Atypical chest pain with non-specific ST changes: an incidental finding of myocardial bridge without flow limiting coronary lesion

Myocardial bridging is a developmental anomaly characterized by intramural course of a short segment of epicardial coronary artery which mostly remains silent in the initial few decades of life. A 42 years old male non diabetic, hypertensive on single regime therapy presented with atypical chest pain for the last two hours. Serial 12 lead ECGs on an interval of half-hour showing nonspecific dynamic ST changes in lead II, III and aVF suggesting of inferior wall changes with negative bio markers like troponin-T and troponin-I. Coronary angiography reveals myocardial bridge in mid segment of left anterior descending artery (LAD). Considering superficial type of bridging in this case, a conservative management strategy was planned accordingly. Physicians should be more vigilant on possibilities of underlying myocardial bridging as a major differential in emergency scenarios with low suspicion of atherosclerosis but with a picture equivalent to acute coronary syndrome (ACS). Myocardial bridge carries a wide array of complications depending on variabilities like depth of tunnelling, collapsibility, loss of wall sheer stress and vasospastic changes. Hence it needs to be promptly diagnosed with immediate treatment

Neutropenic enterocolitis in a non-immunocompromised patient presenting with lower respiratory tract infection: a case report

Neutropenic enterocolitis (NEC) has been widely reported in adults with myelofibrotic disorders, solid malignant tumors, bone marrow transplantation as well as in myelotoxic chemotherapy. Here we reported a case of a 66-year-old non-diabetic, hypertensive female without any prior history of immunosuppression or any underlying malignancy or related chemotherapy; who presented with severe dyspnoea, low grade fever and cough. Followed by a course of effective conservative management and initial stabilization, on investigation her TLC was found to be abnormally low with severe neutropenia and a hyperinflammatory response induced myelosuppression with LRTI was suspected. Subsequently, subcutaneous G-CSF, broad spectrum antibiotics were initiated along with supportive management. She developed abdominal distension, diffused pain and tenderness with hypoactive bowel on the following day. After 3 days of G-CSF trial, neutrophil count started to increase along with her overall improvement. CECT was performed with positive findings of multiple colonic short segment involvement without any stricture, pericolic fat stranding and perforation; reflecting towards a resolving neutropenic enteropathy

Structural basis for Cas9 off-target activity

The target DNA specificity of the CRISPR-associated genome editor nuclease Cas9 is determined by complementarity to a 20-nucleotide segment in its guide RNA. However, Cas9 can bind and cleave partially complementary off-target sequences, which raises safety concerns for its use in clinical applications. Here, we report crystallographic structures of Cas9 bound to bona fide off-target substrates, revealing that off-target binding is enabled by a range of noncanonical base-pairing interactions within the guide:off-target heteroduplex. Off-target substrates containing single-nucleotide deletions relative to the guide RNA are accommodated by base skipping or multiple noncanonical base pairs rather than RNA bulge formation. Finally, PAM-distal mismatches result in duplex unpairing and induce a conformational change in the Cas9 REC lobe that perturbs its conformational activation. Together, these insights provide a structural rationale for the off-target activity of Cas9 and contribute to the improved rational design of guide RNAs and off-target prediction algorithms

It Costs to Get Costs! A Heuristic-Based Scalable Goal Assignment Algorithm for Multi-Robot Systems

The goal assignment problem for a multi-robot application involves assigning a unique goal to each robot to minimize the total cost of movement for all the robots. A significant step in the state-of-the-art algorithms solving this problem is to find the cost associated with each robot-goal pair. For a large multi-robot system with many robots and many goals in a complex workspace, the computation time required to find the paths for all robot-goal pairs may become prohibitively large. We present an algorithm that solves the optimal goal assignment problem without computing the paths between all the robot-goal pairs. Instead, our algorithm computes the obstacle-free optimal path for any robot-goal pair in a demand-driven way, i.e., if it is absolutely required to ensure the optimality of the goal assignment. We evaluate our algorithm extensively on both randomly generated and standard workspaces for hundreds of robots. Our experimental results demonstrate that the proposed algorithm achieves an order-of-magnitude speedup over the state-of-the-art baseline algorithm. To the best of our knowledge, our algorithm is the first one to solve the multi-robot optimal goal assignment problem without computing the paths for all robot-goal pairs explicitly, guaranteeing high scalability

Dynamics and mechanisms of CRISPR-Cas9 through the lens of computational methods

The clustered regularly interspaced short palindromic repeat (CRISPR) genome-editing revolution established the beginning of a new era in life sciences. Here, we review the role of state-of-the-art computations in the CRISPR-Cas9 revolution, from the early refinement of cryo-EM data to enhanced simulations of large-scale conformational transitions. Molecular simulations reported a mechanism for RNA binding and the formation of a catalytically competent Cas9 enzyme, in agreement with subsequent structural studies. Inspired by single-molecule experiments, molecular dynamics offered a rationale for the onset of off-target effects, while graph theory unveiled the allosteric regulation. Finally, the use of a mixed quantum-classical approach established the catalytic mechanism of DNA cleavage. Overall, molecular simulations have been instrumental in understanding the dynamics and mechanism of CRISPR-Cas9, contributing to understanding function, catalysis, allostery, and specificity

Frontiers of metal-coordinating drug design

Introduction: The occurrence of metal ions in biomolecules is required to exert vital cellular functions. Metal-containing biomolecules can be modulated by small-molecule inhibitors targeting their metal-moiety. As well, the discovery of cisplatin ushered the rational discovery of metal-containing-drugs. The use of both drug types exploiting metal-ligand interactions is well established to treat distinct pathologies. Therefore, characterizing and leveraging metal-coordinating drugs is a pivotal, yet challenging, part of medicinal chemistry.Area covered: Atomic-level simulations are increasingly employed to overcome the challenges met by traditional drug-discovery approaches and to complement wet-lab experiments in elucidating the mechanisms of drugs' action. Multiscale simulations, allow deciphering the mechanism of metal-binding inhibitors and metallo-containing-drugs, enabling a reliable description of metal-complexes in their biological environment. In this compendium, the authors review selected applications exploiting the metal-ligand interactions by focusing on understanding the mechanism and design of (i) inhibitors targeting iron and zinc-enzymes, and (ii) ruthenium and gold-based anticancer agents targeting the nucleosome and aquaporin protein, respectively.Expert opinion: The showcased applications exemplify the current role and the potential of atomic-level simulations and reveal how their synergic use with experiments can contribute to uncover fundamental mechanistic facets and exploit metal-ligand interactions in medicinal chemistry

Molecular Dynamics Reveals a DNA-Induced Dynamic Switch Triggering Activation of CRISPR-Cas12a

CRISPR-Cas12a is a genome-editing system, recently also harnessed for nucleic acid detection, which is promising for the diagnosis of the SARS-CoV-2 coronavirus through the DETECTR technology. Here, a collective ensemble of multimicrosecond molecular dynamics characterizes the key dynamic determinants allowing nucleic acid processing in CRISPR-Cas12a. We show that DNA binding induces a switch in the conformational dynamics of Cas12a, which results in the activation of the peripheral REC2 and Nuc domains to enable cleavage of nucleic acids. The simulations reveal that large-amplitude motions of the Nuc domain could favor the conformational activation of the system toward DNA cleavages. In this process, the REC lobe plays a critical role. Accordingly, the joint dynamics of REC and Nuc shows the tendency to prime the conformational transition of the DNA target strand toward the catalytic site. Most notably, the highly coupled dynamics of the REC2 region and Nuc domain suggests that REC2 could act as a regulator of the Nuc function, similar to what was observed previously for the HNH domain in the CRISPR-associated nuclease Cas9. These mutual domain dynamics could be critical for the nonspecific binding of DNA and thereby for the underlying mechanistic functioning of the DETECTR technology. Considering that REC is a key determinant in the system's specificity, our findings provide a rational basis for future biophysical studies aimed at characterizing its function in CRISPR-Cas12a. Overall, our outcomes advance our mechanistic understanding of CRISPR-Cas12a and provide grounds for novel engineering efforts to improve genome editing and viral detection