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The mitotic kinase AURORA-A is essential for cell cycle progression and is considered a priority cancer target. Although the catalytic activity of AURORA-A is essential for its mitotic function, recent reports indicate an additional non-catalytic function, which is difficult to target by conventional small molecules. We therefore developed a series of chemical degraders (PROTACs) by connecting a clinical kinase inhibitor of AURORA-A to E3 ligase-binding molecules (for example, thalidomide). One degrader induced rapid, durable and highly specific degradation of AURORA-A. In addition, we found that the degrader complex was stabilized by cooperative binding between AURORA-A and CEREBLON. Degrader-mediated AURORA-A depletion caused an S-phase defect, which is not the cell cycle effect observed upon kinase inhibition, supporting an important non-catalytic function of AURORA-A during DNA replication. AURORA-A degradation induced rampant apoptosis in cancer cell lines and thus represents a versatile starting point for developing new therapeutics to counter AURORA-A function in cancer. A bifunctional AURORA-A degrader induces the fast and specific degradation of this kinase in cancer cell lines, which enables targeting of non-catalytic, oncogenic functions of AURORA-A resulting in S-phase arrest and rampant apoptosis.

Cell membrane coated nanoparticles (NPs) is a biomimetic strategy developed to engineer therapeutic devices consisting of a NP core coated with membrane derived from natural cells such as erythrocytes, white blood cells, cancer cells, stem cells, platelets or bacterial cells. These biomimetic NPs have gained a lot of attention recently owing to their cell surface mimetic features and tailored nanomaterial characteristics. They have shown strong potential in diagnostic and therapeutic applications including those in drug delivery, immune modulation, vaccination and detoxification. Herein we review the various types of cell membrane coated NPs reported in the literature and the unique strengths of these biomimetic NPs with an emphasis on how these bioinspired camouflage strategies have led to improved therapeutic efficacy. We also highlight the recent progress made by each platform in advancing healthcare and precis the major challenges associated with these NPs.

The contribution of deubiquitylating enzymes (DUBs) to β-Catenin stabilization in intestinal stem cells and colorectal cancer (CRC) is poorly understood. Here, and by using an unbiassed screen, we discovered that the DUB USP10 stabilizes β-Catenin specifically in APC-truncated CRC in vitro and in vivo. Mechanistic studies, including in vitro binding together with computational modelling, revealed that USP10 binding to β-Catenin is mediated via the unstructured N-terminus of USP10 and is outcompeted by intact APC, favouring β-catenin degradation. However, in APC-truncated cancer cells USP10 binds to β-catenin, increasing its stability which is critical for maintaining an undifferentiated tumour identity. Elimination of USP10 reduces the expression of WNT and stem cell signatures and induces the expression of differentiation genes. Remarkably, silencing of USP10 in murine and patient-derived CRC organoids established that it is essential for NOTUM signalling and the APC super competitor-phenotype, reducing tumorigenic properties of APC-truncated CRC. These findings are clinically relevant as patient-derived organoids are highly dependent on USP10, and abundance of USP10 correlates with poorer prognosis of CRC patients. Our findings reveal, therefore, a role for USP10 in CRC cell identity, stemness, and tumorigenic growth by stabilising β-Catenin, leading to aberrant WNT signalling and degradation resistant tumours. Thus, USP10 emerges as a unique therapeutic target in APC truncated CRC.

We have designed and developed a simple, visual, and narrative K-12 cybersecurity curriculum leveraging the Scratch programming platform to demonstrate and teach fundamental cybersecurity concepts such as confidentiality, integrity protection, and authentication. The visual curriculum simulates a real-world scenario of a user and a bank performing a bank transaction and an adversary attempting to attack the transaction.We have designed six visual scenarios, the curriculum first introduces students to three visual scenarios demonstrating attacks that exist when systems do not integrate concepts such as confidentiality, integrity protection, and authentication. Then, it introduces them to three visual scenarios that build on the attacks to demonstrate and teach how these fundamental concepts can be used to defend against them. We conducted an evaluation of our curriculum through a study with 18 middle and high school students. To evaluate the student's comprehension of these concepts we distributed a technical survey, where overall average of students answering these questions related to the demonstrated concepts is 9.28 out of 10. Furthermore, the survey results revealed that 66.7% found the system extremely easy and the remaining 27.8% found it easy to use and understand.

This paper describes the design and evaluation of DSAScratch, an extension to Scratch, a widely used block-based programming language. The DSAScratch framework implements advanced data structures such as arrays, sets, dictionaries, and searching and sorting algorithms. By presenting these concepts in an intuitive block-based interface, these blocks abstract away technical details and simplify data structures and algorithms concepts for K-12 students to grasp and apply to programming problems more readily. A preliminary evaluation of the tool's usability and learning outcomes is presented in this paper. Given the information we have gathered about DSAScratch, we show that the extension is beneficial for students to develop a deeper understanding of programming and an intuitive understanding of these concepts in high school. We present the methodology and preliminary results of a user study conducted with ten high school students. During the user study, 70% of the participants understood the key ideas behind DSAScratch implemented data structures and algorithms through a mixture of lectures and hands-on activities. We show that DSAScratch was also an important part of the workshop for 90% of the students who participated, as it enhanced their understanding of algorithms and data structures. Furthermore, they indicated that they would recommend DSAScratch to their peers.

The PAN-INDIA 1000 SARS-CoV-2 RNA Genome Sequencing Consortium has achieved its initial goal of completing the sequencing of 1000 SARS-CoV-2 genomes from nasopharyngeal and oropharyngeal swabs collected from individuals testing positive for COVID-19 by Real Time PCR. The samples were collected across 10 states covering different zones within India. Given the importance of this information for public health response initiatives investigating transmission of COVID-19, the sequence data is being released in GISAID database. This information will improve our understanding on how the virus is spreading, ultimately helping to interrupt the transmission chains, prevent new cases of infection, and provide impetus to research on intervention measures. This will also provide us with information on evolution of the virus, genetic predisposition (if any) and adaptation to human hosts. One thousand and fifty two sequences were used for phylodynamic, temporal and geographic mutation patterns and haplotype network analyses. Initial results indicate that multiple lineages of SARS-CoV-2 are circulating in India, probably introduced by travel from Europe, USA and East Asia. A2a (20A/B/C) was found to be predominant, along with few parental haplotypes 19A/B. In particular, there is a predominance of the D614G mutation, which is found to be emerging in almost all regions of the country. Additionally, mutations in important regions of the viral genome with significant geographical clustering have also been observed. The temporal haplotype diversities landscape in each region appears to be similar pan India, with haplotype diversities peaking between March-May, while by June A2a (20A/B/C) emerged as the predominant one. Within haplotypes, different states appear to have different proportions. Temporal and geographic patterns in the sequences obtained reveal interesting clustering of mutations. Some mutations are present at particularly high frequencies in one state as compared to others. The negative estimate Tajimas D (D = −2.26817) is consistent with the rapid expansion of SARS-CoV-2 population in India. Detailed mutational analysis across India to understand the gradual emergence of mutants at different regions of the country and its possible implication will help in better disease management.