bioRxiv. 2023 Nov 16:2023.11.13.566889. doi: 10.1101/2023.11.13.566889. Preprint.

ABSTRACT

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we present a new paradigm of proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified over 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain glycoproteome into networks of co-regulated glycoforms and glycans and discovered glycoform and glycan modules associated with AD clinical phenotype, amyloid-β accumulation, and tau pathology. Our findings provide novel insights and a rich resource of glycoform and glycan changes in AD and pave the way forward for developing glycosylation-based therapies and biomarkers for AD.

PMID:38014218 | PMC:PMC10680592 | DOI:10.1101/2023.11.13.566889

Res Sq. 2023 Nov 17:rs.3.rs-3611240. doi: 10.21203/rs.3.rs-3611240/v1. Preprint.

ABSTRACT

More than 20% of the population across the world is affected by non-communicable inflammatory skin diseases including psoriasis, atopic dermatitis, hidradenitis suppurativa, rosacea, etc. Many of these chronic diseases are painful and debilitating with limited effective therapeutic interventions. However, recent advances in psoriasis treatment have improved the effectiveness and provide better management of the disease. This study aims to identify common regulatory pathways and master regulators that regulate molecular pathogenesis. We designed an integrative systems biology framework to identify the significant regulators across several inflammatory skin diseases. With conventional transcriptome analysis, we identified 55 shared genes, which are enriched in several immune-associated pathways in eight inflammatory skin diseases. Next, we exploited the gene co-expression-, and protein-protein interaction-based networks to identify shared genes and protein components in different diseases with relevant functional implications. Additionally, the network analytics unravels 55 high-value proteins as significant regulators in molecular pathogenesis. We believe that these significant regulators should be explored with critical experimental approaches to identify the putative drug targets for more effective treatments. As an example, we identified IKZF1 as a shared significant master regulator in three inflammatory skin diseases, which can serve as a putative drug target with known disease-derived molecules for developing efficacious combinatorial treatments for hidradenitis suppurativa, atopic dermatitis, and rosacea. The proposed framework is very modular, which can indicate a significant path of molecular mechanism-based drug development from complex transcriptomics data and other multi-omics data.

PMID:38014119 | PMC:PMC10680929 | DOI:10.21203/rs.3.rs-3611240/v1

New Phytol. 2023 Nov 28. doi: 10.1111/nph.19433. Online ahead of print.

ABSTRACT

Chitin oligomers (COs) are among the most common and active fungal elicitors of plant responses. Short-chain COs from symbiotic arbuscular mycorrhizal fungi activate accommodation responses in the host root, while long-chain COs from pathogenic fungi are acknowledged to trigger defence responses. The modulation of intracellular calcium concentration - a common second messenger in a wide variety of plant signal transduction processes - plays a central role in both signalling pathways with distinct signature features. Nevertheless, mounting evidence suggests that plant immunity and symbiosis signalling partially overlap at multiple levels. We here elaborate on recent findings on this topic, highlighting the nonbinary nature of chitin-based fungal signals, their perception and their interpretation through Ca2+ -mediated intracellular signals. Based on this, we propose that plant perception of symbiotic and pathogenic fungi is less clear-cut than previously described and involves a more complex scenario in which partially overlapping and blurred signalling mechanisms act upstream of the unambiguous regulation of gene expression driving accommodation or defence responses.

PMID:38013492 | DOI:10.1111/nph.19433

Amyotroph Lateral Scler Frontotemporal Degener. 2023 Nov 27:1-7. doi: 10.1080/21678421.2023.2285428. Online ahead of print.

ABSTRACT

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease with profound unmet need. In patients carrying genetic mutations, elevations in neurofilament light (NfL) have been shown to precede symptom onset, however, the natural history of NfL in general ALS patients is less characterized.

METHODS: We performed a secondary analysis of the UK Biobank Pharma Proteomics Project (UKB-PPP), a subset of the UK Biobank, a population-based cohort study in the United Kingdom, to examine plasma NfL levels in 237 participants subsequently diagnosed with ALS. We applied logistic and Cox proportional hazards regression to compare cases to 42,752 population-based and 948 age and sex-matched controls. Genetic information was obtained from exome and genotype array data.Results and Conclusions: We observed that NfL was 1.42-fold higher in cases vs population-based controls. At two to three years pre-diagnosis, NfL levels in patients exceeded the 95th percentile of age and sex-matched controls. A time-to-diagnosis analysis showed that a 2-fold increase in NfL levels was associated with a 3.4-fold risk of diagnosis per year, with NfL being most predictive of case status at two years (AUC = 0.96). Participants with genetic variation that might put them at risk for familial disease (N = 46) did not show a different pattern of association than those without (N = 191).

DISCUSSION: Our findings show that NfL is elevated and discriminative of future ALS diagnosis up to two years prior to diagnosis in patients with and without genetic risk variants.

PMID:38013452 | DOI:10.1080/21678421.2023.2285428

Medicine (Baltimore). 2023 Nov 24;102(47):e36287. doi: 10.1097/MD.0000000000036287.

ABSTRACT

Rheumatoid arthritis is an autoimmune disease characterized by chronic polyarticular pain, for which no cure currently exists. In Chinese medicine, rheumatoid arthritis (RA) is believed to be caused by phlegm and blood stagnation. Shentong Zhuyu decoction can be used to treat RA, as it promotes blood circulation, resolves blood stasis, and relieves pain. In our study, we used network pharmacology and computer-aided drug design to evaluate the components, active compounds, and targets of Shentong Zhuyu decoction (STZY). Our results suggest that STZY contains active compounds such as quercetin, luteolin, and formononetin that regulate immune network targets. RA associated genes are enriched in pathways including those associated with nuclear factor kappa B, phosphatidylinositol-3-kinase/AKT, and hypoxia inducible factor 1 signaling. The main active compounds in STZY (quercetin and luteolin) were derived from Achyranthis Bidentatae Radix, Carthami Flos, licorice, Cyperi Rhizoma, and Myrrha and targeted the pro-inflammatory cytokines interleukin 2, interleukin 1 alpha, interleukin 1 beta, and interleukin 6. In addition, the compounds quercetin, luteolin, and formononetin in these herbs can target the anti-inflammatory cytokines interleukin 4 and interleukin 10. Our results suggest that STZY can balance the immune network, promote an anti-inflammatory environment, and reduce the clinical symptoms of RA. Based on the close relationship between inflammatory response and osteoclast formation, we hypothesized that STZY may inhibit inflammation and alleviate bone destruction in RA. Our findings indicate that STZY can treat RA through multiple components, targets, and pathways. This study may provide a reference for the clinical application of STZY in RA treatment.

PMID:38013316 | DOI:10.1097/MD.0000000000036287

Environ Toxicol Pharmacol. 2023 Nov 25:104328. doi: 10.1016/j.etap.2023.104328. Online ahead of print.

ABSTRACT

The present study was aimed at investigating DNA damage, micronuclei frequency and meta-nuclear alterations in buccal cells of workers involved in pigment-grade TiO2 production (15 exposed and 20 not-exposed). We also assessed associations of genotoxicity biomarkers with oxidative stress/inflammatory biomarkers in urine and exhaled breath condensate (EBC), as well as possible associations between biomarkers and reported respiratory symptoms. In spite of compliance with TiO2 Occupational Exposure Limits, results showed increased direct/oxidative DNA damage and micronuclei frequency in exposed workers. Genotoxicity parameters were associated with oxidative stress/inflammation biomarkers in urine and EBC, thus confirming that TiO2 exposure can affect the oxidative balance. Workers with higher genotoxic/oxidative stress biomarkers levels reported early respiratory symptoms suggesting that molecular alterations can be predictive of early health dysfunctions. These findings suggest the need to assess early health impairment in health surveillance programs and to address properly safety issues in workplaces where TiO2 is handled.

PMID:38013010 | DOI:10.1016/j.etap.2023.104328

Plant J. 2023 Nov 27. doi: 10.1111/tpj.16558. Online ahead of print.

ABSTRACT

Understanding the underlying mechanisms of plant development is crucial to successfully steer or manipulate plant growth in a targeted manner. Leaves, the primary sites of photosynthesis, are vital organs for many plant species, and leaf growth is controlled by a tight temporal and spatial regulatory network. In this review, we focus on the genetic networks governing leaf cell proliferation, one major contributor to final leaf size. First, we provide an overview of six regulator families of leaf growth in Arabidopsis: DA1, PEAPODs, KLU, GRFs, the SWI/SNF complexes, and DELLAs, together with their surrounding genetic networks. Next, we discuss their evolutionary conservation to highlight similarities and differences among species, because knowledge transfer between species remains a big challenge. Finally, we focus on the increase in knowledge of the interconnectedness between these genetic pathways, the function of the cell cycle machinery as their central convergence point, and other internal and environmental cues.

PMID:38012838 | DOI:10.1111/tpj.16558

Commun Biol. 2023 Nov 27;6(1):1208. doi: 10.1038/s42003-023-05549-9.

NO ABSTRACT

PMID:38012377 | DOI:10.1038/s42003-023-05549-9

Proteomics. 2023 Nov 27:e2200220. doi: 10.1002/pmic.202200220. Online ahead of print.

ABSTRACT

How cells regulate protein levels is a central question of biology. Over the past decades, molecular biology research has provided profound insights into the mechanisms and the molecular machinery governing each step of the gene expression process, from transcription to protein degradation. Recent advances in transcriptomics and proteomics have complemented our understanding of these fundamental cellular processes with a quantitative, systems-level perspective. Multi-omic studies revealed significant quantitative, kinetic and functional differences between the genome, transcriptome and proteome. While protein levels often correlate with mRNA levels, quantitative investigations have demonstrated a substantial impact of translation and protein degradation on protein expression control. In addition, protein-level regulation appears to play a crucial role in buffering protein abundances against undesirable mRNA expression variation. These findings have practical implications for many fields, including gene function prediction and precision medicine.

PMID:38012370 | DOI:10.1002/pmic.202200220

Nat Plants. 2023 Nov 27. doi: 10.1038/s41477-023-01565-z. Online ahead of print.

ABSTRACT

Tea is one of the world's oldest crops and is cultivated to produce beverages with various flavours. Despite advances in sequencing technologies, the genetic mechanisms underlying key agronomic traits of tea remain unclear. In this study, we present a high-quality pangenome of 22 elite cultivars, representing broad genetic diversity in the species. Our analysis reveals that a recent long terminal repeat burst contributed nearly 20% of gene copies, introducing functional genetic variants that affect phenotypes such as leaf colour. Our graphical pangenome improves the efficiency of genome-wide association studies and allows the identification of key genes controlling bud flush timing. We also identified strong correlations between allelic variants and flavour-related chemistries. These findings deepen our understanding of the genetic basis of tea quality and provide valuable genomic resources to facilitate its genomics-assisted breeding.

PMID:38012346 | DOI:10.1038/s41477-023-01565-z

Sci Rep. 2023 Nov 27;13(1):20795. doi: 10.1038/s41598-023-47816-z.

ABSTRACT

Breast cancer is a major global health concern, and recent researches have highlighted the critical roles of non-coding RNAs in both cancer and the immune system. The competing endogenous RNA hypothesis suggests that various types of RNA, including coding and non-coding RNAs, compete for microRNA targets, acting as molecular sponges. This study introduces the Pre_CLM_BCS pipeline to investigate the potential of long non-coding RNAs and circular RNAs as biomarkers in breast cancer subtypes. The pipeline identifies specific modules within each subtype that contain at least one long non-coding RNA or circular RNA exhibiting significantly distinct expression patterns when compared to other subtypes. The results reveal potential biomarker genes for each subtype, such as circ_001845, circ_001124, circ_003925, circ_000736, and circ_003996 for the basal-like subtype, circ_00306 and circ_00128 for the luminal B subtype, circ_000709 and NPHS1 for the normal-like subtype, CAMKV and circ_001855 for the luminal A subtype, and circ_00128 and circ_00173 for the HER2+ subtype. Additionally, certain long non-coding RNAs and circular RNAs, including RGS5-AS1, C6orf223, HHLA3-AS1, circ_000349, circ_003996, circ_003925, circ_002665, circ_001855, and DLEU1, are identified as potential regulators of T cell mechanisms, underscoring their importance in understanding breast cancer progression in various subtypes. This pipeline provides valuable insights into cancer and immune-related processes in breast cancer subtypes.

PMID:38012271 | DOI:10.1038/s41598-023-47816-z

Nat Commun. 2023 Nov 27;14(1):7751. doi: 10.1038/s41467-023-43699-w.

NO ABSTRACT

PMID:38012189 | DOI:10.1038/s41467-023-43699-w

Nat Commun. 2023 Nov 27;14(1):7767. doi: 10.1038/s41467-023-43656-7.

ABSTRACT

Chimeric antigen receptor (CAR) T cell therapy is effective in treating B cell malignancies, but factors influencing the persistence of functional CAR+ T cells, such as product composition, patients' lymphodepletion, and immune reconstitution, are not well understood. To shed light on this issue, here we conduct a single-cell multi-omics analysis of transcriptional, clonal, and phenotypic profiles from pre- to 1-month post-infusion of CAR+ and CAR- T cells from patients from a CARTELL study (ACTRN12617001579381) who received a donor-derived 4-1BB CAR product targeting CD19. Following infusion, CAR+ T cells and CAR- T cells shows similar differentiation profiles with clonally expanded populations across heterogeneous phenotypes, demonstrating clonal lineages and phenotypic plasticity. We validate these findings in 31 patients with large B cell lymphoma treated with CD19 CAR T therapy. For these patients, we identify using longitudinal mass-cytometry data an association between NK-like subsets and clinical outcomes at 6 months with both CAR+ and CAR- T cells. These results suggest that non-CAR-derived signals can provide information about patients' immune recovery and be used as correlate of clinically relevant parameters.

PMID:38012187 | DOI:10.1038/s41467-023-43656-7

Nat Commun. 2023 Nov 27;14(1):7719. doi: 10.1038/s41467-023-43233-y.

ABSTRACT

Application of microfluidic platforms facilitated high-precision measurements of yeast replicative lifespan (RLS); however, comparative quantification of lifespan across strain libraries has been missing. Here we microfluidically measure the RLS of 307 yeast strains, each deleted for a single gene. Despite previous reports of extended lifespan in these strains, we found that 56% of them did not actually live longer than the wild-type; while the remaining 44% showed extended lifespans, the degree of extension was often different from what was previously reported. Deletion of SIS2 gene led to the largest RLS increase observed. Sis2 regulated yeast lifespan in a dose-dependent manner, implying a role for the coenzyme A biosynthesis pathway in lifespan regulation. Introduction of the human PPCDC gene in the sis2Δ background neutralized the lifespan extension. RNA-seq experiments revealed transcriptional increases in cell-cycle machinery components in sis2Δ background. High-precision lifespan measurement will be essential to elucidate the gene network governing lifespan.

PMID:38012152 | DOI:10.1038/s41467-023-43233-y

Annu Rev Plant Biol. 2023 Nov 27. doi: 10.1146/annurev-arplant-060223-030954. Online ahead of print.

ABSTRACT

Crops are plant species that were domesticated starting about 11,000 years ago from several centers of origin, most prominently the Fertile Crescent, East Asia, and Mesoamerica. From their domestication centers, these crops spread across the globe and had to adapt to differing environments as a result of this dispersal. We discuss broad patterns of crop spread, including the early diffusion of crops associated with the rise and spread of agriculture, the later movement via ancient trading networks, and the exchange between the Old and New Worlds over the last ∼550 years after the European colonization of the Americas. We also examine the various genetic mechanisms associated with the evolutionary adaptation of crops to their new environments after dispersal, most prominently seasonal adaptation associated with movement across latitudes, as well as altitudinal, temperature, and other environmental factors. Expected final online publication date for the Annual Review of Plant Biology, Volume 75 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

PMID:38012052 | DOI:10.1146/annurev-arplant-060223-030954

PLoS Comput Biol. 2023 Nov 27;19(11):e1011653. doi: 10.1371/journal.pcbi.1011653. Online ahead of print.

ABSTRACT

The effective reproductive number Rt has taken a central role in the scientific, political, and public discussion during the COVID-19 pandemic, with numerous real-time estimates of this quantity routinely published. Disagreement between estimates can be substantial and may lead to confusion among decision-makers and the general public. In this work, we compare different estimates of the national-level effective reproductive number of COVID-19 in Germany in 2020 and 2021. We consider the agreement between estimates from the same method but published at different time points (within-method agreement) as well as retrospective agreement across eight different approaches (between-method agreement). Concerning the former, estimates from some methods are very stable over time and hardly subject to revisions, while others display considerable fluctuations. To evaluate between-method agreement, we reproduce the estimates generated by different groups using a variety of statistical approaches, standardizing analytical choices to assess how they contribute to the observed disagreement. These analytical choices include the data source, data pre-processing, assumed generation time distribution, statistical tuning parameters, and various delay distributions. We find that in practice, these auxiliary choices in the estimation of Rt may affect results at least as strongly as the selection of the statistical approach. They should thus be communicated transparently along with the estimates.

PMID:38011276 | DOI:10.1371/journal.pcbi.1011653

PLoS Comput Biol. 2023 Nov 27;19(11):e1011655. doi: 10.1371/journal.pcbi.1011655. Online ahead of print.

ABSTRACT

Generative models of protein sequence families are an important tool in the repertoire of protein scientists and engineers alike. However, state-of-the-art generative approaches face inference, accuracy, and overfitting- related obstacles when modeling moderately sized to large proteins and/or protein families with low sequence coverage. Here, we present a simple to learn, tunable, and accurate generative model, GENERALIST: GENERAtive nonLInear tenSor-factorizaTion for protein sequences. GENERALIST accurately captures several high order summary statistics of amino acid covariation. GENERALIST also predicts conservative local optimal sequences which are likely to fold in stable 3D structure. Importantly, unlike current methods, the density of sequences in GENERALIST-modeled sequence ensembles closely resembles the corresponding natural ensembles. Finally, GENERALIST embeds protein sequences in an informative latent space. GENERALIST will be an important tool to study protein sequence variability.

PMID:38011273 | DOI:10.1371/journal.pcbi.1011655

PLoS One. 2023 Nov 27;18(11):e0294718. doi: 10.1371/journal.pone.0294718. eCollection 2023.

ABSTRACT

Creatine kinase (CK) and adenylate kinase (AK) are energy transfer systems. Different studies on permeabilized cardiomyocytes suggest that ADP-channelling from mitochondrial CK alone stimulates respiration to its maximum, VO2_max, in rat but not mouse cardiomyocytes. Results are ambiguous on ADP-channelling from AK to mitochondria. This study was undertaken to directly compare the CK and AK systems in rat and mouse hearts. In homogenates, we assessed CK- and AK-activities, and the CK isoform distribution. In permeabilized cardiomyocytes, we assessed mitochondrial respiration stimulated by ADP from CK and AK, VO2_CK and VO2_AK, respectively. The ADP-channelling from CK or AK to mitochondria was assessed by adding PEP and PK to competitively inhibit the respiration rate. We found that rat compared to mouse hearts had a lower aerobic capacity, higher VO2_CK/VO2_max, and different CK-isoform distribution. Although rat hearts had a larger fraction of mitochondrial CK, less ADP was channeled from CK to the mitochondria. This suggests different intracellular compartmentalization in rat and mouse cardiomyocytes. VO2_AK/VO2_max was similar in mouse and rat cardiomyocytes, and AK did not channel ADP to the mitochondria. In the absence of intracellular compartmentalization, the AK- and CK-activities in homogenate should have been similar to the ADP-phosphorylation rates estimated from VO2_AK and VO2_CK in permeabilized cardiomyocytes. Instead, we found that the ADP-phosphorylation rates estimated from permeabilized cardiomyocytes were 2 and 9 times lower than the activities recorded in homogenate for CK and AK, respectively. Our results highlight the importance of energetic compartmentalization in cardiac metabolic regulation and signalling.

PMID:38011179 | DOI:10.1371/journal.pone.0294718

Hum Vaccin Immunother. 2023 Dec 15;19(3):2282693. doi: 10.1080/21645515.2023.2282693. Epub 2023 Nov 27.

ABSTRACT

The identification of immune correlates of protection against infectious pathogens will accelerate the design and optimization of recombinant and subunit vaccines. Systematic analyses such as immunoprofiling including serological, cellular, and molecular assessments supported by computational tools are key to not only identify correlates of protection but also biomarkers of disease susceptibility. The current study expands our previous cellular and serological profiling of vaccine-induced responses to a whole parasite malaria vaccine. The irradiated sporozoite model was chosen as it is considered the most effective vaccine against malaria. In contrast to whole blood transcriptomics analysis, we stimulated peripheral blood mononuclear cells (PBMC) with sporozoites and enriched for antigen-specific cells prior to conducting transcriptomics analysis. By focusing on transcriptional events triggered by antigen-specific stimulation, we were able to uncover quantitative and qualitative differences between protected and non-protected individuals to controlled human malaria infections and identified differentially expressed genes associated with sporozoite-specific responses. Further analyses including pathway and gene set enrichment analysis revealed that vaccination with irradiated sporozoites induced a transcriptomic profile associated with Th1-responses, Interferon-signaling, antigen-presentation, and inflammation. Analyzing longitudinal time points not only post-vaccination but also post-controlled human malaria infection further revealed that the transcriptomic profile of protected vs non-protected individuals was not static but continued to diverge over time. The results lay the foundation for comparing protective immune signatures induced by various vaccine platforms to uncover immune correlates of protection that are common across platforms.

PMID:38010150 | DOI:10.1080/21645515.2023.2282693

New Phytol. 2023 Nov 27. doi: 10.1111/nph.19420. Online ahead of print.

ABSTRACT

The Arabidopsis thaliana transcription factor BRANCHED1 (BRC1) plays a pivotal role in the control of shoot branching as it integrates environmental and endogenous signals that influence axillary bud growth. Despite its remarkable activity as a growth inhibitor, the mechanisms by which BRC1 promotes bud dormancy are largely unknown. We determined the genome-wide BRC1 binding sites in vivo and combined these with transcriptomic data and gene co-expression analyses to identify bona fide BRC1 direct targets. Next, we integrated multi-omics data to infer the BRC1 gene regulatory network (GRN) and used graph theory techniques to find network motifs that control the GRN dynamics. We generated an open online tool to interrogate this network. A group of BRC1 target genes encoding transcription factors (BTFs) orchestrate this intricate transcriptional network enriched in abscisic acid-related components. Promoter::β-GLUCURONIDASE transgenic lines confirmed that BTFs are expressed in axillary buds. Transient co-expression assays and studies in planta using mutant lines validated the role of BTFs in modulating the GRN and promoting bud dormancy. This knowledge provides access to the developmental mechanisms that regulate shoot branching and helps identify candidate genes to use as tools to adapt plant architecture and crop production to ever-changing environmental conditions.

PMID:38009929 | DOI:10.1111/nph.19420