Miravirsen (SPC3649) can inhibit the biogenesis of miR-122

MicroRNAs (miRNAs) are short noncoding RNAs, which bind to messenger RNAs and regulate protein expression. The biosynthesis of miRNAs includes two precursors, a primary miRNA transcript (pri-miRNA) and a shorter pre-miRNA, both of which carry a common stem-loop bearing the mature miRNA. MiR-122 is a liver-specific miRNA with an important role in the life cycle of hepatitis C virus (HCV). It is the target of miravirsen (SPC3649), an antimiR drug candidate currently in clinical testing for treatment of HCV infections. Miravirsen is composed of locked nucleic acid (LNAs) ribonucleotides interspaced throughout a DNA phosphorothioate sequence complementary to mature miR-122. The LNA modifications endow the drug with high affinity for its target and provide resistance to nuclease degradation. While miravirsen is thought to work mainly by hybridizing to mature miR-122 and blocking its interaction with HCV RNA, its target sequence is also present in pri- and pre-miR-122. Using new in vitro and cellular assays specifically developed to discover ligands that suppress biogenesis of miR-122, we show that miravirsen binds to the stem-loop structure of pri- and pre-miR-122 with nanomolar affinity, and inhibits both Dicer- and Drosha-mediated processing of miR-122 precursors. This inhibition may contribute to the pharmacological activity of the drug in ma

All-Atom Simulations Uncover Structural and Dynamical Properties of STING Proteins in the Membrane System

Recent studies have shown that the stimulator of interferon gene (STING) protein plays a central role in the immune system by facilitating the production of Type I interferons in cells. The STING signaling pathway is also a prominent activator of cancer-killing T cells that initiates a powerful adaptive immune response. Since biomolecular signaling pathways are complicated and not easily identified through traditional experiments, molecular dynamics (MD) has often been used to study these biological pathways’ structural and dynamical responses. Here, we carried out MD simulations for full-length chicken and human STING (chSTING and hSTING) proteins. Specifically, we investigated ligand-bound closed and ligand-unbound open forms of each STING in the membrane system by comparing conformational and dynamical differences among them. Our research provides clues for understanding the mechanism of the STING signaling pathway by uncovering some detailed insights for the examined systems: the residues from each chain in the binding pocket are strongly correlated to one another in the open STING structure compared with those in the closed STING structure. Ligand-bound closed STING displays approximately 170° rotation of the ligand-binding domain (LBD) relative to the open-STING structure. The detailed dynamical analysis of residue Cys148 in the linker region of hSTING does not support the earlier hypothesis that Cys148 can form disulfide bonds between adjacent STING dimers. We also reveal that using the full-length proteins is critical as the MD simulations of the LBD portion only cannot properly describe the global conformational properties of multiple domain proteins, such as STING

Che razza di letteratura è? Intersezioni di diversità nella letteratura italiana contemporanea

La forza performativa della finzione letteraria costituisce il punto di partenza di questo studio che, attraverso un nuovo approccio critico, prende in esame i modi con cui la letteratura riesce sia a rappresentare, sia a produrre nuove realtà. Nell’analizzare opere quali Il paese dove non si muore mai (Ornela Vorpsi, 2005) e Timira. Romanzo meticcio (Isabella Marincola, Antar Mohamed e Wu Ming 2, 2012) questo studio applica per la prima volta un approccio pienamente intersezionale ai testi della letteratura legata alle migrazioni. Esso mostra come l’efficacia delle figure letterarie della diversità messe in scena in questi romanzi sia esito di una sottile tessitura, che fa interagire tra loro fattori connessi al genere, all’estrazione socio-culturale e all’appartenenza/esclusione a un gruppo

A landmark federal interagency collaboration to promote data science in health care: Million Veteran Program-Computational Health Analytics for Medical Precision to Improve Outcomes Now

ObjectivesIn 2016, the Department of Veterans Affairs (VA) and the Department of Energy (DOE) established an Interagency Agreement (IAA), the Million Veteran Program-Computational Health Analytics for Medical Precision to Improve Outcomes Now (MVP-CHAMPION) research collaboration.Materials and methodsOversight fell under the VA Office of Research Development (VA ORD) and DOE headquarters. An Executive Committee and 2 senior scientific liaisons work with VA and DOE leadership to optimize efforts in the service of shared scientific goals. The program supported centralized data management and genomic analysis including creation of a scalable approach to cataloging phenotypes. Cross-cutting methods including natural language processing, image processing, and reusable code were developed.ResultsThe 79.6 million dollar collaboration has supported centralized data management and genomic analysis including a scalable approach to cataloging phenotypes and launched over 10 collaborative scientific projects in health conditions highly prevalent in veterans. A ground-breaking analysis on the Summit and Andes supercomputers at the Oak Ridge National Laboratory (ORNL) of the genetic underpinnings of over 2000 health conditions across 44 million genetic variants which resulted in the identification of 38 270 independent genetic variants associating with one or more health traits. Of these, over 2000 identified associations were unique to non-European ancestry. Cross-cutting methods have advanced state-of-the-art artificial intelligence (AI) including large language natural language processing and a system biology study focused on opioid addiction awarded the 2018 Gordon Bell Prize for outstanding achievement in high-performance computing. The collaboration has completed work in prostate cancer, suicide prevention, and cardiovascular disease, and cross-cutting data science. Predictive models developed in these projects are being tested for application in clinical management.DiscussionEight new projects were launched in 2023, taking advantage of the momentum generated by the previous collaboration. A major challenge has been limitations in the scope of appropriated funds at DOE which cannot currently be used for health research.ConclusionExtensive multidisciplinary interactions take time to establish and are essential to continued progress. New funding models for maintaining high-performance computing infrastructure at the ORNL and for supporting continued collaboration by joint VA-DOE research teams are needed

Digital interprofessional communication with families in a cardiac surgery unit: insights from the pandemic.

BACKGROUND The COVID-19 pandemic entailed cutting off the usual access to hospitals, denying patients daily visits from their relatives and friends. The standard communication between medical staff and relatives also suffered, with a perceived negative impact on overall care. We developed an electronic communication solution to re-establish a proactive daily communication with patients' families. METHODS The communication software allowed families to receive daily interprofessional (medical, nursing, and physiotherapy) updates by text message, on patients' postoperative clinical state. Appreciation and performance of this communication was evaluated through a prospective randomised study. Two groups were compared (group D, 32 patients "Digital" receiving daily SMS, and group S, 16 patients "Standard" without SMS), assessing satisfaction through dedicated surveys under COVID-19 restrictions. Moreover, private outgoing vs. incoming communication flow between patients and their relatives (phone calls and text messages, for both groups) were analysed at different timeframes of the postoperative hospital stay. RESULTS Mean age of the population was 66 ± 7 years for both groups. The digital communication service was successfully adopted in group D in all cases, sending overall 155 communications (4.84 per patient). Calls received from relatives were 13 in group D vs. 22 in group S (0.4 vs. 1.4 calls per patient, p = 0.002). Patients' outgoing vs. incoming traffic flow was equal in the two groups for every timeframe (first two postoperative days vs. the rest), independently from digital communication. Comparing satisfaction of communication (from 1 to 7), level of information and understandability resulted in 6.7 in group D vs. 5.6 in group S (p = 0.004). Appreciation of digital communication was highest during the first three postoperative days. CONCLUSION The restrictions caused by the COVID-19 pandemic generated simple and effective ideas on digital solutions for interprofessional communication. Offering this digital service, which complements rather than replace the classic communication, eased the need of the families to be informed and significantly enhanced the overall satisfaction regarding the healthcare service. SUMMARY The COVID-19 pandemic has interrupted access to hospital patients and cut off physical contact, denying patients, their families, and medical staff the necessary constant communication about the progress of their stay. It has become necessary, therefore, to compensate for the lack of "physical" face-to-face interaction by introducing innovative digital communication solutions. Our interprofessional project aims to assess the overall satisfaction and acceptance of digital communication service between the hospital and the families, updating on postoperative clinical condition of patients. Specifically, the introduction of a digital communication module attached to the electronic patient record allows relatives to be informed on a daily basis. The development of this module/software enabled families to receive daily, interprofessional and proactive digital updates, on their relative ones' postoperative stay

An analysis and evaluation of the WeFold collaborative for protein structure prediction and its pipelines in CASP11 and CASP12

Every two years groups worldwide participate in the Critical Assessment of Protein Structure Prediction (CASP) experiment to blindly test the strengths and weaknesses of their computational methods. CASP has significantly advanced the field but many hurdles still remain, which may require new ideas and collaborations. In 2012 a web-based effort called WeFold, was initiated to promote collaboration within the CASP community and attract researchers from other fields to contribute new ideas to CASP. Members of the WeFold coopetition (cooperation and competition) participated in CASP as individual teams, but also shared components of their methods to create hybrid pipelines and actively contributed to this effort. We assert that the scale and diversity of integrative prediction pipelines could not have been achieved by any individual lab or even by any collaboration among a few partners. The models contributed by the participating groups and generated by the pipelines are publicly available at the WeFold website providing a wealth of data that remains to be tapped. Here, we analyze the results of the 2014 and 2016 pipelines showing improvements according to the CASP assessment as well as areas that require further adjustments and research