Aberrant glycosylation of secretory mucin from the oral cavity in tobacco consumers: a pilot study.

Mucins are a family of high-molecular-weight O-linked glycoproteins which are the primary structural components of mucus and maintain homeostasis in the oral cavity. The present study was conducted as the first step towards establishing a correlation of aberrant mucin glycosylation with tobacco-associated clinical conditions. Tobacco habituates for the study were identified on the basis of type, duration, amount, and frequency of using tobacco products. The secretory mucin and its saccharides were determined from the saliva collected from smokers, smokeless tobacco habituates, and healthy, nonsmoking individuals. On the one hand, the salivary mucin content was markedly reduced in smokeless tobacco habituates with respect to smokers. On the other hand, the amount of sialic acid and fucose moieties of salivary mucin was increased in both smokers and smokeless tobacco habituates compared to the healthy cohort. Furthermore, the duration of tobacco exposure have been identified as the main factor influencing the extent of damage to the oral mucosa in terms of mucin secretion. The reduced secretory mucin content with aberrant glycosylation in the oral cavity may have a significant role in the further development or progression of oral diseases.

Explainable deep-neural-network supported scheme for tuberculosis detection from chest radiographs.

Chest radiographs are examined in typical clinical settings by competent physicians for tuberculosis diagnosis. However, this procedure is time consuming and subjective. Due to the growing usage of machine learning techniques in applied sciences, researchers have begun applying comparable concepts to medical diagnostics, such as tuberculosis screening. In the period of extremely deep neural nets which comprised of hundreds of convolution layers for feature extraction, we create a shallow-CNN for screening of TB condition from Chest X-rays so that the model is able to offer appropriate interpretation for right diagnosis. The suggested model consists of four convolution-maxpooling layers with various hyperparameters that were optimized for optimal performance using a Bayesian optimization technique. The model was reported with a peak classification accuracy, F1-score, sensitivity and specificity of 0.95. In addition, the receiver operating characteristic (ROC) curve for the proposed shallow-CNN showed a peak area under the curve value of 0.976. Moreover, we have employed class activation maps (CAM) and Local Interpretable Model-agnostic Explanations (LIME), explainer systems for assessing the transparency and explainability of the model in comparison to a state-of-the-art pre-trained neural net such as the DenseNet.

Multi-omics assisted breeding for biotic stress resistance in soybean.

Biotic stress is a critical factor limiting soybean growth and development. Soybean responses to biotic stresses such as insects, nematodes, fungal, bacterial, and viral pathogens are governed by complex regulatory and defense mechanisms. Next-generation sequencing has availed research techniques and strategies in genomics and post-genomics. This review summarizes the available information on marker resources, quantitative trait loci, and marker-trait associations involved in regulating biotic stress responses in soybean. We discuss the differential expression of related genes and proteins reported in different transcriptomics and proteomics studies and the role of signaling pathways and metabolites reported in metabolomic studies. Recent advances in omics technologies offer opportunities to reshape and improve biotic stress resistance in soybean by altering gene regulation and/or other regulatory networks. We suggest using 'integrated omics' to precisely understand how soybean responds to different biotic stresses. We also discuss the potential challenges of integrating multi-omics for the functional analysis of genes and their regulatory networks and the development of biotic stress-resistant cultivars. This review will help direct soybean breeding programs to develop resistance against different biotic stresses.

30-day readmission rates among upper gastrointestinal bleeds: A systematic review and meta-analysis.

BACKGROUND AND AIM: Upper gastrointestinal bleeding (UGIB) is a common emergency, with high rates of hospitalization and in-patient mortality compared to other gastrointestinal diseases. Despite readmission rates being a common quality metric, little data are available for UGIBs. This study aimed to determine readmission rates for patients discharged following an UGIB. METHODS: Adhering to PRISMA guidelines, MEDLINE, Embase, CENTRAL, and Web of Science were searched to October 16, 2021. Randomized and non-randomized studies that reported hospital readmission for patients following an UGIB were included. Abstract screening, data extraction, and quality assessment were conducted in duplicate. A random-effects meta-analysis was performed, with statistical heterogeneity measured using I2 . The GRADE framework, with a modified Downs and Black tool, was used to determine certainty of evidence. RESULTS: Seventy studies were included of 1847 screened abstracted, with moderate interrater reliability. Within these studies, 4 292 714 patients were analyzed with a mean age of 66.6 years, and 54.7% male. UGIB had a 30-day all-cause readmission rate of 17.4% (95% confidence interval [CI] 16.7-18.2%), stratification revealed a higher rate for variceal UGIB [19.6% (95% CI 17.6-21.5%)] than non-variceal [16.8% (95% CI 16.0-17.5%)]. Only one third were readmitted due to recurrent UGIB (4.8% [95% CI 3.1-6.4%]). UGIB due to peptic ulcer bleeding had the lowest 30-day readmission rate [6.9% (95% CI 3.8-10.0%)]. Certainty of evidence was low or very low for all outcomes. CONCLUSIONS: Almost one in five patients discharged after an UGIB are readmitted within 30 days. These data should prompt clinicians to reflect on their own practice to identify areas of strength or improvement.

Thermal, structural, optical, and photon shielding studies of cerium-doped barium tellurite glasses.

A series of tellurite-based glasses are prepared by using a melt-quenching method. The effect of cerium on the physical, thermal, structural, optical, spectroscopic, and shielding properties of barium tellurite glass samples is studied. It has been observed that the thermal stability factor increases with increasing cerium ion (Ce3+ ) concentration. The density and other physical parameters such as ion concentration and molar volume are calculated using the Archimedes principle. An increase in optical band gap and density suggests a decrement in non-bridging oxygens. These results are in accordance with Raman results. The blue emission in prepared glasses is studied in terms of International Commission on Illumination chromaticity coordinates. Moreover, various shielding properties such as mass attenuation coefficient, linear attenuation coefficient, effective atomic number, half-value layer, and tenth-value layer have also been determined to understand the photon shielding characteristics of as-prepared glass samples.

Structural, luminescent and in vitro studies of europium-doped soda lime phosphate glasses.

In this article, we have reported the effect of varying concentration of europium (Eu) in (50 - x)% P2 O5 -25% Na2 O-24% CaO-% Eu2 O3 , where x = 1, 3, 5. The glass samples were synthesised via conventional melt-quench method. The impact of europium ion (Eu3+ ) on the structural, optical and luminescent properties of phosphate soda lime glasses has been studied using X-ray diffraction (XRD), Fourier-transformed infrared (FTIR) spectroscopy, ultraviolet-visible spectroscopy, scanning electron microscopy coupled with energy-dispersive spectroscopy and photoluminescent techniques. The amorphous nature of glass samples was confirmed by XRD patterns. FTIR confirmed the presence of various functional groups. The emission spectra of synthesised samples exhibited intense emission peaks corresponding to Eu3+ under excitation at 393 nm. Among all the peaks, the maximum intensity was observed for 5 D0 → 7 F2 transition. Judd-Ofelt (J-O) parameters (Ω2 , Ω4 ) and other radiative parameters such as band width, radiative transition probabilities, stimulated emission cross-sections and branching ratio were determined from emission spectra. The other photometric parameters such as CIE coordinates and colour purity were also determined. Furthermore, cytotoxic studies were carried out on normal cell line human embryonic kidney cells (HEK-293) using MTT assay. Results showed that the prepared samples significantly enhanced growth in glass sample-treated cells as compared to control cells. These findings suggest that synthesised glass samples are biocompatible in nature and have potential for applications in display devices and biomedical research area.

Genotoxic and mutagenic potential of 7-methylxanthine: an investigational drug molecule for the treatment of myopia.

7-Methylxanthine (7-MX, CAS No. 552-62-5, purity 99.46%) is the first orally administered drug candidate, which showed anti-myopic activity in different pre-clinical studies. In the present study, we investigated the in-vivo genotoxic and mutagenic toxicity of 7-MX in Wistar rats using comet/single-cell gel electrophoresis, chromosomal aberration and micronucleus assays after oral administration. For the single-dose study (72 h), two doses of 7-MX 300 and 2000 mg/kg body weight were selected. For a repeated dose 28 d study, three doses (250, 500, and 1000 mg/kg) of 7-MX were selected. The doses were administered via oral gavage in the suspension form. Blood and major vital organs such as bone marrow, lung and liver were used to perform comet/single cell gel electrophoresis, chromosomal aberration, and micronucleus assays. The in-vitro Ames test was performed on TA98 and TA100 strains. In the chromosomal aberration study, a non-significant increase in deformities such as stickiness, ring chromosome, and endoreduplication was observed in bone marrow cells of 7-MX treated groups. These chromosomal alterations were observed upon treatment with doses of 2000 mg/kg single dose for 72 h and 1000 mg/kg repeated dose for 28 d. At a dose of 500 mg/kg, DNA damage in terms of tail length, tail moment, % tail DNA and the olive tail moment was also found to be non-significant in 7-MX treated groups. The Ames test showed the non-mutagenic nature of 7-MX in both strains of TA98 and TA100 of Salmonella typhimurium with or without metabolic activation. Thus, the present work is interesting in view of the non- genotoxicity and non-mutagenicity of repeated doses of 7-MX.

Regulation of Oocyte Apoptosis: A View from Gene Knockout Mice.

Apoptosis is a form of programmed cell death that plays a critical role in cellular homeostasis and development, including in the ovarian reserve. In humans, hundreds of thousands of oocytes are produced in the fetal ovary. However, the majority die by apoptosis before birth. After puberty, primordial follicles develop into mature follicles. While only a large dominant follicle is selected to ovulate, smaller ones undergo apoptosis. Despite numerous studies, the mechanism of oocyte death at the molecular level remains elusive. Over the last two and a half decades, many knockout mouse models disrupting key genes in the apoptosis pathway have been generated. In this review, we highlight some of the phenotypes and discuss distinct and overlapping roles of the apoptosis regulators in oocyte death and survival. We also review how the transcription factor p63 and its family members may trigger oocyte apoptosis in response to DNA damage.

An updated checklist of mosquitoes (Diptera: Culicidae) from Chandigarh, India and its surrounding area.

Background & objectives: The affirmation about the prevalence of mosquito species at a particular place and time is very significant, not only to predict the danger of diseases or future outbreaks but also to control the vectors in time. Despite mosquitoes being medically important, the information about its faunal diversity is very scanty as far as Chandigarh in India and its nearby areas are concerned. So, this study was carried out to survey the mosquito fauna from areas in and around Chandigarh in northern India. Methods: Detailed mosquito surveys were carried out to explore the mosquito fauna from various habitats of developed urban areas, gardens, slums and surrounding villages of Chandigarh from June 2017-November 2019 using hand nets and oral aspirators. Results: A total of 34 mosquito species belonging to 8 genera viz; Anopheles, Aedes, Armigeres, Culex, Coquillet-tidia, Mansonia, Mimomyia and Verrallina were recorded, identified and preserved along with detailed collection data, of which eight are new records from Chandigarh. Interpretation & conclusion: The present checklist of mosquito fauna comprising 34 species provides information on the occurrence of mosquito vectors in Chandigarh and its adjoining areas which will be beneficial for the health authorities to adopt appropriate measures in time for the control of these vectors.

SARS-CoV-2 structural coverage map reveals viral protein assembly, mimicry, and hijacking mechanisms.

We modeled 3D structures of all SARS-CoV-2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post-translational modifications, block host translation, and disable host defenses; a further ˜29% self-assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is-and is not-known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria-COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark.

Nonvolatile Optically Reconfigurable Radiative Metasurface with Visible Tunability for Anticounterfeiting.

Control of thermal emission underpins fundamental science, as it is related to both heat and infrared electromagnetic wave transport. However, realizing nonvolatile reconfigurable thermal emission is challenging due to the inherent complexity or limitation in conventional radiative materials or structures. Here, we experimentally demonstrate a nonvolatile optically reconfigurable mid-infrared coding radiative metasurface. By applying laser pulses, infrared emissive patterns are directly encoded into an ultrathin (∼25 nm) Ge2Sb2Te5 layer integrated into a planar optical cavity with the optically crystallized Ge2Sb2Te5 spots, and the peak spectral emissivity is repeatedly switched between low (∼0.1) and high (∼0.7) values. In addition, the visible scattering patterns are independently modulated with submicron-sized bumps generated by high-power laser pulses. An anticounterfeiting label is demonstrated with spatially different infrared emission and visible light scattering information encoded. This approach constitutes a new route toward thermal emission control and has broad applications in encryption, camouflage, and so on.

Outdoor Personal Thermal Management with Simultaneous Electricity Generation.

Outdoor personal thermal comfort is of substantial significance to ameliorate the health conditions of pedestrian and outdoor laborer. However, the uncontrollable sunlight, substantial radiative loss, and intense temperature fluctuations in the outdoor environment present majestic challenges to outdoor personal thermal management. Here, we report an eco-friendly passive nanostructured textile which harvests energy from the sun and the outer space for optional localized heating and cooling. Compared to conventional heating/cooling textiles like black/white cotton, its heating/cooling mode enables a skin simulator temperature increase/decrease of 8.1 °C/6 °C, respectively, under sunlight exposure. Meanwhile, the temperature gradient created between the textile and human skin allows a continuous electricity generation with thermoelectric modules. Owing to the exceptional outdoor thermoregulation ability, this Janus textile is promising to help maintain a comfortable microclimate for individuals in outdoor environment and provide a platform for pervasive power generation.

Targeting Akt/NF-κB/p53 Pathway and Apoptosis Inducing Potential of 1,2-Benzenedicarboxylic Acid, Bis (2-Methyl Propyl) Ester Isolated from Onosma bracteata Wall. against Human Osteosarcoma (MG-63) Cells.

Onosma bracteata Wall. is an important medicinal and immunity-enhancing herbs. This plant is commonly used in the preparation of traditional Ayurvedic drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the present study aimed to investigate the antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human osteosarcoma (MG-63) cells. Among all the fractions isolated from O. bracteata, ethyl acetate fraction (Obea) showed good antioxidant activity in superoxide radical scavenging assay and lipid peroxidation assay with an EC50 value of 95.12 and 80.67 µg/mL, respectively. Silica gel column chromatography of ethyl acetate (Obea) fraction of O. bracteata yielded a pure compound, which was characterized by NMR, FTIR, and HR-MS analysis and was identified as 1,2-benzene dicarboxylic acid, bis (2-methyl propyl) ester (BDCe fraction). BDCe fraction was evaluated for the antiproliferative potential against human osteosarcoma MG-63, human neuroblastoma IMR-32, and human lung carcinoma A549 cell lines by MTT assay and exhibited GI50 values of 37.53 µM, 56.05 µM, and 47.12 µM, respectively. In MG-63 cells, the BDCe fraction increased the level of ROS and simultaneously decreased the mitochondria membrane potential (MMP) potential by arresting cells at the G0/G1 phase, suggesting the initiation of apoptosis. Western blotting analysis revealed the upregulation of p53, caspase3, and caspase9 while the expressions of p-NF-κB, p-Akt and Bcl-xl were decreased. RT-qPCR studies also showed upregulation in the expression of p53 and caspase3 and downregulation in the expression of CDK2, Bcl-2 and Cyclin E genes. Molecular docking analysis displayed the interaction between BDCe fraction with p53 (-151.13 kcal/mol) and CDK1 (-133.96 kcal/mol). The results of the present work suggest that the BDCe fraction has chemopreventive properties against osteosarcoma (MG-63) cells through the induction of cell cycle arrest and apoptosis via Akt/NF-κB/p53 pathways. This study contributes to the understanding of the utilization of BDCe fraction in osteosarcoma treatment.

The role of contrast-enhanced ultrasound in the evaluation of hepatobiliary lesions and its correlation with pathological findings.

Purpose: To evaluate the efficacy of contrast-enhanced ultrasound (CEUS) in assessing hepatobiliary lesions, and to correlate the findings of CEUS for hepatobiliary lesions with those of pathological examination performed through fine needle aspiration. Material and methods: This prospective observational study included 50 patients with hepatobiliary lesions, who were referred for CEUS. The findings of CEUS were correlated with pathological findings. Results: CEUS was determined to be a highly sensitive and specific imaging modality for the detection and characterization of hepatobiliary lesions, with the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of CEUS being 100.0%, 96.8%, 66.7%, 100.0%, and 96.7%, respectively, when correlated with pathological findings. Conclusions: CEUS is a highly sensitive and specific imaging modality for the detection and characterization of hepatobiliary lesions, with wide availability in the present scenario.

trans-Anethole Abrogates Cell Proliferation and Induces Apoptosis through the Mitochondrial-Mediated Pathway in Human Osteosarcoma Cells.

trans-Anethole, the major bioactive component of Illicium verum Hook. commonly known as star anise exhibits various pharmacological activities including anti-inflammatory, antimicrobial, insecticidal, and antitumor. Osteosarcoma is an extremely aggressive malignant bone tumor that affects children and young adults and accounts for around 60% of all sarcomas. The study was planned to evaluate the potential of trans-Anethole against Human osteosarcoma cell line MG-63. The antiproliferative activity of trans-Anethole was assessed by MTT assay. trans-Anethole exhibited apoptotic cell death as monitored by confocal/electron microscopy and flow cytometry studies. Modulation of gene expression was studied by Western blot and RT-PCR analysis. The present study revealed that trans-Anethole inhibited osteosarcoma proliferation in a dose-dependent manner with a GI50 value of 60.25 µM and showed pro-apoptotic activity as analyzed by Annexin V-FITC/PI assay. Flow cytometric analysis revealed that trans-Anethole induced cell cycle arrest at the G0/G1 phase with the generation of reactive oxygen species and reduction in mitochondrial membrane potential (ΔΨm). Immunoblotting results showed the increased expression of caspase-9/-3, p53, and decreased expression of Bcl-xL suggesting the involvement of the p53 and mitochondrial intrinsic pathway. This work provides a rationale that trans-Anethole might be considered as a promising chemotherapeutic/nutraceutical agent for the management of osteosarcoma.Highlightstrans-Anethole inhibited cell growth and caused G0/G1 arrest in Human osteosarcoma MG-63 cell line.trans-Anethole led to the loss of mitochondrial membrane permeability along with ROS generation.trans-Anethole upregulates the expression of p53, Caspase-9/-3, and downregulate Bcl-xL expression.

Hydrophilic and hydrophobic carboxamide pincers as anion hosts.

Hydrophobic and hydrophilic, monotopic and ditopic carboxamide pincer hosts containing ethyl, hexyl, 2-hydroxyethyl and 2-hydroxyethyl ethyl ether pendant arms were synthesized. Solubility trends indicated that solubilities in water or hydrocarbon solvents varied depending on the nature of the pendant arms. Binding constants for hydrophilic pincers were larger in general than their hydrophobic analogs. Significant synergistic binding effects for the ditopic hosts were not observed.

Novel Vitamin E TPGS based docetaxel nanovesicle formulation for its safe and effective parenteral delivery: Toxicological, pharmacokinetic and pharmacodynamic evaluation.

Docetaxel (DTX) is a highly lipophilic, BCS class IV drug with poor aqueous solubility (12.7 µg/mL). Presently, only injectable formulation is available in the market which uses a large amount of surfactant (Tween 80) and dehydrated alcohol as a solubilizer. High concentrations of Tween 80 in injectable formulations are associated with severe consequences i.e. nephrotoxicity, fluid retention, and hypersensitivity reactions. The present study aims to eliminate Tween 80, thus novel biocompatible surfactant Vitamin E TPGS based nanovesicle formulation of DTX (20 mg/mL) was developed and evaluated for different quality control parameters. Optimized nanovesicular formulation (NV-TPGS-3) showed nanometric size (102.9 ± 2.9 nm), spherical vesicular shape, high drug encapsulation efficiency (95.2 ± 0.5%), sustained-release profile and high dilution integrity with normal saline. In vitro cytotoxicity assay, showed threefold elevation in the IC50 value of the optimized formulation in comparison to the commercial formulation. Further, no mortality and toxicity were observed during 28 days repeated dose sub-acute toxicity studies in Swiss albino mice up to the dose of 138 mg/kg, whereas, commercial formulation showed toxicity at 40 mg/kg. In addition, in vivo anticancer activity on Ehrlich Ascites Carcinoma induced mice showed a significant tumour growth inhibition of 76.3 ± 5.3% with the NV-TPGS-3 treatment when compared to Ehrlich Ascites Carcinoma control. Results demonstrated that the developed Vitamin E TPGS based nanovesicular formulation of DTX could be a better alternative to increase its clinical uses with improved therapeutic efficacy, reduced toxicity and dosing frequency, and sustained drug release behaviour.

Near-IR oxime-based solvatochromic perylene diimide probe as a chemosensor for Pd species and Cu2+ ions in water and live cells.

A near-IR perylene diimide probe (OPR-PDI) containing an oxime-propargyl hybrid moiety at the bay position, was designed and synthesized for detection of Pd species and Cu2+ ions in 90% water, the solid state and MG-63 live cells. The aggregation tendency of OPR-PDI in different polarity solvents transmits solvatochromic and fluorochromic properties to differentiate certain organic solvents. Supramolecular aggregates of OPR-PDI in 90% water act as a dual chemosensor for palladium (Pd) species via de-propargylation or hydrolysis of the Schiff-base and Cu2+ ions via complexation with the O/N binding site with a low limit of detection (LOD) of the order of 7.9 × 10-8 M and 3.4 × 10-7 M respectively. TLC strips coated with OPR-PDI can be applied for sensing of Pd0 and Cu2+ ions in the solid state at levels as low as 34.6 ng cm-2 and 10.5 ng cm-2. OPR-PDI imprinted TLC strips could be used as paper sheets for writing coloured alphabets using Pd0 and Cu2+ ions as ink. Moreover, MTT assay showed that OPR-PDI has very low cytotoxicity (IC50 = 230 µM), good permeability, biocompatibility and can be applied for bio-imaging of Pd species and Cu2+ ions in MG-63 cells. DFT calculations, and cyclic voltammetric (CV) and NMR titration studies have also been discussed.

Multilevel genome typing: genomics-guided scalable resolution typing of microbial pathogens.

BackgroundBoth long- and short-term epidemiology are fundamental to disease control and require accurate bacterial typing. Genomic data resulting from implementation of whole genome sequencing in many public health laboratories can potentially provide highly sensitive and accurate descriptions of strain relatedness. Previous typing efforts using these data have mainly focussed on outbreak detection.AimWe aimed to develop multilevel genome typing (MGT), using consecutive multilocus sequence typing (MLST) schemes of increasing sizes, stepping up from seven-gene MLST to core genome MLST, to allow examination of genetic relatedness at multiple resolution levels.MethodsThe system was applied to Salmonellaenterica serovar Typhimurium. The MLST scheme used at each step (MGT level), defined a given MGT-level specific sequence type (ST). The list of STs generated from all of these increasing MGT levels, was named a genome type (GT). Using MGT, we typed 9,096 previously characterised isolates with publicly available data.ResultsOur approach could identify previously described S. Typhimurium populations, such as the DT104 multidrug resistance lineage (GT 19-2-11) and two invasive lineages of African isolates (GT 313-2-3 and 313-2-752). Further, we showed that MGT-derived clusters can accurately distinguish five outbreaks from each other and five background isolates.ConclusionMGT provides a universal and stable nomenclature at multiple resolutions for S. Typhimurium strains and could be implemented as an internationally standardised strain identification system. While established so far only for S. Typhimurium, the results here suggest that MGT could form the basis for typing systems in other similar microorganisms.

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway.

The tumor suppressor p53 and its homologues, p63 and p73, play a pivotal role in the regulation of the DNA damage response, cellular homeostasis, development, aging, and metabolism. A number of mouse studies have shown that a genetic defect in the p53 family could lead to spontaneous tumor development, embryonic lethality, or severe tissue abnormality, indicating that the activity of the p53 family must be tightly regulated to maintain normal cellular functions. While the p53 family members are regulated at the level of gene expression as well as post-translational modification, they are also controlled at the level of protein stability through the ubiquitin proteasomal pathway. Over the last 20 years, many ubiquitin E3 ligases have been discovered that directly promote protein degradation of p53, p63, and p73 in vitro and in vivo. Here, we provide an overview of such E3 ligases and discuss their roles and functions.