Barriers in establishing systematic diabetic retinopathy screening through telemedicine in low- and middle-income countries.

Vision-threatening diabetic retinopathy (VTDR) is one of the leading causes of impaired vision in the working-age population. Early identification, timely diagnosis, and prompt treatment of VTDR have to be tackled simultaneously to reduce the rate of blindness due to this condition. Considerable emphasis has been placed globally on establishing diabetic retinopathy screening (DRS) programs to enable early identification and referral of VTDR for treatment. However, there is an urgent need to shift from the common practice of opportunistic screening to a systematic DRS pathway to ensure that individuals with diabetes are screened at regular intervals and treated appropriately. While systematic DRS programs have been successfully established in countries such as the United Kingdom (UK), it continues to be a challenge to initiate and sustain such programs in low- and middle-income countries (LMIC), home to approximately 80% of people with diabetes. Telemedicine is widely recognized as an ideal DRS screening program. Although it has resulted in an upsurge of opportunistic screening, systematic recall of screened patients remains a challenge. In addition, the link between referred patients from the telemedicine programs to treatment centers is often not established or has failed to deliver; so, there is minimal impact of these telemedicine programs on VTDR blindness at present. This review covers the various barriers of establishing and sustaining systematic telemedicine DRS programs, especially in resource-constrained settings, and the challenges in aligning telemedicine to VTDR treatment pathways to ensure patients with VTDR are treated promptly and effectively.

Molecular docking-aided identification of small molecule inhibitors targeting ß-catenin-TCF4 interaction.

Here we report a molecular docking-based approach to identify small molecules that can target the ß-catenin (ß-cat)-TCF4 protein-protein interaction (PPI), a key effector complex for nuclear Wnt signaling activity. Specifically, we developed and optimized a computational model of ß-cat using publicly available ß-cat protein crystal structures, and existing ß-cat-TCF4 interaction inhibitors as the training set. Using our computational model to an in silico screen predicted 27 compounds as good binders to ß-cat, of which 3 were identified to be effective against a Wnt-responsive luciferase reporter. In vitro functional validation experiments revealed GB1874 as an inhibitor of the Wnt pathway that targets the ß-cat-TCF4 PPI. GB1874 also affected the proliferation and stemness of Wnt-addicted colorectal cancer (CRC) cells in vitro. Encouragingly, GB1874 inhibited the growth of CRC tumor xenografts in vivo, thus demonstrating its potential for further development into therapeutics against Wnt-associated cancer indications.

Quantitative mapping of the cellular small RNA landscape with AQRNA-seq.

Current next-generation RNA-sequencing (RNA-seq) methods do not provide accurate quantification of small RNAs within a sample, due to sequence-dependent biases in capture, ligation and amplification during library preparation. We present a method, absolute quantification RNA-sequencing (AQRNA-seq), that minimizes biases and provides a direct, linear correlation between sequencing read count and copy number for all small RNAs in a sample. Library preparation and data processing were optimized and validated using a 963-member microRNA reference library, oligonucleotide standards of varying length, and RNA blots. Application of AQRNA-seq to a panel of human cancer cells revealed >800 detectable miRNAs that varied during cancer progression, while application to bacterial transfer RNA pools, with the challenges of secondary structure and abundant modifications, revealed 80-fold variation in tRNA isoacceptor levels, stress-induced site-specific tRNA fragmentation, quantitative modification maps, and evidence for stress-induced, tRNA-driven, codon-biased translation. AQRNA-seq thus provides a versatile means to quantitatively map the small RNA landscape in cells.

Internal mammary harvesting: Techniques and evidence from the literature.

Coronary artery bypass graft (CABG) is one of the most commonly performed cardiac surgeries in the world. CABG using the internal mammary artery (IMA) remains the gold standard intervention for myocardial intervention in multivessel coronary artery disease. IMA harvesting can be performed with various techniques and approaches: pedicled vs skeletonized harvesting technique as well as approaches such as conventional sternotomy, robotic and endoscopic approaches. While each technique and approach have their respective advantages and disadvantages, evidence remains varied between cohorts. Traditionally, IMA has been used as an in situ conduit; however, IMA free grafts also provide satisfactory outcomes in certain situations. This literature review aims to explore the efficacy of different techniques and approaches of IMA harvesting and grafting. With evidence compiled, this will provide an overview of the complexity of CABG and locate gaps in current literature to direct future research.

Dynamic expression of tRNA-derived small RNAs define cellular states.

Transfer RNA (tRNA)-derived small RNAs (tsRNAs) have recently emerged as important regulators of protein translation and shown to have diverse biological functions. However, the underlying cellular and molecular mechanisms of tsRNA function in the context of dynamic cell-state transitions remain unclear. Expression analysis of tsRNAs in distinct heterologous cell and tissue models of stem vs. differentiated states revealed a differentiation-dependent enrichment of 5'-tsRNAs. We report the identification of a set of 5'-tsRNAs that is upregulated in differentiating mouse embryonic stem cells (mESCs). Notably, interactome studies with differentially enriched 5'-tsRNAs revealed a switch in their association with "effector" RNPs and "target" mRNAs in different cell states. We demonstrate that specific 5'-tsRNAs can preferentially interact with the RNA-binding protein, Igf2bp1, in the RA-induced differentiated state. This association influences the transcript stability and thereby translation of the pluripotency-promoting factor, c-Myc, thus providing a mechanistic basis for how 5'-tsRNAs can modulate stem cell states in mESCs. Together our study highlights the role of 5'-tsRNAs in defining distinct cell states.