SPOP Promotes Ubiquitination and Degradation of the ERG Oncoprotein to Suppress Prostate Cancer Progression

The ERG gene is fused to TMPRSS2 in approximately 50% of prostate cancers (PrCa), resulting in its overexpression. However, whether this is the sole mechanism underlying ERG elevation in PrCa is currently unclear. Here we report that ERG ubiquitination and degradation are governed by the Cullin 3-based ubiquitin ligase SPOP and that deficiency in this pathway leads to aberrant elevation of the ERG oncoprotein. Specifically, we find that truncated ERG (ΔERG), encoded by the ERG fusion gene, is stabilized by evading SPOP-mediated destruction, whereas prostate cancer-associated SPOP mutants are also deficient in promoting ERG ubiquitination. Furthermore, we show that the SPOP/ERG interaction is modulated by CKI-mediated phosphorylation. Importantly, we demonstrate that DNA damage drugs, topoisomerase inhibitors, can trigger CKI activation to restore the SPOP/ΔERG interaction and its consequent degradation. Therefore, SPOP functions as a tumor suppressor to negatively regulate the stability of the ERG oncoprotein in prostate cancer

dbAPIS: a database of anti-prokaryotic immune system genes

Anti-prokary otic immune sy stem (APIS) proteins, typically encoded b y phages, prophages, and plasmids, inhibit prokaryotic immune systems (e.g. restriction modification, to xin-antito xin, CRISPR-Cas). A gro wing number of APIS genes ha v e been characterized and dispersed in the literature. Here w e de v eloped dbAPIS ( https:// bcb.unl.edu/ dbAPIS ), as the first literature curated data repository for experimentally verified APIS genes and their associated protein f amilies. T he k e y features of dbAPIS include: (i) e xperimentally v erified APIS genes with their protein sequences, functional annotation, PDB or AlphaFold predicted str uct ures, genomic context, sequence and str uct ural homologs from different microbiome / virome databases; (ii) classification of APIS proteins into sequence-based families and construction of hidden Mark o v models (HMMs); (iii) user-friendly web interface for data browsing by the inhibited immune system types or by the hosts, and functions for searching and batch downloading of pre-computed data; (iv) Inclusion of all types of APIS proteins (e x cept f or anti-CRISPRs) that inhibit a v ariety of prokary otic defense systems (e.g. RM, TA, CB A SS , Thoeris, Gabija). The current release of dbAPIS contains 41 verified APIS proteins and ∼4400 sequence homologs of 92 families and 38 clans. dbAPIS will facilitate the discovery of novel anti-defense genes and genomic islands in phages, by providing a user-friendly data repository and a web resource for an easy homology search against known APIS proteins

dbAPIS: a database of anti-prokaryotic immune system genes

Anti-prokaryotic immune system (APIS) proteins, typically encoded b y phages, prophages, and plasmids, inhibit prokaryotic immune systems (e.g. restriction modification, to xin-antito xin, CRISPR-Cas). A growing number of APIS genes have been characterized and dispersed in the literature. Here we developed dbAPIS ( https:// bcb.unl.edu/ dbAPIS ), as the first literature curated data repository for experimentally verified APIS genes and their associated protein families. The key features of dbAPIS include: (i) experimentally verified APIS genes with their protein sequences, functional annotation, PDB or AlphaFold predicted structures, genomic context, sequence and structural homologs from different microbiome / virome databases; (ii) classification of APIS proteins into sequence-based families and construction of hidden Markov models (HMMs); (iii) user-friendly web interface for data browsing by the inhibited immune system types or by the hosts, and functions for searching and batch downloading of pre-computed data; (iv) Inclusion of all types of APIS proteins (except f or anti-CRISPRs) that inhibit a variety of prokaryotic defense systems (e.g. RM, TA, CB A SS , Thoeris, Gabija). The current release of dbAPIS contains 41 verified APIS proteins and ∼4400 sequence homologs of 92 families and 38 clans. dbAPIS will facilitate the discovery of novel anti-defense genes and genomic islands in phages, by providing a user-friendly data repository and a web resource for an easy homology search against known APIS proteins

Genome mining for anti-CRISPR operons using machine learning

Motivation: Encoded by (pro-)viruses, anti-CRISPR (Acr) proteins inhibit the CRISPR-Cas immune system of their prokaryotic hosts. As a result, Acr proteins can be employed to develop more controllable CRISPR-Cas genome editing tools. Recent studies revealed that known acr genes often coexist with other acr genes and with phage structural genes within the same operon. For example, we found that 47 of 98 known acr genes (or their homologs) co-exist in the same operons. None of the current Acr prediction tools have considered this important genomic context feature. We have developed a new software tool AOminer to facilitate the improved discovery of new Acrs by fully exploiting the genomic context of known acr genes and their homologs. Results: AOminer is the first machine learning based tool focused on the discovery of Acr operons (AOs). A two-state HMM (hidden Markov model) was trained to learn the conserved genomic context of operons that contain known acr genes or their homologs, and the learnt features could distinguish AOs and non-AOs. AOminer allows automated mining for potential AOs from query genomes or operons. AOminer outperformed all existing Acr prediction tools with an accuracy¼0.85. AOminer will facilitate the discovery of novel anti-CRISPR operons

The chromosome-level rambutan genome reveals a significant role of segmental duplication in the expansion of resistance genes

Rambutan (Nephelium lappaceum var. lappaceum), a tropical fruit tree native to southeastern Asia, belongs to the family Sapindaceae. Rambutan is a popular table fruit and is also processed into preserves, juices, wines, and sorbets [1]. At present, only three Sapindaceae genomes are publicly available: Xanthoceras sorbifolium [2], Dimocarpus longan (longan) [3], and Acer yangbiense [4]. During the process of submitting this manuscript, the genome paper for the rambutan cultivar Baoyan7 became available online, but its genome sequence has not yet been released [5]

Homeobox transcription factor HbxA influences expression of over one thousand genes in the model fungus \u3ci\u3eAspergillus nidulans\u3c/i\u3e

In fungi, conserved homeobox-domain proteins are transcriptional regulators governing development. In Aspergillus species, several homeobox-domain transcription factor genes have been identified, among them, hbxA/hbx1. For instance, in the opportunistic human pathogen Aspergillus fumigatus, hbxA is involved in conidial production and germination, as well as virulence and secondary metabolism, including production of fumigaclavines, fumiquinazolines, and chaetominine. In the agriculturally important fungus Aspergillus flavus, disruption of hbx1 results in fluffy aconidial colonies unable to produce sclerotia. hbx1 also regulates production of aflatoxins, cyclopiazonic acid and aflatrem. Furthermore, transcriptome studies revealed that hbx1 has a broad effect on the A. flavus genome, including numerous genes involved in secondary metabolism. These studies underline the importance of the HbxA/Hbx1 regulator, not only in developmental processes but also in the biosynthesis of a broad number of fungal natural products, including potential medical drugs and mycotoxins. To gain further insight into the regulatory scope of HbxA in Aspergilli, we studied its role in the model fungus Aspergillus nidulans. Our present study of the A. nidulans hbxA-dependent transcriptome revealed that more than one thousand genes are differentially expressed when this regulator was not transcribed at wild-type levels, among them numerous transcription factors, including those involved in development as well as in secondary metabolism regulation. Furthermore, our metabolomics analyses revealed that production of several secondary metabolites, some of them associated with A. nidulans hbxA-dependent gene clusters, was also altered in deletion and overexpression hbxA strains compared to the wild type, including synthesis of nidulanins A, B and D, versicolorin A, sterigmatocystin, austinol, dehydroaustinol, and three unknown novel compounds

Three \u3ci\u3ede novo\u3c/i\u3e assembled wild cacao genomes from the Upper Amazon

Theobroma cacao, the chocolate tree, is indigenous to the Amazon basin, the greatest biodiversity hotspot on earth. Recent advancement in plant genomics highlights the importance of de novo sequencing of multiple reference genomes to capture the genome diversity present in different cacao populations. In this study, three high-quality chromosome-level genomes of wild cacao were constructed, de novo assembled with HiFi long reads sequencing, and scaffolded using a reference-free strategy. These genomes represent the three most important genetic clusters of cacao trees from the Upper Amazon region. The three wild cacao genomes were compared with two reference genomes of domesticated cacao. The five cacao genetic clusters were inferred to have diverged in the early and middle Pleistocene period, approximately 1.83–0.69 million years ago. The results shown here serve as an example of understanding how the Amazonian biodiversity was developed. The three wild cacao genomes provide valuable resources for studying genetic diversity and advancing genetic improvement of this species

Clinical Characteristics of Inpatients With New-Onset Diabetes Mellitus in Eastern China: Based on Novel Clustering Analysis

IntroductionThis study aimed to explore the novel classification of inpatients with new-onset diabetes in Eastern China by the cluster-based classification method and compare the clinical characteristics among the different subgroups.MethodsA total of 1017 Inpatients with new-onset diabetes of five hospitals in Eastern China were included in the study. Clustering analysis was used to cluster the data into five subgroups according to six basic variables. The differences in clinical characteristics, treatments, and the prevalence of diabetes-related diseases among the five subgroups were analyzed by multiple groups comparisons and pairwise comparisons. The risk of diabetes-related diseases in the five subgroups was compared by calculating odd ratio (OR). P value < 0.05 was considered significant.ResultsFive subgroups were obtained by clustering analysis with the highest proportion of patients with severe insulin-deficient diabetes (SIDD) 451 (44.35%), followed by patients with mild age-related diabetes (MARD) 236 (23.21%), patients with mild obesity-related diabetes (MOD) 207 (20.35%), patients with severe insulin-resistant diabetes (SIRD) 81 (7.96%), and patients with severe autoimmune diabetes (SAID) 42 (4.13%). Five subtypes had their own unique characteristics and treatments. The prevalence and risk of diabetes-related complications and comorbidities were also significantly different among the five subtypes. Diabetic kidney disease (DKD) was the most common in SIRD group. Patients in SIDD, SIRD, and MARD groups were more likely to develop cardiovascular disease (CVD) and/or stroke, diabetic peripheral vascular disease (DPVD), and diabetic distal symmetric polyneuropathy (DSPN). The prevalence and risk of metabolic syndrome (MS) were the highest in MOD and SIRD groups. Patients in SAID group had the highest prevalence and risk of diabetic ketoacidosis (DKA). Patients with MOD were more likely to develop non-alcoholic fatty liver disease (NAFLD).ConclusionsThe inpatients with new-onset diabetes in Eastern China had the unique clustering distribution. The clinical characteristics, treatments, and diabetes-related complications and comorbidities of the five subgroups were different, which may provide the basis for precise treatments of diabetes

Expert consensus on drug treatment of chronic subdural hematoma

Chronic subdural hematoma (CSDH) is a chronic space-occupying lesion formed by blood accumulation between arachnoid and dura mater, which is usually formed in the third week after traumatic brain injury. Surgical treatment is usually the first choice for patients with CSDH having a significant space-occupying effect. Most of the patients showed good results of surgical treatment, but still some patients had a postoperative recurrence (the recurrence rate was up to 33%). Because CSDH is often seen in the elderly, patients are weak and have many basic diseases. The risk of surgical treatment is high; serious complications and even death (the death rate is up to 32%) can often occur. The overall good prognosis rate of patients aged more than 90 years is 24%. The drug treatment can provide a safe and effective treatment for elderly patients who are weak, intolerable to surgery, or failed in surgery. Low-dose and long-term use of atorvastatin (20mg/d) is suggested for continuous treatment for at least 8 weeks, while low-dose and short-term use of dexamethasone can improve the therapeutic effect of atorvastatin on CSDH. Patients should undergo CT or MRI scanning at least one time within 2 weeks after the start of drug treatment.published_or_final_versio

Genomes of multicellular algal sisters to land plants illuminate signaling network evolution

Zygnematophyceae are the algal sisters of land plants. Here we sequenced four genomes of filamentous Zygnematophyceae, including chromosome-scale assemblies for three strains of Zygnema circumcarinatum. We inferred traits in the ancestor of Zygnematophyceae and land plants that might have ushered in the conquest of land by plants: expanded genes for signaling cascades, environmental response, and multicellular growth. Zygnematophyceae and land plants share all the major enzymes for cell wall synthesis and remodifications, and gene gains shaped this toolkit. Co-expression network analyses uncover gene cohorts that unite environmental signaling with multicellular developmental programs. Our data shed light on a molecular chassis that balances environmental response and growth modulation across more than 600 million years of streptophyte evolution