all were seizure-free for at least 12 months after surgery. Our findings illustrated significant and unique desynchronization between EZ and the rest of the brain in early to mid-seizure. We showed that aging and duration of epilepsy intensify this desynchronization, which can be the outcome of abnormal neuroplasticity. Additionally, we illustrated that seizures evolve with various network topologies, confirming the existence of different epileptogenic networks in each patient. Our findings suggest not only the importance of early intervention in epilepsy but the possible factor which correlates with disease severity. Moreover, by analyzing the propagation patterns of different seizures, we asserted the necessity of collecting sufficient data for identifying the epileptogenic networks.

PMID:36929752 | DOI:10.7554/eLife.68531

Cancer. 2023 Mar 17. doi: 10.1002/cncr.34740. Online ahead of print.

ABSTRACT

BACKGROUND: There is a paucity of information on health outcomes of adolescent and young adult (AYA) cancer survivors living outside North America and Europe. This study compared outcomes in AYA cancer survivors in Israel with individuals without cancer and similar demographics and access to health care, and to AYA cancer survivors living in the United States.

METHODS: This study included 12,674 2-year survivors of AYA (aged 15-39 years) cancer diagnosed between 2000 and 2018 at Clalit Health Services (CHS) in Israel. CHS participants without cancer (N = 50,696) were matched 4:1 to survivors on age, sex, ethnicity, and membership duration. Poisson regression was used to determine incidence rate ratios (IRRs) for chronic conditions. The US Kaiser Permanente Southern California AYA cohort (N = 6778) was used to estimate weighted (age, sex) standardized incidence ratios (SIRs) for CHS survivors.

RESULTS: CHS AYA cancer survivors were more likely to have any chronic condition (IRR, 1.6 95% CI, 1.5-1.7), compared with participants without cancer. Survivors had an increased risk across nearly all conditions examined, with especially elevated risks for osteoporosis (IRR, 4.7; 95% CI, 4.1-5.5) and cardiomyopathy (IRR, 4.2 95% CI, 3.4-5.3). Compared with the Kaiser Permanente Southern California cohort, CHS survivors had an overall lower (SIR, 0.68; 95% CI, 0.65-0.72) incidence of developing any health condition, with noticeably lower incidence of hyperlipidemia (SIR, 0.7; 95% CI, 0.64-0.75).

CONCLUSION: AYA cancer survivors in Israel are at increased risk for developing chronic conditions compared with individuals without cancer, but the overall incidence was lower than in US survivors. These findings may allow for refinement of surveillance recommendations for AYA survivors, taking into consideration regional differences in sociodemographic characteristics and cancer care.

PLAIN LANGUAGE SUMMARY: The burden of chronic conditions was consistently greater in Israeli adolescent and young adult cancer survivors compared with individuals without cancer, with clear differences in risk of specific conditions by cancer diagnosis. However, the overall incidence of chronic conditions in Israeli survivors was generally lower than in US survivors.

PMID:36929478 | DOI:10.1002/cncr.34740

Mol Nutr Food Res. 2023 Mar 17:e2200775. doi: 10.1002/mnfr.202200775. Online ahead of print.

ABSTRACT

SCOPE: To avoid ingestion of potentially harmful substances humans are equipped with about 25 bitter taste receptor genes (TAS2R) expressed in oral taste cells. Humans exhibit considerable variances in their bitter tasting abilities, which are associated with genetic polymorphisms in bitter taste receptor genes. One of these variant receptor genes, TAS2R2, was initially believed to represent a pseudogene. However, TAS2R2 exists in a putative functional variant within some populations and can therefore be considered as an additional functional bitter taste receptor.

METHODS AND RESULTS: To learn more about the function of the experimentally neglected TAS2R2, we performed a functional screening with 122 bitter compounds. We observed responses with 8 of the 122 bitter substances and identified the substance phenylbutazone as a unique activator of TAS2R2 among the family of TAS2Rs, thus filling one more gap in the array of cognate bitter substances.

CONCLUSIONS: The comprehensive characterization of the receptive range of TAS2R2 allowed the classification into the group of TAS2Rs with a medium number of bitter agonists. The variability of bitter taste and its potential influence on food choice in some human populations might be even higher than assumed. This article is protected by copyright. All rights reserved.

PMID:36929150 | DOI:10.1002/mnfr.202200775

Nucleic Acids Res. 2023 Mar 17:gkad172. doi: 10.1093/nar/gkad172. Online ahead of print.

ABSTRACT

BRCA1 mutations are associated with increased breast and ovarian cancer risk. BRCA1-mutant tumors are high-grade, recurrent, and often become resistant to standard therapies. Herein, we performed a targeted CRISPR-Cas9 screen and identified MEPCE, a methylphosphate capping enzyme, as a synthetic lethal interactor of BRCA1. Mechanistically, we demonstrate that depletion of MEPCE in a BRCA1-deficient setting led to dysregulated RNA polymerase II (RNAPII) promoter-proximal pausing, R-loop accumulation, and replication stress, contributing to transcription-replication collisions. These collisions compromise genomic integrity resulting in loss of viability of BRCA1-deficient cells. We also extend these findings to another RNAPII-regulating factor, PAF1. This study identifies a new class of synthetic lethal partners of BRCA1 that exploit the RNAPII pausing regulation and highlight the untapped potential of transcription-replication collision-inducing factors as unique potential therapeutic targets for treating cancers associated with BRCA1 mutations.

PMID:36928661 | DOI:10.1093/nar/gkad172

Nat Neurosci. 2023 Mar 16. doi: 10.1038/s41593-023-01285-9. Online ahead of print.

ABSTRACT

Recognizing sounds implicates the cerebral transformation of input waveforms into semantic representations. Although past research identified the superior temporal gyrus (STG) as a crucial cortical region, the computational fingerprint of these cerebral transformations remains poorly characterized. Here, we exploit a model comparison framework and contrasted the ability of acoustic, semantic (continuous and categorical) and sound-to-event deep neural network representation models to predict perceived sound dissimilarity and 7 T human auditory cortex functional magnetic resonance imaging responses. We confirm that spectrotemporal modulations predict early auditory cortex (Heschl's gyrus) responses, and that auditory dimensions (for example, loudness, periodicity) predict STG responses and perceived dissimilarity. Sound-to-event deep neural networks predict Heschl's gyrus responses similar to acoustic models but, notably, they outperform all competing models at predicting both STG responses and perceived dissimilarity. Our findings indicate that STG entails intermediate acoustic-to-semantic sound representations that neither acoustic nor semantic models can account for. These representations are compositional in nature and relevant to behavior.

PMID:36928634 | DOI:10.1038/s41593-023-01285-9

Nat Biotechnol. 2023 Mar 16. doi: 10.1038/s41587-023-01696-w. Online ahead of print.

ABSTRACT

Sequencing-based approaches for the analysis of microbial communities are susceptible to contamination, which could mask biological signals or generate artifactual ones. Methods for in silico decontamination using controls are routinely used, but do not make optimal use of information shared across samples and cannot handle taxa that only partially originate in contamination or leakage of biological material into controls. Here we present Source tracking for Contamination Removal in microBiomes (SCRuB), a probabilistic in silico decontamination method that incorporates shared information across multiple samples and controls to precisely identify and remove contamination. We validate the accuracy of SCRuB in multiple data-driven simulations and experiments, including induced contamination, and demonstrate that it outperforms state-of-the-art methods by an average of 15-20 times. We showcase the robustness of SCRuB across multiple ecosystems, data types and sequencing depths. Demonstrating its applicability to microbiome research, SCRuB facilitates improved predictions of host phenotypes, most notably the prediction of treatment response in melanoma patients using decontaminated tumor microbiome data.

PMID:36928429 | DOI:10.1038/s41587-023-01696-w

Nucleic Acids Res. 2023 Mar 17:gkad195. doi: 10.1093/nar/gkad195. Online ahead of print.

ABSTRACT

The pandemic caused by SARS-CoV-2 has called for concerted efforts to generate new insights into the biology of betacoronaviruses to inform drug screening and development. Here, we establish a workflow to determine the RNA recognition and druggability of the nucleocapsid N-protein of SARS-CoV-2, a highly abundant protein crucial for the viral life cycle. We use a synergistic method that combines NMR spectroscopy and protein-RNA cross-linking coupled to mass spectrometry to quickly determine the RNA binding of two RNA recognition domains of the N-protein. Finally, we explore the druggability of these domains by performing an NMR fragment screening. This workflow identified small molecule chemotypes that bind to RNA binding interfaces and that have promising properties for further fragment expansion and drug development.

PMID:36928389 | DOI:10.1093/nar/gkad195