Nat Commun. 2024 Mar 16;15(1):2381. doi: 10.1038/s41467-024-46786-8.

ABSTRACT

Candida auris has become a serious threat to public health. The mechanisms of how this fungal pathogen adapts to the mammalian host are poorly understood. Here we report the rapid evolution of an adaptive C. auris multicellular aggregative morphology in the murine host during systemic infection. C. auris aggregative cells accumulate in the brain and exhibit obvious advantages over the single-celled yeast-form cells during systemic infection. Genetic mutations, specifically de novo point mutations in genes associated with cell division or budding processes, underlie the rapid evolution of this aggregative phenotype. Most mutated C. auris genes are associated with the regulation of cell wall integrity, cytokinesis, cytoskeletal properties, and cellular polarization. Moreover, the multicellular aggregates are notably more recalcitrant to the host antimicrobial peptides LL-37 and PACAP relative to the single-celled yeast-form cells. Overall, to survive in the host, C. auris can rapidly evolve a multicellular aggregative morphology via genetic mutations.

PMID:38493178 | DOI:10.1038/s41467-024-46786-8

Cardiovasc Diabetol. 2024 Mar 16;23(1):97. doi: 10.1186/s12933-024-02188-0.

ABSTRACT

BACKGROUND: Tissue-specific insulin resistance (IR) predominantly in muscle (muscle IR) or liver (liver IR) has previously been linked to distinct fasting metabolite profiles, but postprandial metabolite profiles have not been investigated in tissue-specific IR yet. Given the importance of postprandial metabolic impairments in the pathophysiology of cardiometabolic diseases, we compared postprandial plasma metabolite profiles in response to a high-fat mixed meal between individuals with predominant muscle IR or liver IR.

METHODS: This cross-sectional study included data from 214 women and men with BMI 25-40 kg/m2, aged 40-75 years, and with predominant muscle IR or liver IR. Tissue-specific IR was assessed using the muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI), which were calculated from the glucose and insulin responses during a 7-point oral glucose tolerance test. Plasma samples were collected before (T = 0) and after (T = 30, 60, 120, 240 min) consumption of a high-fat mixed meal and 247 metabolite measures, including lipoproteins, cholesterol, triacylglycerol (TAG), ketone bodies, and amino acids, were quantified using nuclear magnetic resonance spectroscopy. Differences in postprandial plasma metabolite iAUCs between muscle and liver IR were tested using ANCOVA with adjustment for age, sex, center, BMI, and waist-to-hip ratio. P-values were adjusted for a false discovery rate (FDR) of 0.05 using the Benjamini-Hochberg method.

RESULTS: Sixty-eight postprandial metabolite iAUCs were significantly different between liver and muscle IR. Liver IR was characterized by greater plasma iAUCs of large VLDL (p = 0.004), very large VLDL (p = 0.002), and medium-sized LDL particles (p = 0.026), and by greater iAUCs of TAG in small VLDL (p = 0.025), large VLDL (p = 0.003), very large VLDL (p = 0.002), all LDL subclasses (all p < 0.05), and small HDL particles (p = 0.011), compared to muscle IR. In liver IR, the postprandial plasma fatty acid (FA) profile consisted of a higher percentage of saturated FA (p = 0.013), and a lower percentage of polyunsaturated FA (p = 0.008), compared to muscle IR.

CONCLUSION: People with muscle IR or liver IR have distinct postprandial plasma metabolite profiles, with more unfavorable postprandial metabolite responses in those with liver IR compared to muscle IR.

PMID:38493102 | DOI:10.1186/s12933-024-02188-0

Trends Microbiol. 2024 Mar 15:S0966-842X(24)00046-5. doi: 10.1016/j.tim.2024.02.006. Online ahead of print.

ABSTRACT

The natural process of evolutionary adaptation is often exploited as a powerful tool to obtain microbes with desirable traits. For industrial microbes, evolutionary engineering is often used to generate variants that show increased yields or resistance to stressful industrial environments, thus obtaining superior microbial cell factories. However, even in large populations, the natural supply of beneficial mutations is typically low, which implies that obtaining improved microbes is often time-consuming and inefficient. To overcome this limitation, different techniques have been developed that boost mutation rates. While some of these methods simply increase the overall mutation rate across a genome, others use recent developments in DNA synthesis, synthetic biology, and CRISPR-Cas techniques to control the type and location of mutations. This review summarizes the most important recent developments and methods in the field of evolutionary engineering in model microorganisms. It discusses how both in vitro and in vivo approaches can increase the genetic diversity of the host, with a special emphasis on in vivo techniques for the optimization of metabolic pathways for precision fermentation.

PMID:38493013 | DOI:10.1016/j.tim.2024.02.006

Gastroenterology. 2024 Mar 14:S0016-5085(24)00290-7. doi: 10.1053/j.gastro.2024.03.009. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Isthmic progenitors, tissue-specific stem cells in the stomach corpus, maintain mucosal homeostasis by balancing between proliferation and differentiation to gastric epithelial lineages. The progenitor cells rapidly adopt an active state in response to mucosal injury. However, it remains unclear how the isthmic progenitor cell niche is controlled during the regeneration of damaged epithelium.

METHODS: We recapitulated tissue recovery process after acute mucosal injury in the mouse stomach. BrdU incorporation was utilized to trace newly generated cells during the injury and recovery phases. To define epithelial lineage commitment process during recovery, we performed single cell RNA-sequencing (scRNA-seq) on epithelial cells from the mouse stomachs. We validated the effects of amphiregulin (AREG) on mucosal recovery, utilizing recombinant AREG treatment or AREG deficient mice.

RESULTS: We determined that an EGFR ligand, AREG, can control progenitor cell lineage commitment. Based on the identification of lineage-committed subpopulations in the corpus epithelium through scRNA-seq and BrdU incorporation, we showed that isthmic progenitors mainly transition into short-lived surface cell lineages, but are less frequently committed to long-lived parietal cell lineages in homeostasis. However, mucosal regeneration after damage directs the lineage commitment of isthmic progenitors towards parietal cell lineages. During recovery, AREG treatment promoted repopulation with parietal cells, while suppressing surface cell commitment of progenitors. In contrast, TGF-alpha did not alter parietal cell regeneration, but did induce expansion of surface cell populations. AREG deficiency impairs parietal cell regeneration, but increases surface cell commitment.

CONCLUSIONS: These data demonstrate that different EGF receptor ligands can distinctly regulate isthmic progenitor-driven mucosal regeneration and lineage commitment.

PMID:38492892 | DOI:10.1053/j.gastro.2024.03.009

Int J Parasitol. 2024 Mar 14:S0020-7519(24)00054-7. doi: 10.1016/j.ijpara.2024.03.005. Online ahead of print.

ABSTRACT

Lactate dehydrogenase (LDH) from Schistosoma mansoni has peculiar properties for a eukaryotic LDH. Schistosomal LDH (SmLDH) isolated from schistosomes, and the recombinantly expressed protein, are strongly inhibited by ATP, which is neutralized by fructose-1,6-bisphosphate (FBP). In the conserved FBP/anion binding site we identified two residues in SmLDH (Val187 and Tyr190) that differ from the conserved residues in LDHs of other eukaryotes, but are identical to conserved residues in FBP-sensitive prokaryotic LDHs. Three-dimensional (3D) models were generated to compare the structure of SmLDH with other LDHs. These models indicated that residues Val187, and especially Tyr190, play a crucial role in the interaction of FBP with the anion pocket of SmLDH. These 3D models of SmLDH are also consistent with a competitive model of SmLDH inhibition in which ATP (inhibitor) and FBP (activator) compete for binding in a well-defined anion pocket. The model of bound ATP predicts a distortion of the nearby key catalytic residue His195, resulting in enzyme inhibition. To investigate a possible physiological role of this allosteric regulation of LDH in schistosomes we made a kinetic model in which the allosteric regulation of the glycolytic enzymes can be varied. The model showed that inhibition of LDH by ATP prevents fermentation to lactate in the free-living stages in water and ensures complete oxidation via the Krebs cycle of the endogenous glycogen reserves. This mechanism of allosteric inhibition by ATP prevents the untimely depletion of these glycogen reserves, the only fuel of the free-living cercariae. Neutralization by FBP of this ATP inhibition of LDH prevents accumulation of glycolytic intermediates when S. mansoni schistosomula are confronted with the sudden large increase in glucose availability upon penetration of the final host. It appears that the LDH of S. mansoni is special and well suited to deal with the variations in glucose availability the parasite encounters during its life cycle.

PMID:38492780 | DOI:10.1016/j.ijpara.2024.03.005

Cell Rep Methods. 2024 Mar 12:100728. doi: 10.1016/j.crmeth.2024.100728. Online ahead of print.

ABSTRACT

Chimeric antigen receptor (CAR) T cells have shown remarkable response rates in hematological malignancies. In contrast, CAR T cell treatment of solid tumors is associated with several challenges, in particular the expression of most tumor-associated antigens at lower levels in vital organs, resulting in on-target/off-tumor toxicities. Thus, innovative approaches to improve the tumor specificity of CAR T cells are urgently needed. Based on the observation that many human solid tumors activate epidermal growth factor receptor (EGFR) on their surface through secretion of EGFR ligands, we developed an engineering strategy for CAR-binding domains specifically directed against the ligand-activated conformation of EGFR. We show, in several experimental systems, that the generated binding domains indeed enable CAR T cells to distinguish between active and inactive EGFR. We anticipate that this engineering concept will be an important step forward to improve the tumor specificity of CAR T cells directed against EGFR-positive solid cancers.

PMID:38492569 | DOI:10.1016/j.crmeth.2024.100728

Bioinformatics. 2024 Mar 16:btae150. doi: 10.1093/bioinformatics/btae150. Online ahead of print.

ABSTRACT

MOTIVATION: Taxonomic classification of short reads and taxonomic profiling of metagenomic samples are well-studied yet challenging problems. The presence of species belonging to ranks without close representation in a reference dataset is particularly challenging. While k-mer-based methods have performed well in terms of running time and accuracy, they tend to have reduced accuracy for such novel species. Thus, there is a growing need for methods that combine the scalability of k-merswith increased sensitivity.

RESULTS: Here, we show that using locality-sensitive hashing (LSH) can increase the sensitivity of the k-mer-based search. Our method, which combines LSH with several heuristics techniques including soft LCA labeling and voting is, more accurate than alternatives in both taxonomic classification of individual reads and abundance profiling.

AVAILABILITY AND IMPLEMENTATION: CONSULT-II is implemented in C ++, and the software, together with reference libraries, is publicly available on GitHub https://github.com/bo1929/CONSULT-II.

CONTACT: Siavash Mirarab. E-mail: smirarab@ucsd.edu. Address: UC San Diego, 9500 Gilman Drive, La Jolla, CA, USA 92093-0407.

SUPPLEMENTARY INFORMATION: Supplementary information is available at Bioinformatics online.

PMID:38492564 | DOI:10.1093/bioinformatics/btae150

J Exp Bot. 2024 Mar 16:erae119. doi: 10.1093/jxb/erae119. Online ahead of print.

ABSTRACT

During the last decade, the knowledge about BBX proteins has abruptly increased. Genome-wide studies identified BBX gene family in several ornamental, industry and food crops; however, the reports regarding the role of these genes as regulators of agronomically important traits are scarce. Here, by phenotyping a knockout mutant, we performed a comprehensive functional characterization of the tomato locus Solyc12g089240, hereafter called SlBBX20. The data revealed the encoded protein as a positive regulator of light signaling affecting several physiological processes during plant lifespan. By the inhibition of PHYTOCHROME INTERACTING FACTOR 4 (SlPIF4)-auxin crosstalk, SlBBX20 regulates photomorphogenesis. Later, it controls the balance between cell division and expansion to guarantee the correct vegetative and reproductive development. In fruits, SlBBX20 is transcriptionally induced by the master transcription factor RIPENING INHIBITOR (SlRIN) and, together with ELONGATED HYPOCOTYL 5 (SlHY5), upregulates flavonoids biosynthetic genes. Finally, SlBBX20 promotes the accumulation of steroidal glycoalkaloids and attenuates Botrytis cinerea infection. This work clearly demonstrates that BBX proteins are multilayer regulators of plant physiology, not only because they affect multiple processes along plant development but also regulate other genes at the transcriptional and post-translational levels.

PMID:38492237 | DOI:10.1093/jxb/erae119

Bioprocess Biosyst Eng. 2024 Mar 16. doi: 10.1007/s00449-024-02966-w. Online ahead of print.

ABSTRACT

Biological conversion of waste methane to biodegradable plastics is a way of reducing their production cost. This study addresses the computational modeling of the growth phase reactor of the process of polyhydroxybutyrate production. The model was used for investigating the effect of gas recycling and inlet gas retention time on the reactor performance. The model was run by the use of a genome-scale metabolic network of Methylocystis hirsuta in a dynamic flux balance analysis framework. The reactor has been modeled for two separate feeding scenarios: a pure methane feed and a biogas feed. The mass transfer coefficient parameter was predicted as a function of superficial gas velocities by the regression of data from published experiments. The results show an increase of removal efficiency by 38% and biomass concentration by 2.8 g/L with the increase of gas recycle ratio from 0 to 30 at the empty bed residence time of 60 min .

PMID:38492006 | DOI:10.1007/s00449-024-02966-w

Nat Protoc. 2024 Mar 15. doi: 10.1038/s41596-024-00968-2. Online ahead of print.

ABSTRACT

As different taxa evolve, gene order often changes slowly enough that chromosomal 'blocks' with conserved gene orders (synteny) are discernible. The MCScanX toolkit ( https://github.com/wyp1125/MCScanX ) was published in 2012 as freely available software for the detection of such 'colinear blocks' and subsequent synteny and evolutionary analyses based on genome-wide gene location and protein sequence information. Owing to its simplicity and high efficiency for colinear block detection, MCScanX provides a powerful tool for conducting diverse synteny and evolutionary analyses. Moreover, the detection of colinear blocks has been embraced as an integral step for pangenome graph construction. Here, new application trends of MCScanX are explored, striving to better connect this increasingly used tool to other tools and accelerate insight generation from exponentially growing sequence data. We provide a detailed protocol that covers how to install MCScanX on diverse platforms, tune parameters, prepare input files from data from the National Center for Biotechnology Information, run MCScanX and its visualization and evolutionary analysis tools, and connect MCScanX with external tools, including MCScanX-transposed, Circos and SynVisio. This protocol is easily implemented by users with minimal computational background and is adaptable to new data of interest to them. The data and utility programs for this protocol can be obtained from http://bdx-consulting.com/mcscanx-protocol .

PMID:38491145 | DOI:10.1038/s41596-024-00968-2

Nat Commun. 2024 Mar 15;15(1):2372. doi: 10.1038/s41467-024-46655-4.

ABSTRACT

Tricarboxylic acid cycle (TCA cycle) plays an important role for aerobic growth of heterotrophic bacteria. Theoretically, eliminating TCA cycle would decrease carbon dissipation and facilitate chemicals biosynthesis. Here, we construct an E. coli strain without a functional TCA cycle that can serve as a versatile chassis for chemicals biosynthesis. We first use adaptive laboratory evolution to recover aerobic growth in minimal medium of TCA cycle-deficient E. coli. Inactivation of succinate dehydrogenase is a key event in the evolutionary trajectory. Supply of succinyl-CoA is identified as the growth limiting factor. By replacing endogenous succinyl-CoA dependent enzymes, we obtain an optimized TCA cycle-deficient E. coli strain. As a proof of concept, the strain is engineered for high-yield production of four separate products. This work enhances our understanding of the role of the TCA cycle in E. coli metabolism and demonstrates the advantages of using TCA cycle-deficient E. coli strain for biotechnological applications.

PMID:38491007 | DOI:10.1038/s41467-024-46655-4

Nat Commun. 2024 Mar 15;15(1):2356. doi: 10.1038/s41467-024-46486-3.

ABSTRACT

Machine learning applied to large compendia of transcriptomic data has enabled the decomposition of bacterial transcriptomes to identify independently modulated sets of genes, such iModulons represent specific cellular functions. The identification of iModulons enables accurate identification of genes necessary and sufficient for cross-species transfer of cellular functions. We demonstrate cross-species transfer of: 1) the biotransformation of vanillate to protocatechuate, 2) a malonate catabolic pathway, 3) a catabolic pathway for 2,3-butanediol, and 4) an antimicrobial resistance to ampicillin found in multiple Pseudomonas species to Escherichia coli. iModulon-based engineering is a transformative strategy as it includes all genes comprising the transferred cellular function, including genes without functional annotation. Adaptive laboratory evolution was deployed to optimize the cellular function transferred, revealing mutations in the host. Combining big data analytics and laboratory evolution thus enhances the level of understanding of systems biology, and synthetic biology for strain design and development.

PMID:38490991 | DOI:10.1038/s41467-024-46486-3

BMJ Ment Health. 2024 Mar 15;27(1):e300975. doi: 10.1136/bmjment-2023-300975.

ABSTRACT

BACKGROUND: Mental disorders have a high comorbidity with cardiovascular disease (CVD), but the causality between them has not been fully appreciated.

OBJECTIVE: This study aimed to systematically explore the bidirectional causality between the two broad categories of diseases.

METHODS: We conducted Mendelian randomisation (MR) and multivariable MR (MVMR) analyses to evaluate potential causal links between 10 mental disorders, the use of antidepressants and 7 CVDs.

FINDINGS: We discovered that major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD) and insomnia exhibit connections with elevated risks of two or more CVDs. Moreover, the use of antidepressants is linked to heightened risks of each CVD. Each distinct CVD is correlated with a greater probability of taking antidepressants. Our MVMR analysis demonstrated that the use of antidepressants is correlated with the elevation of respective risks across all cardiovascular conditions. This includes arrhythmias (OR: 1.28), atrial fibrillation (OR: 1.44), coronary artery disease (OR: 1.16), hypertension (OR: 1.16), heart failure (OR: 1.16), stroke (OR: 1.44) and entire CVD group (OR: 1.35). However, MDD itself was not linked to a heightened risk of any CVD.

CONCLUSIONS: The findings of our study indicate that MDD, insomnia and ADHD may increase the risk of CVD. Our findings highlight the utilisation of antidepressants as an independent risk factor for CVD, thus explaining the influence of MDD on CVD through the mediating effects of antidepressants.

CLINICAL IMPLICATIONS: When treating patients with antidepressants, it is necessary to take into consideration the potential beneficial and detrimental effects of antidepressants.

PMID:38490691 | DOI:10.1136/bmjment-2023-300975

Lancet. 2024 Mar 12:S0140-6736(24)00015-1. doi: 10.1016/S0140-6736(24)00015-1. Online ahead of print.

ABSTRACT

BACKGROUND: The current standard of care of screening and referring patients for treatment for symptoms, such as depression, pain, and fatigue, is not effective. This trial aimed to test the efficacy of an integrated screening and novel stepped collaborative care intervention versus standard of care for patients with cancer and at least one of the following symptoms: depression, pain, or fatigue.

METHODS: This randomised, parallel, phase 3 trial was conducted in 29 oncology outpatient clinics associated with the UPMC Hillman Cancer Center in the USA. Patients (aged ≥21 years) with any cancer type and clinical levels of depression, pain, or fatigue (or all of these) were eligible. Eligible family caregivers were aged 21 years or older and providing care to a patient diagnosed with cancer who consented for this study. Patients were randomly assigned (1:1) to stepped collaborative care or standard of care using a central, permuted block design (sizes of 2, 4, and 6) stratified by sex and prognostic status. The biostatistician, oncologists, and outcome assessors were masked to treatment assignment. Stepped collaborative care was once-weekly cognitive behavioural therapy for 50-60 min from a care coordinator via telemedicine (eg, telephone or videoconferencing). Pharmacotherapy for symptoms might be initiated or changed if recommended by the treatment team or preferred by the patient. Standard of care was screening and referral to a health-care provider for treatment of symptoms. The primary outcome was health-related quality of life in patients at 6 months. Maintenance of the treatment benefits was assessed at 12 months. Participants included in the primary analysis were per intention to treat, which included patients missing one or both follow-up assessments. This trial was registered with ClinicalTrials.gov (NCT02939755).

FINDINGS: Between Dec 5, 2016, and April 8, 2021, 459 patients and 190 family caregivers were enrolled. 222 patients were assigned to standard of care and 237 to stepped collaborative care. Of 459 patients, 201 (44%) were male and 258 (56%) were female. Patients in the stepped collaborative care group had a greater 0-6-month improvement in health-related quality of life than patients in the standard-of-care group (p=0·013, effect size 0·09). Health-related quality of life was maintained for the stepped collaborative care group (p=0·74, effect size 0·01). Patients in the stepped collaborative care group had greater 0-6-month improvements than the standard-of-care group in emotional (p=0·012), functional (p=0·042), and physical (p=0·033) wellbeing. No adverse events were reported by patients in either group and deaths were considered unrelated to the study.

INTERPRETATION: An integrated screening and novel stepped collaborative care intervention, compared with the current standard of care, is recommended to improve health-related quality of life. The findings of this study will advance the implementation of guideline concordant care (screening and treatment) and has the potential to shift the practice of screening and treatment paradigm nationwide, improving outcomes for patients diagnosed with cancer.

FUNDING: US National Cancer Institute.

PMID:38490230 | DOI:10.1016/S0140-6736(24)00015-1

Am J Hum Genet. 2024 Mar 11:S0002-9297(24)00044-2. doi: 10.1016/j.ajhg.2024.02.012. Online ahead of print.

ABSTRACT

Cigarette smoking adversely affects many aspects of human health, and epigenetic responses to smoking may reflect mechanisms that mediate or defend against these effects. Prior studies of smoking and DNA methylation (DNAm), typically measured in leukocytes, have identified numerous smoking-associated regions (e.g., AHRR). To identify smoking-associated DNAm features in typically inaccessible tissues, we generated array-based DNAm data for 916 tissue samples from the GTEx (Genotype-Tissue Expression) project representing 9 tissue types (lung, colon, ovary, prostate, blood, breast, testis, kidney, and muscle). We identified 6,350 smoking-associated CpGs in lung tissue (n = 212) and 2,735 in colon tissue (n = 210), most not reported previously. For all 7 other tissue types (sample sizes 38-153), no clear associations were observed (false discovery rate 0.05), but some tissues showed enrichment for smoking-associated CpGs reported previously. For 1,646 loci (in lung) and 22 (in colon), smoking was associated with both DNAm and local gene expression. For loci detected in both lung and colon (e.g., AHRR, CYP1B1, CYP1A1), top CpGs often differed between tissues, but similar clusters of hyper- or hypomethylated CpGs were observed, with hypomethylation at regulatory elements corresponding to increased expression. For lung tissue, 17 hallmark gene sets were enriched for smoking-associated CpGs, including xenobiotic- and cancer-related gene sets. At least four smoking-associated regions in lung were impacted by lung methylation quantitative trait loci (QTLs) that co-localize with genome-wide association study (GWAS) signals for lung function (FEV1/FVC), suggesting epigenetic alterations can mediate the effects of smoking on lung health. Our multi-tissue approach has identified smoking-associated regions in disease-relevant tissues, including effects that are shared across tissue types.

PMID:38490207 | DOI:10.1016/j.ajhg.2024.02.012

Semin Immunol. 2024 Mar 13;72:101875. doi: 10.1016/j.smim.2024.101875. Online ahead of print.

ABSTRACT

The integration of multi-'omic datasets into complex systems-wide assessments has become a mainstay in immunologic investigation. This focus on high-dimensional data collection and analysis was on full display in the investigation of COVID-19, the respiratory illness resulting from infection by the novel coronavirus SARS-CoV-2. Particularly in the area of B cell biology, tremendous efforts in both cellular and serologic investigation have resulted in an increasingly detailed mapping of the coordinated effector, memory, and antibody secreting cell responses that underpin the development of humoral immunity in response to primary viral infection. Further, the rapid development and deployment of effective vaccines has allowed for the assessment of developing memory responses across a wide variety of immune contexts, including in patients with compromised immune function. The result has been a period of rapid gains in the understanding of B cell biology unrestricted to the study of COVID-19. Here, we outline the systems-level technologies that have been routinely implemented in these investigations throughout the pandemic, and discuss how their use has led to clear and applicable gains in pursuance of the amelioration of human infectious disease and beyond.

PMID:38489999 | DOI:10.1016/j.smim.2024.101875

Transl Res. 2024 Mar 13:S1931-5244(24)00036-7. doi: 10.1016/j.trsl.2024.02.007. Online ahead of print.

ABSTRACT

Lung cancer has been shown to be targetable by novel immunotherapies which reactivate the immune system and enable tumor cell killing. However, treatment failure and resistance to these therapies is common. Consideration of sex as a factor influencing therapy resistance is still rare. We hypothesize that the success of the treatment is impaired by the presence of the immunosuppressive pregnancy-associated glycoprotein glycodelin that is expressed in patients with non-small-cell lung cancer (NSCLC). We demonstrate that the glycan pattern of NSCLC-derived glycodelin detected by a lectin-based enrichment assay highly resembles amniotic fluid-derived glycodelin A, which is known to have immunosuppressive properties. NSCLC-derived glycodelin interacts with immune cells in vitro and regulates the expression of genes associated with inflammatory and tumor microenvironment pathways. In tumor microarray samples of patients, high glycodelin staining in tumor areas results in an impaired overall survival of female patients. Moreover, glycodelin colocalizes to tumor infiltrating CD8+ T cells and pro-tumorigenic M2 macrophages. High serum concentrations of glycodelin prior to immunotherapy are associated with a poor progression-free survival (p < 0.001) of female patients receiving PD-(L)1 inhibitors. In summary, our findings suggest that glycodelin not only is a promising immunological biomarker for early identification of female patients that do not benefit from the costly immunotherapy, but also represents a promising immunotherapeutic target in NSCLC to improve therapeutic options in lung cancer.

PMID:38490536 | DOI:10.1016/j.trsl.2024.02.007

Cell Rep Methods. 2024 Mar 6:100729. doi: 10.1016/j.crmeth.2024.100729. Online ahead of print.

ABSTRACT

Understanding the dynamic expression of proteins and other key molecules driving phenotypic remodeling in development and pathobiology has garnered widespread interest, yet the exploration of these systems at the foundational resolution of the underlying cell states has been significantly limited by technical constraints. Here, we present DESP, an algorithm designed to leverage independent estimates of cell-state proportions, such as from single-cell RNA sequencing, to resolve the relative contributions of cell states to bulk molecular measurements, most notably quantitative proteomics, recorded in parallel. We applied DESP to an in vitro model of the epithelial-to-mesenchymal transition and demonstrated its ability to accurately reconstruct cell-state signatures from bulk-level measurements of both the proteome and transcriptome, providing insights into transient regulatory mechanisms. DESP provides a generalizable computational framework for modeling the relationship between bulk and single-cell molecular measurements, enabling the study of proteomes and other molecular profiles at the cell-state level using established bulk-level workflows.

PMID:38490205 | DOI:10.1016/j.crmeth.2024.100729

Cell Rep Methods. 2024 Mar 8:100731. doi: 10.1016/j.crmeth.2024.100731. Online ahead of print.

ABSTRACT

Systems vaccinology studies have identified factors affecting individual vaccine responses, but comparing these findings is challenging due to varying study designs. To address this lack of reproducibility, we established a community resource for comparing Bordetella pertussis booster responses and to host annual contests for predicting patients' vaccination outcomes. We report here on our experiences with the "dry-run" prediction contest. We found that, among 20+ models adopted from the literature, the most successful model predicting vaccination outcome was based on age alone. This confirms our concerns about the reproducibility of conclusions between different vaccinology studies. Further, we found that, for newly trained models, handling of baseline information on the target variables was crucial. Overall, multiple co-inertia analysis gave the best results of the tested modeling approaches. Our goal is to engage community in these prediction challenges by making data and models available and opening a public contest in August 2024.

PMID:38490204 | DOI:10.1016/j.crmeth.2024.100731

Curr Biol. 2024 Mar 7:S0960-9822(24)00248-3. doi: 10.1016/j.cub.2024.02.066. Online ahead of print.

ABSTRACT

NRT1.1, a nitrate transceptor, plays an important role in nitrate binding, sensing, and nitrate-dependent lateral root (LR) morphology. However, little is known about NRT1.1-mediated nitrate signaling transduction through plasma membrane (PM)-localized proteins. Through in-depth phosphoproteome profiling using membranes of Arabidopsis roots, we identified receptor kinase QSK1 and plasma membrane H+-ATPase AHA2 as potential downstream components of NRT1.1 signaling in a mild low-nitrate (LN)-dependent manner. QSK1, as a functional kinase and molecular link, physically interacts with NRT1.1 and AHA2 at LN and specifically phosphorylates AHA2 at S899. Importantly, we found that LN, not high nitrate (HN), induces formation of the NRT1.1-QSK1-AHA2 complex in order to repress the proton efflux into the apoplast by increased phosphorylation of AHA2 at S899. Loss of either NRT1.1 or QSK1 thus results in a higher T947/S899 phosphorylation ratio on AHA2, leading to enhanced pump activity and longer LRs under LN. Our results uncover a regulatory mechanism in which NRT1.1, under LN conditions, promotes coreceptor QSK1 phosphorylation and enhances the NRT1.1-QSK1 complex formation to transduce LN sensing to the PM H+-ATPase AHA2, controlling the phosphorylation ratio of activating and inhibitory phosphorylation sites on AHA2. This then results in altered proton pump activity, apoplast acidification, and regulation of NRT1.1-mediated LR growth.

PMID:38490203 | DOI:10.1016/j.cub.2024.02.066