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Penetrating thoracic aortic injuries (PTAI) represent a rare form of thoracic trauma. Unlike blunt thoracic aortic injuries (BTAI), only scarce data, included in small case series, are currently available for PTAI. The purpose of this study was to describe injury patterns, surgical management, and outcomes of patients with PTAI and compare to those with BTAI.A 9-y retrospective cohort study (2007-2015) was conducted using the National Trauma Data Bank. Patient demographics, injury profile, procedures performed, and patient outcomes were compared between the PTAI and BTAI group.A total of 2714 patients with PTAI and 14,037 patients with BTAI were identified. Compared to BTAI, PTAI patients were younger (28 versus 42 y, P 0.001), more often male (89.1% versus 71.7%, P 0.001), and more likely to arrive without signs of life (27.6% versus 7.5%, P 0.001). PTAI patients had less associated injuries, overall, compared to those with BTAI; however, were more likely to have injuries to the esophagus, diaphragm, and heart. Patients with PTAI were less likely to undergo endovascular (5.8% versus 30.5%, P 0.001) or open surgical repair (3.0% versus 4.2%, P 0.001) compared to BTAI. While the large majority of PTAI patients expired before their hospital arrival or in the emergency department, the in-hospital mortality rate among those who survivedemergency department stay was 43.1%.Most patients with PTAI present to the hospital without any signs of life, and their overall mortality rate is extremely high. Only a small portion of PTAI patients who survived the initial resuscitation period underwent surgical interventions for thoracic aortic injuries. Further studies are still warranted to clarify the indications and types of surgical interventions for PTAI.

Pathogenic variation in BRCA1 and BRCA2 (BRCA) causes high risk of breast and ovarian cancer, and BRCA variation data are important markers for BRCA-related clinical cancer applications. However, comprehensive BRCA variation data are lacking from the Asian population despite its large population size, heterogenous genetic background and diversified living environment across the Asia continent. We performed a systematic study on BRCA variation in Asian population including extensive data mining, standardization, annotation and characterization. We identified 7587 BRCA variants from 685 592 Asian individuals in 40 Asia countries and regions, including 1762 clinically actionable pathogenic variants and 4915 functionally unknown variants (https://genemutation.fhs.um.edu.mo/Asian-BRCA/). We observed the highly ethnic-specific nature of Asian BRCA variants between Asian and non-Asian populations and within Asian populations, highlighting that the current European descendant population-based BRCA data is inadequate to reflect BRCA variation in the Asian population. We also provided archeological evidence for the evolutionary origin and arising time of Asian BRCA variation. We further provided structural-based evidence for the deleterious variants enriched within the functionally unknown Asian BRCA variants. The data from our study provide a current view of BRCA variation in the Asian population and a rich resource to guide clinical applications of BRCA-related cancer for the Asian population.

Large quantity of variants of uncertain significance (VUS) has been identified in cancer predisposition genes, but classification of VUS remains a big challenge. We proposed that the impact of VUS on protein structure stability can be used to identify these with deleterious effects by using molecular dynamics simulation (MDS)-based approach and developed a MDS-based method for missense VUS classification. In the current study, we applied the system to classify the missense VUS in BRCA2. BRCA2 plays an important role in maintaining genome stability by repairing double-strand DNA damage through homologous recombination. BRCA2 BRC repeats bring RAD51 from cytoplasm to the break sites in nucleus to initiate the repairing process. Missense variants in BRCA2 BRC repeats can interfere the interaction between BRCA2 and RAD51, impair double-strand break repair, cause genome instability and increase cancer risk. We characterized the missense VUS in BRCA2 BRC4 repeat, the primary site of BRCA2 interacting with RAD51. Based on the well-determined BRC4 structure, we applied MDS to measure the impact of BRC4 missense VUS on the stability of BRC4 structure by testing the equilibrium state, flexibility, compactness, hydrogen bonds and surface accessibility. Of the 46 missense VUS analyzed, we were able to differentiate them into 24 Deleterious and 22 Tolerated variants. Comparison between the MDS-based and other 24 existing computational methods for variant classification showed that the MDS-based approach is highly sensitive and specific for classifying missense VUS in cancer predisposition genes.

The SNO+ experiment is a large-scale, multipurpose neutrino experiment situated 2 km underground at SNOLAB in Canada. Successor to the Sudbury Neutrino Observatory, the SNO+ detector has inherited much of the original infrastructure including the 12-m diameter acrylic vessel which serves as the main detector body. Initially filled with ultrapure water, the SNO+ experiment has completed operations as a water Cherenkov detector, having set new limits on multiple invisible nucleon decay modes, performed measurements on $^8\mathrm{B}$ solar neutrinos, and made the first observation of reactor antineutrinos in pure water. The detector medium has now been replaced with liquid scintillator, and a new physics programme is being pursued including measurements of solar neutrinos and $\Delta\mathrm{m}^2_{12}$ from reactor antineutrinos. The liquid scintillator will be doped with >4 tonnes of $^{\mathrm{nat}}\mathrm{Te}$ to enable a search for neutrinoless double beta decay., Comment: 5 pages, 1 figure

Loss of proteostasis can occur due to mutations, the formation of aggregates, or general deficiency in the correct translation and folding of proteins. These phenomena are commonly observed in pathologies, but most significantly, loss of proteostasis characterizes aging. This loss leads to the chronic activation of stress responses and has a generally deleterious impact on the organism. While finding molecules that can alleviate these symptoms is an important step toward solutions for these conditions, some molecules might be mischaracterized on the way. 4-phenylbutyric acid (4PBA) is known for its role as a chemical chaperone that helps alleviate endoplasmic reticulum (ER) stress, yet a scan of the literature reveals that no biochemical or molecular experiments have shown any protein refolding capacity. Here, we show that 4PBA is a conserved weak inhibitor of mRNA translation, both in vitro and in cellular systems, and furthermore-it does not promote protein folding nor prevents aggregation. 4PBA possibly alleviates proteostatic or ER stress by inhibiting protein synthesis, allowing the cells to cope with misfolded proteins by reducing the protein load. Better understanding of 4PBA biochemical mechanisms will improve its usage in basic science and as a drug in different pathologies, also opening new venues for the treatment of different diseases.

Graphical abstract, The wide application of new DNA sequencing technologies is generating vast quantities of genetic variation data at unprecedented speed. Developing methodologies to decode the pathogenicity of the variants is imperatively demanding. We hypothesized that as deleterious variants may function through disturbing structural stability of their affected proteins, information from structural change caused by genetic variants can be used to identify the variants with deleterious effects. In order to measure the structural change for proteins with large size, we designed a method named RP-MDS composed of Ramachandran plot (RP) and Molecular Dynamics Simulation (MDS). Ramachandran plot captures the variant-caused secondary structural change, whereas MDS provides a quantitative measure for the variant-caused globular structural change. We tested the method using variants in TP53 DNA binding domain of 219 residues as the model. In total, RP-MDS identified 23 of 38 (60.5%) TP53 known Pathogenic variants and 17 of 42 (41%) TP53 VUS that caused significant changes of P53 structure. Our study demonstrates that RP-MDS method provides a powerful protein structure-based tool to screen deleterious genetic variants affecting large-size proteins.

Purpose: The 3 Wishes Project (3WP) promotes holistic end-of-life care in the intensive care unit (ICU) to honor dying patients, support families, and encourage clinician compassion. Organ donation is a wish that is sometimes made by, or on behalf of, critically ill patients. Our objective was to describe the interface between the 3WP and organ donation as experienced by families, clinicians, and organ donation coordinators. Methods: In a multicenter evaluation of the 3WP in 4 Canadian ICUs, we conducted a thematic analysis of transcripts from interviews and focus groups with clinicians, organ donation coordinators, and families of dying or died patients for whom donation was considered. Results: We analyzed transcripts from 26 interviews and 2 focus groups with 18 family members, 17 clinicians, and 6 organ donation coordinators. The central theme describes the mutual goals of the 3WP and organ donation—emphasizing personhood and agency across the temporal continuum of care. During family decision-making, conversations encouraged by the 3WP can facilitate preliminary discussions about donation. During preparation for donation, memory-making activities supported by the 3WP redirect focus toward personhood. During postmortem family care, the 3WP supports families, including when donation is unsuccessful, and highlights aspirational pursuits of donation while encouraging reflections on other fulfilled wishes. Conclusions: Organ donation and the 3WP provide complementary opportunities to engage in value-based conversations during the dying process. The shared values of these programs may help to incorporate organ donation and death into a person’s life narrative and incorporate new life into a person’s death narrative.

Multilegged robots have the ability to perform stable locomotion on relatively rough terrain. However, the complexity of legged robots over wheeled or tracked robots make them difficult to control. This paper presents OpenSHC (Open-source Syropod High-level Controller), a versatile high-level controller {capable of generating gaits and poses for quasi-static multilegged robots, both simulated and with real hardware implementations. With full Robot Operating System (ROS) integration, the controller can be quickly deployed on robots with different actuators and sensor payloads}. The flexibility of OpenSHC is demonstrated on the 30 degrees of freedom hexapod Bullet, analysing the energetic performance of various leg configurations, kinematic arrangements and gaits over different locomotion speeds. With OpenSHC being easily configured to different physical and locomotion specifications, a hardware-based parameter space search for optimal locomotion parameters is conducted. The experimental evaluation shows that the mammalian configuration offers lower power consumption across a range of step frequencies; with the insectoid configuration providing performance advantages at higher body velocities and increased stability at low step frequencies. OpenSHC is open-source and able to be configured for various number of joints and legs., 17 pages, 23 figures, in IEEE Access

The COVID-19 pandemics by SARS-CoV-2 causes catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to ACE2 receptor in host cell membrane. The evolving of SARS-CoV-2 constantly generates new mutations across its genome including RBD. Besides the well-known single mutation in RBD, the recent new mutation strains with RBD “double mutation” is causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of the double mutated strains could be attributed to the alteration of mutated RBD to ACE2 receptor, the molecular details remains to be unclear. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation and antibody escaping, we investigated the relationship between ACE2 receptor and the RBD double mutant L452R/T478K (delta), L452R/E484Q (kappa) and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered RBD structure, led to enhanced binding affinity of mutated RBD to ACE2 receptor, leading to increased transmissibility of SARS-CoV-2 to the host cells.

Background As the number of households with dogs in the United States has increased, so has the incidence of dog bites. Contemporary analysis of nationwide epidemiological data regarding such injuries is scarce. The purpose of this study is to describe dog bite injury patterns and related surgical interventions with a focus on differences between pediatric and adult age groups. Study Design This is a retrospective study (2015-2017) using the National Trauma Data Bank. 10 569 patients were included. Results Of these, 4729 (44.7%) qualified as pediatric (age ≤ 12 years) and 5840 (55.3%) qualified as adults (age ≥ 13 years). Pediatric patients were more frequently admitted with facial injuries (78.1% vs. 29.3%, P < .01) and facial fractures (4.8% vs. 2.5%, P < .01), and had a higher incidence of facial bone surgical procedures (1.3% vs. .5%, P < .01). Adult patients were more frequently admitted with upper extremity injuries (65.8% vs. 21.2%, P < .01) and upper extremity vascular arterial injuries (2.3% vs. .2%, P < .01) with a higher incidence of upper extremity arterial procedures (1.3% vs. .2%, P < .01). Conclusion This study demonstrates the contrast in injury patterns from dog bite between adults and children. These findings can dictate injury prevention policies and prepare clinicians to treat dog bite victims.

M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50 values, which were significantly improved over standard antibiotic drugs.

Heterogeneous teams of robots, leveraging a balance between autonomy and human interaction, bring powerful capabilities to the problem of exploring dangerous, unstructured subterranean environments. Here we describe the solution developed by Team CSIRO Data61, consisting of CSIRO, Emesent, and Georgia Tech, during the DARPA Subterranean Challenge. These presented systems were fielded in the Tunnel Circuit in August 2019, the Urban Circuit in February 2020, and in our own Cave event, conducted in September 2020. A unique capability of the fielded team is the homogeneous sensing of the platforms utilized, which is used to obtain a decentralized multi-agent SLAM solution on each platform (both ground agents and UAVs) using peer-to-peer communications. This approach enabled a shift in focus from constructing a pervasive communications network to relying on multi-agent autonomy, motivated by experiences in early circuit events. These experiences also showed the surprising capability of rugged tracked platforms for challenging terrain, which in turn led to the heterogeneous team structure based on a BIA5 OzBot Titan ground robot and an Emesent Hovermap UAV, supplemented by smaller tracked or legged ground robots. The ground agents use a common CatPack perception module, which allowed reuse of the perception and autonomy stack across all ground agents with minimal adaptation.

BackgroundIdentifying genetic disease-susceptible individuals through population screening is considered as a promising approach for disease prevention. DNA mismatch repair (MMR) genes including MLH1, MSH2, MSH6 and PMS2 play essential roles in maintaining microsatellite stability through DNA mismatch repair, and pathogenic variation in MMR genes causes microsatellite instability and is the genetic predisposition for cancer as represented by the Lynch syndrome. While the prevalence and spectrum of MMR variation has been extensively studied in cancer, it remains largely elusive in the general population. Lack of the knowledge prevents effective prevention for MMR variation–caused cancer. In the current study, we addressed the issue by using the Chinese population as a model.MethodsWe performed extensive data mining to collect MMR variant data from 18 844 ethnic Chinese individuals and comprehensive analyses for the collected MMR variants to determine its prevalence, spectrum and features of the MMR data in the Chinese population.ResultsWe identified 17 687 distinct MMR variants. We observed substantial differences of MMR variation between the general Chinese population and Chinese patients with cancer, identified highly Chinese-specific MMR variation through comparing MMR data between Chinese and non-Chinese populations, predicted the enrichment of deleterious variants in the unclassified Chinese-specific MMR variants, determined MMR pathogenic prevalence of 0.18% in the general Chinese population and determined that MMR variation in the general Chinese population is evolutionarily neutral.ConclusionOur study provides a comprehensive view of MMR variation in the general Chinese population, a resource for biological study of human MMR variation, and a reference for MMR-related cancer applications.

Background Scaling-up and sustaining healthcare interventions can be challenging. Our objective was to describe how the 3 Wishes Project (3WP), a personalized end-of-life intervention, was scaled-up and sustained in an intensive care unit (ICU). Methods In a longitudinal mixed-methods study from January 12,013 - December 31, 2018, dying patients and families were invited to participate if the probability of patient death was > 95% or after a decision to withdraw life support. A research team member or bedside clinician learned more about each of the patients and their family, then elicited and implemented at least 3 personalized wishes for patients and/or family members. We used a qualitative descriptive approach to analyze interviews and focus groups conducted with 25 clinicians who cared for the enrolled patients. We used descriptive statistics to summarize patient, wish, and clinician characteristics, and analyzed outcome data in quarters using Statistical Process Control charts. The primary outcome was enrollment of terminally ill patients and respective families; the secondary outcome was the number of wishes per patient; tertiary outcomes included wish features and stakeholder involvement. Results Both qualitative and quantitative analyses suggested a three-phase approach to the scale-up of this intervention during which 369 dying patients were enrolled, having 2039 terminal wishes implemented. From a research project to clinical program to an approach to practice, we documented a three-fold increase in enrolment with a five-fold increase in total wishes implemented, without a change in cost. Beginning as a study, the protocol provided structure; starting gradually enabled frontline staff to experience and recognize the value of acts of compassion for patients, families, and clinicians. The transition to a clinical program was marked by handover from the research staff to bedside staff, whereby project catalysts mentored project champions to create staff partnerships, and family engagement became more intentional. The final transition involved empowering staff to integrate the program as an approach to care, expanding it within and beyond the organization. Conclusions The 3WP is an end-of-life intervention which was implemented as a study, scaled-up into a clinical program, and sustained by becoming integrated into practice as an approach to care.

Rationale The end of life (EOL) experience in the intensive care unit (ICU) can be psychologically distressing. The 3 Wishes Project (3WP) personalizes the EOL experience by carrying out wishes for dying patients and their families. While the 3WP has been integrated in academic, tertiary care ICUs, implementing this project in a community ICU has yet to be described. Objectives To examine facilitators of, and barriers to, implementing the 3WP in a community ICU from the clinician and key-stakeholder perspective. Methods This mixed-method study evaluated the implementation of the 3WP in a 20-bed community ICU in Southern Ontario, Canada. Patients were considered for the 3WP if they had a high likelihood of imminent death or planned withdrawal of life-sustaining therapy. Quantitative data include patient demographic data and wishes implemented. Following the qualitative descriptive approach, semi-structured interviews were conducted with purposively sampled clinicians and key-stakeholders. Data from transcribed interviews were analyzed in triplicate through qualitative content analysis. Results During the 10-month period, 66 of 67 wishes were completed, with a median of 4.5 wishes per patient-family dyad. Interviews with 12 participants indicated that the 3WP personalized and enriched the EOL experience for patients, families and clinicians. Interviewees indicated higher intensity education strategies were needed to enable spread as the project grew. Clinicians described many physical resources for the project but required more non-clinical project support for orientation, continuing education and data collection. Instead, these roles were completed by clinicians with saturated work capacity which may have inhibited the spread of the project. Conclusions In this community hospital, ICU clinicians and key stakeholders reported the 3WP improved EOL care for patients, families, and clinicians. Project implementation in a community ICU requires investigators take into account project characteristics and adapt the intervention to the community hospital context.

Context Keepsakes are a relatively unexplored form of bereavement support that is frequently provided as part of the 3 Wishes Project (3WP). The 3WP is a palliative care intervention in which individualized wishes are implemented in the adult intensive care unit for dying patients and their families. Objectives We aimed to characterize and enumerate the keepsakes that were created as part of the 3WP and to understand their value from the perspective of bereaved family members. Methods We performed a secondary analysis of family interviews during a multicenter study on the 3WP and characterized all wishes that involved keepsakes. Sixty interviews with family members regarding the 3WP were reanalyzed using qualitative analysis to identify substantive themes related to keepsakes. Results Of 730 patients, 345 (47%) received keepsakes as part of their participation in 3WP. Most keepsakes were either tangible items that served as reminders of the patient's presence (thumbprints and locks of hair) or technology-assisted items (photographs and word clouds). The median cost per keepsake wish was $8.50 (interquartile range $2.00–$25.00). Qualitative analysis revealed two major themes: keepsakes are tangible items that are highly valued by family members; and the creation of the keepsake with clinical staff is valued and viewed as a gesture of compassion. Conclusion Keepsakes are common wishes that clinicians in the intensive care unit are able to provide and sometimes cocreate with families when patients are dying. Both the offering to create the keepsake and receipt of the final product are perceived by family members as helpful.

Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium and a causative agent of tuberculosis (TB), a disease that kills more than 1.5 million people worldwide annually. One of the main reasons for this high mortality rate is the evolution of new Mtb strains that are resistant to available antibiotics. Therefore, new therapeutics for TB are in constant demand. Here, we report the development of small-molecule inhibitors that target two DNA replication enzymes of Mtb, namely DnaG primase and DNA gyrase (Gyr), which share a conserved TOPRIM fold near the inhibitors' binding site. The molecules were developed on the basis of previously reported inhibitors for T7 DNA primase that bind near the TOPRIM fold. To improve the physicochemical properties of the molecules as well as their inhibitory effect on primase and gyrase, 49 novel compounds have been synthesized as potential drug candidates in three stages of optimization. The last stage of chemical optimization yielded two novel inhibitors for both Mtb DnaG and Gyr that also showed inhibitory activity toward the fast-growing non-pathogenic model Mycobacterium smegmatis (Msmg).

Legged robots traversing in confined environments could find their only path is blocked by obstacles. In circumstances where the obstacles are movable, a multilegged robot can manipulate the obstacles using its legs to allow it to continue on its path. We present a method for a hexapod robot to autonomously generate manipulation trajectories for detected obstacles. Using a RGB-D sensor as input, the obstacle is extracted from the environment and filtered to provide key contact points for the manipulation algorithm to calculate a trajectory to move the obstacle out of the path. Experiments on a 30 degree of freedom hexapod robot show the effectiveness of the algorithm in manipulating a range of obstacles in a 3D environment using its front legs., Comment: 9 pages, In proceedings of ACRA2020

TP53 plays critical roles in maintaining genome stability. Deleterious genetic variants damage the function of TP53, causing genome instability and increased cancer risk. Of the large quantity of genetic variants identified in TP53, however, many remain functionally unclassified as variants of unknown significance (VUS) due to the lack of evidence. This is reflected by the presence of 749 (42%) VUS of the 1785 germline variants collected in the ClinVar database. In this study, we addressed the deleteriousness of TP53 missense VUS. Utilizing the protein structure-based Ramachandran Plot-Molecular Dynamics Simulation (RPMDS) method that we developed, we measured the effects of missense VUS on TP53 structural stability. Of the 340 missense VUS tested, we observed deleterious evidence for 193 VUS, as reflected by the TP53 structural changes caused by the VUS-substituted residues. We compared the results from RPMDS with those from other in silico methods and observed higher specificity of RPMDS in classification of TP53 missense VUS than these methods. Data from our current study address a long-standing challenge in classifying the missense VUS in TP53, one of the most important tumor suppressor genes.

Zorlu, Yunus/0000-0003-2811-1872; Worle, Michael/0000-0001-8087-5779; Yucesan, Gundog/0000-0002-5105-7280; Yazaydin, A. Ozgur/0000-0001-8562-723X WOS:000408644100018 We report two novel 3D porous metal-organophosphonate metal organic frameworks (MOFs) [{Cu(4,4'-bpy)(0.5)(1,4-NDPA-H-2)] (1), [{Cu-2(4,4'-bpy)(0.5)}(1,4-NDPA)] (2) and a non-porous [{Cu(4,4'-bpy)}(2,6-NDPA-H-2)] (3) constructed using the structurally rigid 1,4-naphthalenediphosphonic acid (1,4-NDPA-H-4) and 2,6-naphthalenediphosphonic acid (2,6-NDPA-H-4). 1 and 2 exhibit high surface areas obtained using the structurally rigid and short aromatic organophosphonate linkers with copper. The compound 1 has been further analyzed by TGA and Quantum Design PPMS vibrating sample magnetometer. Turkiye Bilimsel ve Teknolojik Arastirma KurumuTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [TUBITAK 212T060]; COST actionEuropean Cooperation in Science and Technology (COST) [TD1304] Financial support by the Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK 212T060) and the COST action TD1304 are gratefully acknowledged.

In this study we propose and computationally demonstrate the concept of electric field controlled molecular gates mounted on the open-metal coordination sites in metal–organic framework (MOF) materials. The MOF-molecular gate complex functions by opening and closing under the effect of an electric field. Our design involves Mg-MOF-74, a MOF with hexagonal channels with open-metal coordination sites at each corner, and a multifunctional gate molecule with permanent dipole which anchors itself on the host MOF material and responds to changes in the direction of an electric field by rotating around its backbone which acts as an axle. By carrying out density functional theory (DFT) calculations and molecular dynamics (MD) simulations we show that the MOF-molecular gate complex can be switched between two stable configurations, open and closed, by turning on and off an external electric field. We further show that the molecular gate can be controlled to block or allow the diffusion of methane molecules through the channels of the MOF like a nanoscale butterfly valve. Electric field controlled molecular gates mounted on MOFs can pave the way for new molecular machines and nanodevices which can store, deliver or select molecules on demand and with atomic precision.

A fast, accurate, and cost-effective design of small-molecule inhibitors that target RNA using a combined NMR-fragment-based and virtual screening., M. tuberculosis (Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of the Mtb ribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50 values, which were significantly improved over standard antibiotic drugs.

M. tuberculosis(Mtb) is a pathogenic bacterium that causes tuberculosis, which kills more than 1.5 million people worldwide every year. Strains resistant to available antibiotics pose a significant healthcare problem. The enormous complexity of the ribosome poses a barrier for drug discovery. We have overcome this in a tractable way by using an RNA segment that represents the peptidyl transferase center as a target. By using a novel combination of NMR transverse relaxation times (T2) and computational chemistry approaches, we have obtained improved inhibitors of theMtbribosomal PTC. Two phenylthiazole derivatives were predicted by machine learning models as effective inhibitors, and this was confirmed by their IC50values, which were significantly improved over standard antibiotic drugs.