Phenomics. 2022 Jun 11;3(2):182-189. doi: 10.1007/s43657-022-00062-1. eCollection 2023 Apr.

ABSTRACT

Recently, an increasing number of young never-smokers are diagnosed with lung cancer. The aim of this study is to investigate the genetic predisposition of lung cancer in these patients and discover candidate pathogenic variants for lung adenocarcinoma in young never-smokers. Peripheral blood was collected from 123 never-smoking east-Asian patients diagnosed with lung adenocarcinoma before the age of 40. Whole-exome sequencing (WES) was conducted on genomic DNA extracted from peripheral blood cells. As a result, 3,481 single nucleotide variants were identified. By bioinformatical tools and the published gene list associated with genetic predisposition of cancer, pathogenic variants were detected in ten germline genes: ATR, FANCD2, FANCE, GATA2, HFE, MSH2, PDGFRA, PMS2, SDHB, and WAS. Patients with pathogenic variants were more likely to occur in females (9/10, 90.0%) and have stage IV lung adenocarcinoma (4/10, 40%). Furthermore, germline mutations in 17 genes (ASB18, B3GALT5, CLEC4F, COL6A6, CYP4B1, C6orf132, EXO1, GATA4, HCK, KCP, NPHP4, PIGX, PPIL2, PPP1R3G, RRBP1, SALL4, and TTC28), which occurred in at least two patients, displayed potentially pathogenic effects. Gene ontology analysis further showed that these genes with germline mutations were mainly located in nucleoplasm and associated with DNA repair-related biological processes. The study provides spectrum of pathogenic variants and functional explanation for genetic predisposition of lung adenocarcinoma in young never-smokers, which sheds a light on prevention and early diagnosis of lung cancer.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-022-00062-1.

PMID:37197646 | PMC:PMC10110802 | DOI:10.1007/s43657-022-00062-1

iScience. 2023 Jun 16;26(6):106802. doi: 10.1016/j.isci.2023.106802. Epub 2023 May 4.

ABSTRACT

Breastmilk contains antibodies that could protect breastfed infants from infections. In this work, we examined if antibodies in breastmilk could neutralize SARS-CoV-2 in 84 breastmilk samples from women that were either vaccinated (Comirnaty, mRNA-1273, or ChAdOx1), infected with SARS-CoV-2, or both infected and vaccinated. The neutralization capacity of these sera was tested using pseudotyped vesicular stomatitis virus carrying either the Wuhan-Hu-1, Delta, or BA.1 Omicron spike proteins. We found that natural infection resulted in higher neutralizing titers and that neutralization correlated positively with levels of immunoglobulin A in breastmilk. In addition, significant differences in the capacity to produce neutralizing antibodies were observed between both mRNA-based vaccines and the adenovirus-vectored ChAdOx1 COVID-19 vaccine. Overall, our results indicate that breastmilk from naturally infected women or those vaccinated with mRNA-based vaccines contains SARS-CoV-2 neutralizing antibodies that could potentially provide protection to breastfed infants from infection.

PMID:37197591 | PMC:PMC10158041 | DOI:10.1016/j.isci.2023.106802

Free Radic Biol Med. 2023 May 15:S0891-5849(23)00428-8. doi: 10.1016/j.freeradbiomed.2023.05.012. Online ahead of print.

NO ABSTRACT

PMID:37196862 | DOI:10.1016/j.freeradbiomed.2023.05.012

Gastroenterology. 2023 May 15:S0016-5085(23)00731-X. doi: 10.1053/j.gastro.2023.04.038. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Elements of field cancerization including atrophic gastritis, metaplasia and dysplasia promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia.

METHODS: We utilized single cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from human gastric cancer patients. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts.

RESULTS: We identified four subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2 or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα+ subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia (SPEM) induced disordered growth, loss of metaplastic markers and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition.

CONCLUSIONS: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic SPEM cell lineages into dysplastic lineages.

PMID:37196797 | DOI:10.1053/j.gastro.2023.04.038

Neuron. 2023 May 9:S0896-6273(23)00338-0. doi: 10.1016/j.neuron.2023.04.028. Online ahead of print.

ABSTRACT

The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of the marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: "patchy" projections that formed many columns of submillimeter scale in nearby and distant regions and "diffuse" projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections' local and global distribution patterns. We also demonstrated column-scale precision of reciprocal corticocortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain.

PMID:37196659 | DOI:10.1016/j.neuron.2023.04.028

Cell Rep Med. 2023 May 16;4(5):101045. doi: 10.1016/j.xcrm.2023.101045.

ABSTRACT

Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.

PMID:37196634 | DOI:10.1016/j.xcrm.2023.101045

Curr Opin Chem Biol. 2023 May 15;75:102318. doi: 10.1016/j.cbpa.2023.102318. Online ahead of print.

ABSTRACT

The review highlights the role of amyloids in various diseases and the challenges associated with targeting human amyloids in therapeutic development. However, due to the better understanding of microbial amyloids' role as virulence factors, there is a growing interest in repurposing and designing anti-amyloid compounds for antivirulence therapy. The identification of amyloid inhibitors has not only significant clinical implications but also provides valuable insights into the structure and function of amyloids. The review showcases small molecules and peptides that specifically target amyloids in both humans and microbes, reducing cytotoxicity and biofilm formation, respectively. The review emphasizes the importance of further research on amyloid structures, mechanisms, and interactions across all life forms to yield new drug targets and improve the design of selective treatments. Overall, the review highlights the potential for amyloid inhibitors in therapeutic development for both human diseases and microbial infections.

PMID:37196450 | DOI:10.1016/j.cbpa.2023.102318

Nature. 2023 May 17. doi: 10.1038/s41586-023-06081-w. Online ahead of print.

ABSTRACT

Microbial organisms have key roles in numerous physiological processes in the human body and have recently been shown to modify the response to immune checkpoint inhibitors1,2. Here we aim to address the role of microbial organisms and their potential role in immune reactivity against glioblastoma. We demonstrate that HLA molecules of both glioblastoma tissues and tumour cell lines present bacteria-specific peptides. This finding prompted us to examine whether tumour-infiltrating lymphocytes (TILs) recognize tumour-derived bacterial peptides. Bacterial peptides eluted from HLA class II molecules are recognized by TILs, albeit very weakly. Using an unbiased antigen discovery approach to probe the specificity of a TIL CD4+ T cell clone, we show that it recognizes a broad spectrum of peptides from pathogenic bacteria, commensal gut microbiota and also glioblastoma-related tumour antigens. These peptides were also strongly stimulatory for bulk TILs and peripheral blood memory cells, which then respond to tumour-derived target peptides. Our data hint at how bacterial pathogens and bacterial gut microbiota can be involved in specific immune recognition of tumour antigens. The unbiased identification of microbial target antigens for TILs holds promise for future personalized tumour vaccination approaches.

PMID:37198490 | DOI:10.1038/s41586-023-06081-w

Nature. 2023 May 17. doi: 10.1038/s41586-023-06057-w. Online ahead of print.

ABSTRACT

Focal copy-number amplification is an oncogenic event. Although recent studies have revealed the complex structure1-3 and the evolutionary trajectories4 of oncogene amplicons, their origin remains poorly understood. Here we show that focal amplifications in breast cancer frequently derive from a mechanism-which we term translocation-bridge amplification-involving inter-chromosomal translocations that lead to dicentric chromosome bridge formation and breakage. In 780 breast cancer genomes, we observe that focal amplifications are frequently connected to each other by inter-chromosomal translocations at their boundaries. Subsequent analysis indicates the following model: the oncogene neighbourhood is translocated in G1 creating a dicentric chromosome, the dicentric chromosome is replicated, and as dicentric sister chromosomes segregate during mitosis, a chromosome bridge is formed and then broken, with fragments often being circularized in extrachromosomal DNAs. This model explains the amplifications of key oncogenes, including ERBB2 and CCND1. Recurrent amplification boundaries and rearrangement hotspots correlate with oestrogen receptor binding in breast cancer cells. Experimentally, oestrogen treatment induces DNA double-strand breaks in the oestrogen receptor target regions that are repaired by translocations, suggesting a role of oestrogen in generating the initial translocations. A pan-cancer analysis reveals tissue-specific biases in mechanisms initiating focal amplifications, with the breakage-fusion-bridge cycle prevalent in some and the translocation-bridge amplification in others, probably owing to the different timing of DNA break repair. Our results identify a common mode of oncogene amplification and propose oestrogen as its mechanistic origin in breast cancer.

PMID:37198482 | DOI:10.1038/s41586-023-06057-w

Nat Metab. 2023 May 17. doi: 10.1038/s42255-023-00774-2. Online ahead of print.

ABSTRACT

Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency1, our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that 'uridine bypass' of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes.

PMID:37198474 | DOI:10.1038/s42255-023-00774-2

Nat Rev Neurol. 2023 May 17. doi: 10.1038/s41582-023-00809-y. Online ahead of print.

ABSTRACT

In the past decade, single-cell technologies have proliferated and improved from their technically challenging beginnings to become common laboratory methods capable of determining the expression of thousands of genes in thousands of cells simultaneously. The field has progressed by taking the CNS as a primary research subject - the cellular complexity and multiplicity of neuronal cell types provide fertile ground for the increasing power of single-cell methods. Current single-cell RNA sequencing methods can quantify gene expression with sufficient accuracy to finely resolve even subtle differences between cell types and states, thus providing a great tool for studying the molecular and cellular repertoire of the CNS and its disorders. However, single-cell RNA sequencing requires the dissociation of tissue samples, which means that the interrelationships between cells are lost. Spatial transcriptomic methods bypass tissue dissociation and retain this spatial information, thereby allowing gene expression to be assessed across thousands of cells within the context of tissue structural organization. Here, we discuss how single-cell and spatially resolved transcriptomics have been contributing to unravelling the pathomechanisms underlying brain disorders. We focus on three areas where we feel these new technologies have provided particularly useful insights: selective neuronal vulnerability, neuroimmune dysfunction and cell-type-specific treatment response. We also discuss the limitations and future directions of single-cell and spatial RNA sequencing technologies.

PMID:37198436 | DOI:10.1038/s41582-023-00809-y

Sci Data. 2023 May 17;10(1):287. doi: 10.1038/s41597-023-02214-y.

ABSTRACT

The apical dendrites of pyramidal neurons in sensory cortex receive primarily top-down signals from associative and motor regions, while cell bodies and nearby dendrites are heavily targeted by locally recurrent or bottom-up inputs from the sensory periphery. Based on these differences, a number of theories in computational neuroscience postulate a unique role for apical dendrites in learning. However, due to technical challenges in data collection, little data is available for comparing the responses of apical dendrites to cell bodies over multiple days. Here we present a dataset collected through the Allen Institute Mindscope's OpenScope program that addresses this need. This dataset comprises high-quality two-photon calcium imaging from the apical dendrites and the cell bodies of visual cortical pyramidal neurons, acquired over multiple days in awake, behaving mice that were presented with visual stimuli. Many of the cell bodies and dendrite segments were tracked over days, enabling analyses of how their responses change over time. This dataset allows neuroscientists to explore the differences between apical and somatic processing and plasticity.

PMID:37198203 | DOI:10.1038/s41597-023-02214-y

ACS Synth Biol. 2023 May 17. doi: 10.1021/acssynbio.3c00009. Online ahead of print.

ABSTRACT

The inner physicochemical heterogeneity of bacterial cells generates three-dimensional (3D)-dependent variations of resources for effective expression of given chromosomally located genes. This fact has been exploited for adjusting the most favorable parameters for implanting a complex device for optogenetic control of biofilm formation in the soil bacterium Pseudomonas putida. To this end, a DNA segment encoding a superactive variant of the Caulobacter crescendus diguanylate cyclase PleD expressed under the control of the cyanobacterial light-responsive CcaSR system was placed in a mini-Tn5 transposon vector and randomly inserted through the chromosome of wild-type and biofilm-deficient variants of P. putida lacking the wsp gene cluster. This operation delivered a collection of clones covering a whole range of biofilm-building capacities and dynamic ranges in response to green light. Since the phenotypic output of the device depends on a large number of parameters (multiple promoters, RNA stability, translational efficacy, metabolic precursors, protein folding, etc.), we argue that random chromosomal insertions enable sampling the intracellular milieu for an optimal set of resources that deliver a preset phenotypic specification. Results thus support the notion that the context dependency can be exploited as a tool for multiobjective optimization, rather than a foe to be suppressed in Synthetic Biology constructs.

PMID:37196337 | DOI:10.1021/acssynbio.3c00009

Hum Reprod. 2023 May 17:dead099. doi: 10.1093/humrep/dead099. Online ahead of print.

ABSTRACT

STUDY QUESTION: What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis?

SUMMARY ANSWER: Endometriosis-associated pain subtypes exhibited distinct plasma proteomic profiles.

WHAT IS KNOWN ALREADY: Endometriosis patients, especially those diagnosed in adolescents and young adults, are often plagued by various pain symptoms. However, it is not clear what biological processes underlie this heterogeneity.

STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional analysis using data and plasma samples from 142 adolescent or young adult participants of the Women's Health Study: From Adolescence to Adulthood cohort with laparoscopically confirmed endometriosis.

PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels by SomaScan. We classified self-reported endometriosis-associated pain into subtypes of dysmenorrhea, acyclic pelvic pain, life impacting pelvic pain, bladder pain, bowel pain, and widespread pain phenotype. We used logistic regression to calculate the odds ratios and 95% confidence intervals for differentially expressed proteins, adjusting for age, BMI, fasting status, and hormone use at blood draw. Ingenuity Pathway Analysis identified enriched biological pathways.

MAIN RESULTS AND THE ROLE OF CHANCE: Our study population consisted mainly of adolescents and young adults (mean age at blood draw = 18 years), with nearly all (97%) scored as rASRM stage I/II at laparoscopic diagnosis of endometriosis, which is a common clinical presentation of endometriosis diagnosed at a younger age. Pain subtypes exhibited distinct plasma proteomic profiles. Multiple cell movement pathways were downregulated in cases with severe dysmenorrhea and life impacting pelvic pain compared to those without (P < 7.5×10-15). Endometriosis cases with acyclic pelvic pain had upregulation of immune cell adhesion pathways (P < 9.0×10-9), while those with bladder pain had upregulation of immune cell migration (P < 3.7×10-8) and those with bowel pain had downregulation (P < 6.5×10-7) of the immune cell migration pathways compared to those without. Having a wide-spread pain phenotype involved downregulation of multiple immune pathways (P < 8.0×10-10).

LIMITATIONS, REASONS FOR CAUTION: Our study was limited by the lack of an independent validation cohort. We were also only able to explore any presence of a pain subtype and could not evaluate multiple combinations by pain subtypes. Further mechanistic studies are warranted to elucidate the differences in pathophysiology by endometriosis-pain subtype.

WIDER IMPLICATIONS OF THE FINDINGS: The observed variation in plasma protein profiles by pain subtypes suggests different underlying molecular mechanisms, highlighting the need for potential consideration of pain subtypes for effectively treating endometriosis patients presenting with various pain symptoms.

STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense W81XWH1910318 and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., and K.L.T. have received funding from the Marriott Family Foundation. C.B.S. is funded by an R35 MIRA Award from NIGMS (5R35GM142676). S.A.M. and K.L.T. are supported by NICHD R01HD094842. S.A.M. reports serving as an advisory board member for AbbVie and Roche, Field Chief Editor for Frontiers in Reproductive Health, personal fees from Abbott for roundtable participation; none of these are related to this study. Other authors report no conflict of interest.

TRIAL REGISTRATION NUMBER: N/A.

PMID:37196326 | DOI:10.1093/humrep/dead099

PLoS One. 2023 May 17;18(5):e0285433. doi: 10.1371/journal.pone.0285433. eCollection 2023.

ABSTRACT

The Global Alliance for Genomics and Health (GA4GH) is a standards-setting organization that is developing a suite of coordinated standards for genomics. The GA4GH Phenopacket Schema is a standard for sharing disease and phenotype information that characterizes an individual person or biosample. The Phenopacket Schema is flexible and can represent clinical data for any kind of human disease including rare disease, complex disease, and cancer. It also allows consortia or databases to apply additional constraints to ensure uniform data collection for specific goals. We present phenopacket-tools, an open-source Java library and command-line application for construction, conversion, and validation of phenopackets. Phenopacket-tools simplifies construction of phenopackets by providing concise builders, programmatic shortcuts, and predefined building blocks (ontology classes) for concepts such as anatomical organs, age of onset, biospecimen type, and clinical modifiers. Phenopacket-tools can be used to validate the syntax and semantics of phenopackets as well as to assess adherence to additional user-defined requirements. The documentation includes examples showing how to use the Java library and the command-line tool to create and validate phenopackets. We demonstrate how to create, convert, and validate phenopackets using the library or the command-line application. Source code, API documentation, comprehensive user guide and a tutorial can be found at https://github.com/phenopackets/phenopacket-tools. The library can be installed from the public Maven Central artifact repository and the application is available as a standalone archive. The phenopacket-tools library helps developers implement and standardize the collection and exchange of phenotypic and other clinical data for use in phenotype-driven genomic diagnostics, translational research, and precision medicine applications.

PMID:37196000 | DOI:10.1371/journal.pone.0285433

Plant Cell. 2023 May 17:koad132. doi: 10.1093/plcell/koad132. Online ahead of print.

ABSTRACT

The regulation of microRNA (miRNA) biogenesis is crucial for maintaining plant homeostasis under biotic and abiotic stress. The crosstalk between the RNA polymerase II (Pol-II) complex and the miRNA processing machinery has emerged as a central hub modulating transcription and co-transcriptional processing of primary miRNA transcripts (pri-miRNAs). However, it remains unclear how miRNA-specific transcriptional regulators recognize MIRNA loci. Here, we show that the Arabidopsis (Arabidopsis thaliana) HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENE15 (HOS15)-HISTONE DEACETYLASE9 (HDA9) complex is a conditional suppressor of miRNA biogenesis, particularly in response to ABA. When treated with ABA, hos15/hda9 mutants show enhanced transcription of pri-miRNAs that is accompanied by increased processing, leading to over-accumulation of a set of mature miRNAs. Moreover, upon recognition of the nascent pri-miRNAs, the ABA-induced recruitment of the HOS15-HDA9 complex to MIRNA loci is guided by HYPONASTIC LEAVES 1 (HYL1). The HYL1-dependent recruitment of the HOS15-HDA9 complex to MIRNA loci suppresses expression of MIRNAs and processing of pri-miRNA. Most importantly, our findings indicate that nascent pri-miRNAs serve as scaffolds for recruiting transcriptional regulators, specifically to MIRNA loci. This indicates that RNA molecules can act as regulators of their own expression by causing a negative feedback loop that turns off their transcription, providing a self-buffering system.

PMID:37195876 | DOI:10.1093/plcell/koad132

Database (Oxford). 2023 May 17;2023:baad035. doi: 10.1093/database/baad035.

ABSTRACT

The great variety of brain cell types is a fundamental element for neuronal circuits. One major goal of modern neuroscience is to decipher the various types of cellular composition and characterize their properties. Due to the high heterogeneity of neuronal cells, until recently, it was not possible to group brain cell types at high resolution. Thanks to the single-cell transcriptome technology, a dedicated database of brain cell types across species has been established. Here, we developed scBrainMap, a database for brain cell types and associated genetic markers for several species. The current scBrainMap database contains 4881 cell types with 26 044 genetic markers identified from 6 577 222 single cells, which link to 14 species, 124 brain regions and 20 different disease states. scBrainMap enables users to perform customized, cross-linked, biologically relevant queries for different cell types of interest. This quantitative information facilitates exploratory research on the role of cell types with regard to brain function in health and disease. Database URL https://scbrainmap.sysneuro.net/.

PMID:37195696 | DOI:10.1093/database/baad035

Plant Cell Rep. 2023 May 17. doi: 10.1007/s00299-023-03023-8. Online ahead of print.

ABSTRACT

F-box E3-ubiquitin ligases regulate critical biological processes in plant development and stress responses. Future research could elucidate why and how plants have acquired a large number of F-box genes. The ubiquitin-proteasome system (UPS) is a predominant regulatory mechanism employed by plants to maintain the protein turnover in the cells and involves the interplay of three classes of enzymes, E1 (ubiquitin-activating), E2 (ubiquitin-conjugating), and E3 ligases. The diverse and most prominent protein family among eukaryotes, F-box proteins, are a vital component of the multi-subunit SCF (Skp1-Cullin 1-F-box) complex among E3 ligases. Several F-box proteins with multifarious functions in different plant systems have evolved rapidly over time within closely related species, but only a small part has been characterized. We need to advance our understanding of substrate-recognition regulation and the involvement of F-box proteins in biological processes and environmental adaptation. This review presents a background of E3 ligases with particular emphasis on the F-box proteins, their structural assembly, and their mechanism of action during substrate recognition. We discuss how the F-box proteins regulate and participate in the signaling mechanisms of plant development and environmental responses. We highlight an urgent need for research on the molecular basis of the F-box E3-ubiquitin ligases in plant physiology, systems biology, and biotechnology. Further, the developments and outlooks of the potential technologies targeting the E3-ubiquitin ligases for developing crop improvement strategies have been discussed.

PMID:37195503 | DOI:10.1007/s00299-023-03023-8

AIDS. 2023 May 10. doi: 10.1097/QAD.0000000000003595. Online ahead of print.

ABSTRACT

BACKGROUND: Data supporting dementia as a risk factor for COVID-19 mortality relied on ICD-10 codes, yet nearly 40% of individuals with probable dementia lack a formal diagnosis. Dementia coding is not well-established for people with HIV (PWH), and its reliance may affect risk assessment.

METHODS: This retrospective cohort analysis of PWH with SARS-CoV-2 polymerase chain reaction positivity includes comparisons to people without HIV (PWoH), matched by age, sex, race, and zipcode. Primary exposures were dementia diagnosis, by ICD-10 codes, and cognitive concerns, defined as possible cognitive impairment up to 12 months before COVID-19 diagnosis after clinical review of notes from the electronic health record. Logistic regression models assessed the effect of dementia and cognitive concerns on odds of death (OR [95% confidence interval]); models adjusted for VACS Index 2.0.

RESULTS: Sixty-four PWH were identified out of 14,129 patients with SARS-CoV-2 infection and matched to 463 PWoH. Compared to PWoH, PWH had a higher prevalence of dementia (15.6% vs. 6%, p = 0.01) and cognitive concerns (21.9% vs. 15.8%, p = 0.04). Death was more frequent in PWH (p < 0.01). Adjusted for VACS Index 2.0, dementia (2.4 [1.0-5.8], p = 0.05) and cognitive concerns (2.4 [1.1-5.3], p = 0.03) were associated with increased odds of death. In PWH, the association between cognitive concern and death trended towards statistical significance (3.92 [0.81-20.19], p = 0.09); there was no association with dementia.

CONCLUSIONS: Cognitive status assessments are important for care in COVID-19, especially among PWH. Larger studies should validate findings and determine long-term COVID-19 consequences in PWH with pre-existing cognitive deficits.

PMID:37195278 | DOI:10.1097/QAD.0000000000003595

J Proteome Res. 2023 May 17. doi: 10.1021/acs.jproteome.3c00050. Online ahead of print.

ABSTRACT

The direct infusion-shotgun proteome analysis (DI-SPA) alongside data-independent acquisition mass spectrometry achieved fast proteome identification and quantification without chromatographic separation. However, robust peptide identification and quantification (label and label-free) for the DI-SPA data is still insufficient. We find that in the absence of chromatography, the identification of DI-SPA can be boosted by extending acquisition cycles repeatedly and maximizing the utilization of the featured repetition characteristics, combined with the machine learning-based automatic peptide scoring strategy. Here, we present the repeat-enhancing featured ion-guided stoichiometry (RE-FIGS), a complete and compact solution to (repeated) DI-SPA data. Using our strategy, the peptide identification can be improved above 30% with high reproducibility (70.0%). Notably, the label-free quantification of repeated DI-SPA can be successfully obtained with high accuracy (mean median error, 0.108) and high reproducibility (median error, 0.001). We believe our RE-FIGS method could boost the broad application of the (repeated) DI-SPA method and offer a new choice for proteomic analysis.

PMID:37194982 | DOI:10.1021/acs.jproteome.3c00050