Efficacy and safety study of targeted small-molecule drugs in the treatment of systemic lupus erythematosus.

BACKGROUND: Targeted small-molecule drugs in the treatment of systemic lupus erythematosus (SLE) have attracted increasing attention from clinical investigators. However, there is still a lack of evidence on the difference in the efficacy and safety of different targeted small-molecule drugs. Therefore, this study was conducted to assess the efficacy and safety of different targeted small-molecule drugs for SLE. METHODS: Randomized controlled trials (RCTs) on targeted small-molecule drugs in the treatment of SLE in PubMed, Web of Science, Embase, and Cochrane Library were systematically searched as of April 25, 2023. Risk of bias assessment was performed for included studies using the Cochrane's tool for evaluating the risk of bias. The primary outcome indicators were SRI-4 response, BICLA response, and adverse reaction. Because different doses and courses of treatment were used in the included studies, Bayesian network meta-regression was used to investigate the effect of different doses and courses of treatment on efficacy and safety. RESULTS: A total of 13 studies were included, involving 3,622 patients and 9 targeted small-molecule drugs. The results of network meta-analysis showed that, in terms of improving SRI-4, Deucravacitinib was significantly superior to that of Baricitinib (RR = 1.32, 95% CI (1.04, 1.68), P < 0.05). Deucravacitinib significantly outperformed the placebo in improving BICLA response (RR = 1.55, 95% CI (1.20, 2.02), P < 0.05). In terms of adverse reactions, targeted small-molecule drugs did not significantly increase the risk of adverse events as compared to placebo (P > 0.05). CONCLUSION: Based on the evidence obtained in this study, the differences in the efficacy of targeted small-molecule drugs were statistically significant as compared to placebo, but the difference in the safety was not statistically significant. The dose and the course of treatment had little impact on the effect of targeted small-molecule drugs. Deucravacitinib could significantly improve BICLA response and SRI-4 response without significantly increasing the risk of AEs. Therefore, Deucravacitinib is very likely to be the best intervention measure. Due to the small number of included studies, more high-quality clinical evidence is needed to further verify the efficacy and safety of targeted small-molecule drugs for SLE.

Effect of different oral anticoagulants on cognitive function in patients with atrial fibrillation: A Bayesian network meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is 1 of the most common types of arrhythmias. At present, the treatment for patients with AF mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation; however, there is a lack of relevant evidence. This study used Bayesian network meta-analysis (NMA) to investigate the effects of different oral anticoagulants on cognitive decline in patients with AF. METHODS: We systematically searched for clinical studies on oral anticoagulants in patients with AF in PubMed, Web of Science, Embase, and the Cochrane Library as of July 3, 2023. Cochrane's randomized controlled trial bias risk assessment tool and the Newcastle-Ottawa Scale were used to assess the bias risk of the included studies. The main outcome measure was decreased cognitive functioning. RESULTS: Ten studies were included, including 2 RCTs and 7 RCSs, including 882,847 patients with AF. Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel. The results of the mesh meta-analysis showed that VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = -1.19, 95% CI (-2.35, -0.06), P < .05) (Table 5). The top 3 drugs in terms of the probability of reducing the incidence of cognitive impairment in patients with AF with different oral anticoagulants were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%). CONCLUSION: Based on the results of this study, VKAs may be the best intervention measure for reducing the risk of cognitive decline in patients with AF. Owing to the limitations of this study, more high-quality randomized controlled trials with large sample sizes and multiple centers are required to provide more evidence.

Strength and leaching behavior of tailing-based paste backfill at high water content amended with lime activated ground granulated blast furnace slag and flocculant.

Flocculent is commonly used in mining activities to improve the concentration of tailing slurry by enhancing the sedimentation process of small tailings particles. The presence of flocculent in thickened tailings is unavoidable, and it affects the heavy metal leaching performances and mechanical and rheological characteristics of tailing-based cemented paste backfill (CPB). This study is carried out to investigate the physicochemical and leachability of CPB amended with flocculants and lime-activated ground granulated blast-furnace slag (GGBS). The stabilized samples were subjected to a series of model tests, including toxicity characteristics leaching procedure (TCLP) and pH, unconfined compressive strength (UCS), scanning electron microscopy (SEM), and X-ray diffraction. Moreover, the CPB amended with anionic polyacrylamide (APAM) demonstrated better performance in terms of a decrease in heavy metal leachability besides higher mechanical strength than poly aluminum chloride (PAC) and poly ferric chloride (PFC) samples. Furthermore, the UCS results showed that increasing binder content up to 15% negatively influences strength improvement of all stabilized samples because of weak connections between soil particles and cementitious material, resulting in high leachability of heavy metals. The analysis of XRD and SEM showed that anionic polyacrylamide (APAM) cases exhibited more voluminous hydration products, resulting in a compact stabilized matrix and substantially reduced heavy metal leachability.

Immobilization of Cd2+ in an aqueous environment using a two-step microbial-induced carbonate precipitation method.

Previous researches indicate that the potent toxicity of cadmium hinders the efficacy of the microbial-induced carbonate precipitation (MICP) process for bioremediation of Cd2+ in aqueous environment. Increasing urea and calcium resource doses, introducing synergists, and utilizing urease-producing consortia can improve bio-immobilization performance of MICP. However, such measures may incur cost increases and/or secondary contamination. This study first verifies the substantial biotoxicity of Cd2+ for urease activity and then analyzes the practical limitation of traditional MICP using Bacillus pasteurii for bioremediation of Cd2+ in an aqueous environment containing 1-40 mM Cd2+ by a series tube tests and numerical simulation. Subsequently, a two-step MICP method, which separates urea hydrolysis and heavy metal precipitation, is introduced in this study to eliminate the inhibitory effect of heavy metal on urease activity. The concentrations of ammonium, Cd2+, and pH were monitored over time. The results indicate that the urease expression in B. pasteurii can be significantly inhibited by Cd2+ particularly at the concentration ranging from 10 to 40 mM, leading to pretty low efficacy of traditional MICP for bioremediation of Cd2+ (Cd2+ removal rate as low as 21.55-38.47% when the initial Cd2+ concentration = 40 mM). In contrast, when the two-step MICP method is applied, the Cd2+ can be almost completely immobilized, even though the concentration ratio of urea to Cd2+ is as low as 1.5:1.0, which is close to the theory minimum concentration ratio for the complete precipitation of carbonate to cadmium ions(1.0:1.0). Therefore, the cost-effective, environmentally sustainable, and straightforward two-step MICP method holds great potential for application in the bioremediation of Cd2+-contaminated solutions in high concentration.

Promotores' perspectives on the virtual adaptation of a hereditary breast cancer education program.

Breast cancer is the most common cancer in women in the United States (U.S.) and the leading cause of cancer related death among U.S. Hispanics/Latinas (H/Ls). H/Ls have lower rates of screening and longer time to follow up after an abnormal mammogram. We developed a comprehensive community health educator (promotores)-led education and risk identification program for Spanish-speaking H/Ls in California to increase mammography screening, genetic testing, and the understanding of the impact of family history on cancer risk. Due to COVID-19, we adapted the program to a virtual platform. The experience of transforming the program to a virtual platform provided unique opportunities for collaboration between researchers, community partners, and participants. Promotores are major partners in community based participatory research and in the provision of health care services, but their voices are often excluded from scientific reports. This commentary is an effort to provide a platform for promotores to share their experiences and for the readers to understand their approach in bridging the gap between health care services and communities.

WDR74 serves as a novel therapeutic target by its oncogenic role in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most refractory human malignancies. WD repeat-containing protein 74 (WDR74) is involved in the tumorigenesis of various cancers, however, its clinical implications and biological function in HCC have yet to be clearly determined. METHODS: Bioinformatics analysis was conducted using various databases, including The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and UALCAN. The expression of WDR74 was confirmed in HCC tumor samples and the corresponding adjacent nontumor samples by qRT-PCR, western blot and immunohistochemistry. Functional enrichment analysis was used for the biological function prediction. In vitro experiments were performed to determine the effects of WDR74 on HCC cell proliferation. RESULTS: Our findings revealed that WDR74 was markedly upregulated in HCC tissues. Increased WDR74 expression had an unfavorable overall survival (OS). Multivariate Cox regression analysis demonstrated that WDR74 was an independent prognostic factor for OS in patients with HCC. Functional enrichment analysis suggested a significant correlation with cytokine-cytokine receptor interaction pathway in both TCGA-LIHC and GSE112790 datasets. Gene set enrichment analysis showed that WDR74 is probably involved in several pathways, such as MYC targets, ribosome, translation, and cell cycle. Finally, WDR74 knockdown reduced HCC cell proliferation by restraining the G1/S cell cycle transition and inducing apoptosis. CONCLUSIONS: The current study demonstrates that elevated WDR74 expression is linked to an accelerated rate of tumor cell proliferation and is indicative of a poorer outcome in patients with HCC. Therefore, WDR74 could be used as a reliable prognostic biomarker and is a potential therapeutic target for HCC.

Ginsenoside Rg1 Ameliorates Pancreatic Injuries via the AMPK/mTOR Pathway in vivo and in vitro.

Background: The main propanaxatriol-type saponin found in ginseng (Panax ginseng C. A. Mey), ginsenoside Rg1 (G-Rg1), has bioactivities that include anti-inflammatory, antioxidant, and anti-diabetic properties. This study aimed to investigate the effects of G-Rg1 on streptozotocin (STZ)-induced Type 1 Diabetes mellitus (T1DM) mice and the insulin-secreting cell line in RIN-m5F cells with high-glucose (HG) treatment. Methods: The STZ-induced DM mice model was treated with G-Rg1 alone or combined with 3-Methyladenine (3-MA, an autophagy inhibitor)/rapamycin (RAPA, an autophagy activator) for 8 weeks, and levels of glucose and lipid metabolism, histopathological changes, as well as autophagy and apoptosis of relevant markers were estimated. In vitro, the HG-induced RIN-m5F cells were treated with G-Rg1, 3-MA, and Compound C (CC), an AMPK inhibitor, or their combinations to estimate the influences on cell apoptosis, autophagy, and AMPK/mTOR pathway-associated target gene levels. Results: G-Rg1 treatment attenuated glucose and lipid metabolism disorder and pancreatic fibrosis in diabetic mice. In addition, subdued autophagy and p-AMPK protein expression, and enhanced p-mTOR protein expression and apoptosis levels in TIDM mice and HG-induced RIN-m5F cells were ameliorated by G-Rg1 treatment. Furthermore, these anti-apoptosis effects of G-Rg1 were partially abolished by 3-MA and CC. Conclusion: Our findings revealed that G-Rg1 exhibits strong anti-apoptosis ability in pancreatic tissues of type 1 diabetic mice and HG-induced RIN-m5F cells, and the mechanisms involved in activating AMPK and inhibiting mTOR-mediated autophagy, indicating that G-Rg1 may have the therapeutic and preventive potential for treating pancreatic injury in diabetic patients.

Cancer screening and breast cancer family history in Spanish-speaking Hispanic/Latina women in California.

Background: Breast cancer is the most common cancer among women in the U.S. and the leading cause of cancer death among Hispanics/Latinas (H/L). H/L are less likely than Non-H/L White (NHW) women to be diagnosed in the early stages of this disease. Approximately 5-10% of breast cancer can be attributed to inherited genetic mutations in high penetrance genes such as BRCA1/2. Women with pathogenic variants in these genes have a 40-80% lifetime risk of breast cancer. Past studies have shown that genetic counseling can help women and their families make informed decisions about genetic testing and early cancer detection or risk-reduction strategies. However, H/L are 3.9-4.8 times less likely to undergo genetic testing than NHW women. We developed a program to outreach and educate the H/L community about hereditary breast cancer, targeting monolingual Spanish-speaking individuals in California. Through this program, we have assessed cancer screening behavior and identified women who might benefit from genetic counseling in a population that is usually excluded from cancer research and care. Materials and Methods: The "Tu Historia Cuenta" program is a promotores-based virtual outreach and education program including the cities of San Francisco, Sacramento, and Los Angeles. Participants responded to three surveys: a demographic survey, a breast cancer family history survey, and a feedback survey. Survey responses were described for participants and compared by area where the program took place using chi-square, Fisher exact tests, and t tests. Multinomial logistic regression models were used for multivariate analyses. Results and Conclusion: We enrolled 1042 women, 892 completed the cancer family history survey and 62 (7%) provided responses compatible with referral to genetic counseling. We identified 272 women (42.8% ages 40 to 74 years) who were due for mammograms, 250 women (24.7% ages 25 to 65 years) due for Papanicolaou test, and 189 women (71.6% ages 50+) due for colorectal cancer screening. These results highlight the need of additional support for programs that spread awareness about cancer risk and facilitate access to resources, specifically within the H/L community.

One-pot room temperature synthesis of orange-emitting carbon dots for highly-sensitive vitamin B12 sensing.

Fluorescent carbon dots (CDs) with the long-wavelength emission have received increasing attention due to their promising application prospects in the biological field. The synthesis of CDs with long wavelength emission mainly focuses on the high temperature method, but the room temperature synthesis is still rarely studied. Herein, a simple room temperature strategy is developed for the preparation of orange-emitting CDs (O-CDs) by Schiff base crosslinking reaction between methyl-p-benzoquinone and triethylenetetramine. The proposed O-CDs show a strong excitation-dependent emission with a relative quantum yield of about 6.56%. Because of the strong inner filter effect, O-CDs can be well applied for the highly-sensitive detection of vitamin B12 (VB12). The intensity ratio (F/F0) of O-CDs is linear against the concentration of VB12 from 50 nM to 200 µM with a low detection limit of 10 nM. Therefore, the obtained O-CDs nanoprobes provide a promising platform for pharmaceutical analysis applications.

Erratum: Cancer screening and breast cancer family history in Spanish-speaking Hispanic/Latina women in California.

[This corrects the article DOI: 10.3389/fonc.2022.940162.].

Strength and Leaching Behavior of Contaminated Mining Sludge at High Water Content Stabilized with Lime Activated GGBS.

Sludge management is one of the major challenges in mining activities. The direct disposal of contaminated mining sludge can bring severe damages to the environment and community. Solidification/stabilization (S/S) is a very efficient technology for the treatment of contaminated mining sludge because it improves the stability of sludge dumping sites and reduces the leachability of contaminants. Very few studies investigate the S/S of mining sludge, especially with high water content. This paper investigated the effectiveness of S/S for the treatment of mining sludge at high water content by using quick lime (CaO) activated ground granulated blast furnace slag (GGBS) in comparison to ordinary Portland cement (OPC). To evaluate the mechanical, leaching, and microstructural behavior of CMS at high water content stabilized by lime-activated GGBS and OPC, a series of laboratory experimental tests were performed. Experimental results indicated that increasing the dosage of binder led to increased strength and decreased leachability of the heavy metal. In contrast, an increase in the water content of the mixture resulted in a decrease in compressive strength and an increase in the leachability of heavy metals. On the other hand, lime-activated GGBS mixes had substantially better performance than OPC mixes in the aspect of strength development of treated mining sludge and showed comparable capability of heavy metal stabilization compared to OPC. The microstructural tests revealed the formation of different hydration products such as calcium silicate hydrate, calcium aluminum silicate hydrate, ettringite, hydrotalcite, and heavy metal complexes in CG and OPC mixes.

Electrochemical Activity and Damage of Single Carbon Fiber.

The electrochemical activity of a carbon fiber was characterized at different potentials in 3.5 wt.% NaCl solution, and the fiber cylindrical surface changed by polarization at different potentials was revealed by SEM, AFM, optical microscopy, FTIR spectroscopy, Raman spectroscopy, and XRD. The results showed that the carbon fiber exhibited different electrochemical activities at some polarization potentials; within a 3V potential range the anodic and cathodic polarization current densities stepped up by more than 5 orders of magnitude, and the carbon fiber (CF) surface dramatically changed with time. Strong anodic polarization appeared to facilitate the breakdown of C-C covalent bonds in the carbon fiber and enhance the amorphization of the fiber surface.

Pramipexole attenuates neuronal injury in Parkinson's disease by targeting miR-96 to activate BNIP3-mediated mitophagy.

BACKGROUND: Parkinson's disease is a common neurodegenerative problem. Pramipexole (PPX) plays protective role in Parkinson's disease. Nevertheless, the mechanism of PPX in Parkinson's disease-like neuronal injury is largely uncertain. METHODS: 1-methyl-4-phenylpyridinium (MPP+)-stimulated neuronal cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice were used as the model of Parkinson's disease. MPP+-induced neuronal injury was assessed via cell viability, lactic dehydrogenase (LDH) release and apoptosis. microRNA-96 (miR-96) and BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) abundances were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or Western blotting. Mitophagy was tested by Western blotting and immunofluorescence staining. MPTP-induced neuronal injury in mice was investigated via behavioral tests and TUNEL. RESULTS: PPX alleviated MPP+-induced neuronal injury via increasing cell viability and decreasing LDH release and apoptosis. PPX reversed MPP+-induced miR-96 expression and inhibition of mitophagy. miR-96 overexpression or BNIP3 interference weakened the suppressive role of PPX in MPP+-induced neuronal injury. miR-96 targeted BNIP3 to inhibit PTEN-induced putative kinase 1 (PINK1)/Parkin signals-mediated mitophagy. miR-96 overexpression promoted MPP+-induced neuronal injury via decreasing BNIP3. PPX weakened MPTP-induced neuronal injury in mice via regulating miR-96/BNIP3-mediated mitophagy. CONCLUSION: PPX mitigated neuronal injury in MPP+-induced cells and MPTP-induced mice by activating BNIP3-mediated mitophagy via directly decreasing miR-96.

Pharmacokinetic and bioavailability study of kurarinone in dog plasma by UHPLC-MS/MS.

Kurarinone, a natural prenylated flavonone isolated from Sophora flavescens, has been exhibited various activities. This study aimed to establish a simple and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for determining kurarinone in dog plasma. Acetonitrile-mediated precipitation was applied for sample pretreatment. Chromatographic separation was achieved on a Waters ACQUITY HSS T3 (100 × 2.1 mm, i. d., 1.8 µm) column with gradient elution using water containing 0.1% formic acid and acetonitrile as mobile phase. Quantitation was performed using an electrospray ionization source in negative multiple reaction monitoring mode. The linearity of this method was over the concentration range 0.1-500 ng/mL with the lowest limit of quantification (LLOQ) of 0.1 ng/mL. The intra- and inter-day precision was less than 10.51% and the accuracy ranged from 94.85% to 97.72%, respectively. The extraction recovery of kurarinone in dog plasma was more than 82.37% and no significant matrix effect was observed. The analyte was stable under tested storage conditions. The validated method was further successfully applied to a preclinical pharmacokinetic study of kurarinone in dog after a single intravenous (2 mg/kg) and oral (20 mg/kg) administration. The results revealed that kurarinone was rapidly absorbed into plasma with good bioavailability (38.19%) and low clearance.

Using stress wave technology for leakage detection in a landfill impervious layer.

This paper proposes a stress wave monitoring method for monitoring and locating leakage through the impervious layer at a landfill to resolve the "first pollution, then discovery" problem caused by the existing electrical monitoring method. The experimental results show that the linear distance to the geophones from the leak point should be less than 31.5 m to provide a well-defined rupture signal. The amplitudes of the stress wave signals generated during the yield and rupture stages of the high-density polyethylene (HDPE) film are more obvious and easily identified by the geophones; the rupture signal duration is approximately 100 ms, and the bandwidth is distributed within 0 kHz to 1 kHz. By studying the stress wave first arrival times calculated by the picking model, the average error of the picking model is approximately 0.35 ms, and the iteration of the model is ceased when the thresholds of the discriminating indices are 3.5 and 0.9. Experiments reveal that the positioning model should stop iterating when the absolute value of each element in the calibration vector is less than 140. The average positioning error is 0.248 m, and the maximum fiducial errors of the positioning model in the X-axis and Y-axis directions are 0.32% and 0.58%, respectively.

Protocol Update for large-scale genome and gene function analysis with the PANTHER classification system (v.14.0).

The PANTHER classification system ( http://www.pantherdb.org ) is a comprehensive system that combines genomes, gene function classifications, pathways and statistical analysis tools to enable biologists to analyze large-scale genome-wide experimental data. The current system (PANTHER v.14.0) covers 131 complete genomes organized into gene families and subfamilies; evolutionary relationships between genes are represented in phylogenetic trees, multiple sequence alignments and statistical models (hidden Markov models (HMMs)). The families and subfamilies are annotated with Gene Ontology (GO) terms, and sequences are assigned to PANTHER pathways. A suite of tools has been built to allow users to browse and query gene functions and analyze large-scale experimental data with a number of statistical tests. PANTHER is widely used by bench scientists, bioinformaticians, computer scientists and systems biologists. Since the protocol for using this tool (v.8.0) was originally published in 2013, there have been substantial improvements and updates in the areas of data quality, data coverage, statistical algorithms and user experience. This Protocol Update provides detailed instructions on how to analyze genome-wide experimental data in the PANTHER classification system.

Ancestral Genomes: a resource for reconstructed ancestral genes and genomes across the tree of life.

A growing number of whole genome sequencing projects, in combination with development of phylogenetic methods for reconstructing gene evolution, have provided us with a window into genomes that existed millions, and even billions, of years ago. Ancestral Genomes (http://ancestralgenomes.org) is a resource for comprehensive reconstructions of these 'fossil genomes'. Comprehensive sets of protein-coding genes have been reconstructed for 78 genomes of now-extinct species that were the common ancestors of extant species from across the tree of life. The reconstructed genes are based on the extensive library of over 15 000 gene family trees from the PANTHER database, and are updated on a yearly basis. For each ancestral gene, we assign a stable identifier, and provide additional information designed to facilitate analysis: an inferred name, a reconstructed protein sequence, a set of inferred Gene Ontology (GO) annotations, and a 'proxy gene' for each ancestral gene, defined as the least-diverged descendant of the ancestral gene in a given extant genome. On the Ancestral Genomes website, users can browse the Ancestral Genomes by selecting nodes in a species tree, and can compare an extant genome with any of its reconstructed ancestors to understand how the genome evolved.

PANTHER version 14: more genomes, a new PANTHER GO-slim and improvements in enrichment analysis tools.

PANTHER (Protein Analysis Through Evolutionary Relationships, http://pantherdb.org) is a resource for the evolutionary and functional classification of genes from organisms across the tree of life. We report the improvements we have made to the resource during the past two years. For evolutionary classifications, we have added more prokaryotic and plant genomes to the phylogenetic gene trees, expanding the representation of gene evolution in these lineages. We have refined many protein family boundaries, and have aligned PANTHER with the MEROPS resource for protease and protease inhibitor families. For functional classifications, we have developed an entirely new PANTHER GO-slim, containing over four times as many Gene Ontology terms as our previous GO-slim, as well as curated associations of genes to these terms. Lastly, we have made substantial improvements to the enrichment analysis tools available on the PANTHER website: users can now analyze over 900 different genomes, using updated statistical tests with false discovery rate corrections for multiple testing. The overrepresentation test is also available as a web service, for easy addition to third-party sites.

The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database.

The MEROPS database (http://www.ebi.ac.uk/merops/) is an integrated source of information about peptidases, their substrates and inhibitors. The hierarchical classification is: protein-species, family, clan, with an identifier at each level. The MEROPS website moved to the EMBL-EBI in 2017, requiring refactoring of the code-base and services provided. The interface to sequence searching has changed and the MEROPS protein sequence libraries can be searched at the EMBL-EBI with HMMER, FastA and BLASTP. Cross-references have been established between MEROPS and the PANTHER database at both the family and protein-species level, which will help to improve curation and coverage between the resources. Because of the increasing size of the MEROPS sequence collection, in future only sequences of characterized proteins, and from completely sequenced genomes of organisms of evolutionary, medical or commercial significance will be added. As an example, peptidase homologues in four proteomes from the Asgard superphylum of Archaea have been identified and compared to other archaean, bacterial and eukaryote proteomes. This has given insights into the origins and evolution of peptidase families, including an expansion in the number of proteasome components in Asgard archaeotes and as organisms increase in complexity. Novel structures for proteasome complexes in archaea are postulated.

PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements.

The PANTHER database (Protein ANalysis THrough Evolutionary Relationships, http://pantherdb.org) contains comprehensive information on the evolution and function of protein-coding genes from 104 completely sequenced genomes. PANTHER software tools allow users to classify new protein sequences, and to analyze gene lists obtained from large-scale genomics experiments. In the past year, major improvements include a large expansion of classification information available in PANTHER, as well as significant enhancements to the analysis tools. Protein subfamily functional classifications have more than doubled due to progress of the Gene Ontology Phylogenetic Annotation Project. For human genes (as well as a few other organisms), PANTHER now also supports enrichment analysis using pathway classifications from the Reactome resource. The gene list enrichment tools include a new 'hierarchical view' of results, enabling users to leverage the structure of the classifications/ontologies; the tools also allow users to upload genetic variant data directly, rather than requiring prior conversion to a gene list. The updated coding single-nucleotide polymorphisms (SNP) scoring tool uses an improved algorithm. The hidden Markov model (HMM) search tools now use HMMER3, dramatically reducing search times and improving accuracy of E-value statistics. Finally, the PANTHER Tree-Attribute Viewer has been implemented in JavaScript, with new views for exploring protein sequence evolution.