Unlocking the Hidden Pathway: A Rare Encounter With Right Coronary Artery Fistula to Coronary Sinus and Right Ventricle.

Coronary artery fistulas (CAFs) are rare vascular anomalies characterized by abnormal connections between coronary arteries and cardiac chambers or adjacent structures. Advances in cardiac interventions have led to an increasing recognition of acquired CAFs, which are typically congenital. We present a case of a 62-year-old male with a complex medical history, including hypertension, atrial fibrillation, and heart failure, who presented with exertional chest pain and palpitations. Diagnostic evaluation revealed a significant CAF originating from the right coronary artery (RCA) and terminating into the coronary sinus and right ventricle. Despite the absence of significant coronary artery occlusions, the fistula was deemed clinically significant due to its potential to cause myocardial ischemia. Management involved guideline-directed medical therapy and lifestyle modifications. This case underscores the importance of early recognition and appropriate management of CAFs to optimize patient outcomes. Further research is needed to better understand the natural history and optimal management strategies of CAFs.

Sinoatrial nodal artery fistula to bronchial arteries originating from the right coronary artery in the setting of chronic bronchiectasis and coronary artery disease.

We present a 67-year-old male with past medical history of hyperlipidemia, hypertension, and emphysema, and who was a former smoker, with dyspnea on exertion and chest pain.

Prevalence of Antimicrobial Resistance and Respective Genes among Bacillus spp., a Versatile Bio-Fungicide.

The plant rhizosphere is not only a reservoir of microbes but also a hub of antimicrobial resistance genes. Rhizospheric Bacillus spp. are the potential bio-inoculants with a versatile application in agriculture as bio-fertilizer and bio-fungicide. In the current study, the potential bio-control agent that is the Bacillus species (n = 7) was screened for the antimicrobial resistance pattern to assess their risk before registering them as a bio-inoculant. All of the Bacillus spp. were categorized as multi-drug-resistant (MDR), bacteria but none of them was either pan-drug-resistant (PDR) or extensive-drug-resistant (XDR). The multiple antimicrobial resistance (MAR) index of Bacillus spp. was higher than the critical value (0.2). The Bacillus spp. showed resistance to antimicrobial classes such as ß lactam, macrolides, sulfonamides, tetracycline, aminoglycosides, and lincosamide. Various antimicrobial resistance genes, namely VmiR, ImrB, tetL, mphK, ant-6, penp, and bla OXA, associated with different mechanisms of resistance, were also detected in Bacillus spp. The Bacillus spp. also showed stress-tolerance traits such as ACC deaminase and EPS activity except the strains MAZ-117 and FZV-34, respectively. A significant correlation was observed between the PGPR and antimicrobial resistance, which shows that they may have adapted drug-resistance mechanisms to tolerate the environmental stress. These findings suggest that bio-fungicidal Bacillus spp. could be used very carefully on a commercial scale.

TGF-ß signaling: A recap of SMAD-independent and SMAD-dependent pathways.

Transforming growth factor-ß (TGF-ß) is a proinflammatory cytokine known to control a diverse array of pathological and physiological conditions during normal development and tumorigenesis. TGF-ß-mediated physiological effects are heterogeneous and vary among different types of cells and environmental conditions. TGF-ß serves as an antiproliferative agent and inhibits tumor development during primary stages of tumor progression; however, during the later stages, it encourages tumor development and mediates metastatic progression and chemoresistance. The fundamental elements of TGF-ß signaling have been divulged more than a decade ago; however, the process by which the signals are relayed from cell surface to nucleus is very complex with additional layers added in tumor cell niches. Although the intricate understanding of TGF-ß-mediated signaling pathways and their regulation are still evolving, we tried to make an attempt to summarize the TGF-ß-mediated SMAD-dependent andSMAD-independent pathways. This manuscript emphasizes the functions of TGF-ß as a metastatic promoter and tumor suppressor during the later and initial phases of tumor progression respectively.

Multiple strokes due to pulmonary arteriovenous malformation.

We present a case of recurrent strokes in a patient with absent left internal carotid artery (ICA) and pulmonary arteriovenous malformation. Pulmonary arteriovenous malformations (PAVMs) are abnormal communications between pulmonary artery and pulmonary vein, cause extracardiac right to left shunting of blood and are known to significantly increase the risk of stroke primarily due to paradoxical embolization. They are often hereditary and are commonly associated with hereditary hemorrhagic telangiectasias (HHT). Delayed bubbles seen in the left ventricle (after 3 cardiac cycles) on transthoracic echocardiogram with bubble study is often the first clue to the presence of PAVMs. CT scan of the chest can confirm the diagnosis. Percutaneous embolotherapy is the treatment of choice with reduction in stroke risk post embolization.

mTORC1 induces eukaryotic translation initiation factor 4E interaction with TOS-S6 kinase 1 and its activation.

Eukaryotic translation initiation factor 4E was recently shown to be a substrate of mTORC1, suggesting it may be a mediator of mTORC1 signaling. Here, we present evidence that eIF4E phosphorylated at S209 interacts with TOS motif of S6 Kinase1 (S6K1). We also show that this interaction is sufficient to overcome rapamycin sensitivity and mTORC1 dependence of S6K1. Furthermore, we show that eIF4E-TOS interaction relieves S6K1 from auto-inhibition due to carboxy terminal domain (CTD) and primes it for hydrophobic motif (HM) phosphorylation and activation in mTORC1 independent manner. We conclude that the role of mTORC1 is restricted to engaging eIF4E with S6K1-TOS motif to influence its state of HM phosphorylation and inducing its activation.

Expansion of the CRISPR/Cas Genome-Sculpting Toolbox: Innovations, Applications and Challenges.

The emergence of the versatile gene-editing technology using programmable sequence-specific endonuclease system (CRISPR-Cas9) has instigated a major upheaval in biomedical research. In a brief span of time, CRISPR/Cas has been adopted by research labs around the globe because of its potential for significant progress and applicability in terms of efficiency, versatility and simplicity. It is a breakthrough technique for systematic genetic engineering, genome labelling, epigenetic and transcriptional modulation, and multiplexed gene editing, amongst others. This review provides an illustrative overview of the current research trends using CRISPR/Cas technology. We highlight the latest developments in CRISPR/Cas technique including CRISPR imaging, discovery of novel CRISPR systems, and applications in altering the genome, epigenome or RNA in different organisms. Finally, we address the potential challenges of this technique for its future use. Development of new CRISPR/Cas systems.

Incidental Intramyocardial Bridging in a Myocarditis Patient Presenting With Focal ST Segment Depressions.

Myopericarditis is an entity known to present with typical symptoms of viral prodrome and diffuse ST elevation (STE) and/or PR depressions on electrocardiogram (EKG). Atypical presentations of myocarditis such as focal STE have been cited in the literature, reflecting true coronary ischemia. However, myocarditis or pericarditis presenting with focal ST depressions is rarely seen. Myocarditis is usually overlooked as a differential for ST depressions seen on EKGs; hence, the case we present in this report highlights the importance of nonischemic causes presenting as ischemic changes on EKG. This case is unique as we have postulated a possible explanation for this finding. This report discusses the case of a young patient with myopericarditis presenting with focal ST depressions. This patient was also incidentally found to have intramyocardial bridging, usually a benign finding, on cardiac catheterization (which is shown in the case report). Our hypothesis is that the inflammation due to myocarditis in this patient led to inflammation of intramyocardial vessels, presenting as ST depressions. Since intramyocardial bridging is a common anomaly, we propose the question as to whether this could be a risk factor for sudden cardiac death and if it depends on the characteristic of the intramyocardial vessel. We would like to emphasize on the atypical presentations of this usual condition, a possible explanation for this finding, and the need for further testing for risk stratification in patients with this anomaly.

Three months of COVID-19: A systematic review and meta-analysis.

The pandemic of 2019 novel coronavirus (SARS-CoV-2019), reminiscent of the 2002-SARS-CoV outbreak, has completely isolated countries, disrupted health systems and partially paralyzed international trade and travel. In order to be better equipped to anticipate transmission of this virus to new regions, it is imperative to track the progress of the virus over time. This review analyses information on progression of the pandemic in the past 3 months and systematically discusses the characteristics of SARS-CoV-2019 virus including its epidemiologic, pathophysiologic, and clinical manifestations. Furthermore, the review also encompasses some recently proposed conceptual models that estimate the spread of this disease based on the basic reproductive number for better prevention and control procedures. Finally, we shed light on how the virus has endangered the global economy, impacting it both from the supply and demand side.

Eukaryotic Initiation Factor 4E phosphorylation acts a switch for its binding to 4E-BP1 and mRNA cap assembly.

Translational regulation has invited considerable interest consequent of its circumstantial dysregulation during cancer genesis. eIF4E (Eukaryotic Initiation Factor 4E) has been identified as an important factor involved in tumor progression by way of instrumenting the convergence of oncogenic signals for up-regulation of Cap-dependent translation. In the backdrop of dramatic eIF4E over-expression in a large population of human cancers, we suggest that the tumorigenic property of eIF4E is strictly attributed to its phosphorylation state. We provide evidence that while phosphorylated eIF4E fails to be sequestered by 4E-BP1, its dephosphorylated form shows overwhelming binding with 4E-BP1 without any consideration to the state of 4E-BP1 phosphorylation to suggest that eIF4E-4EBP1 binding is governed by eIF4E phosphorylation instead of 4E-BP1. We also show that eIF4E engages in Cap-assembly formation preferably in a phosphorylation-dependent manner to suggest that eIF4E phosphorylation rather than 4E-BP1 regulates its availability for Cap-assembly.

Eukaryotic initiation factor 4E is a novel effector of mTORC1 signaling pathway in cross talk with Mnk1.

Cellular signals that influence Cap-dependent translation have assumed significant relevance in the backdrop of their enforced dysregulation during oncogenesis. Eukaryotic initiation factor 4E(eIF4E), the mRNA cap-binding protein, has emerged as a key player to facilitate tumor progression through upregulated cap-dependent translation synchronized with enhanced cell division. We provide evidence that eIF4E phosphorylation is regulated by mTORC1 by virtue of its interaction with Raptor through a novel TPTPNPP motif and consequent phosphorylation invitro and in vivo in a Rapamycin-sensitive manner. While we show that phosphorylation pattern of eIF4E responds faithfully to Rapamycin inhibition, the prolonged exposure to Rapamycin rescues the loss of eIF4E phosphorylation through Mnk1 activation. We also present evidence that eIF4E interacts with the amino terminal domain of S6K1 in a phospho-dependent manner, and this interaction is instrumental in overriding Rapamycin inhibition of S6K1. The data endorses eIF4E as a regulatory subunit that modulates the functional attributes of mTOR effectors to synchronize cap-dependent translation with growth assertion.

Eukaryotic initiation factor 4E (eIF4E): A recap of the cap-binding protein.

Eukaryotic initiation factor 4E (eIF4E), a fundamental effector and rate limiting element of protein synthesis, binds the 7-methylguanosine cap at the 5' end of eukaryotic messenger RNA (mRNA) specifically as a constituent of eIF4F translation initiation complex thus facilitating the recruitment of mRNA to the ribosomes. This review focusses on the engagement of signals contributing to growth factor originated maxim and their role in the activation of eIF4E to achieve a collective influence on cellular growth, with a key focus on conjuring vital processes like protein synthesis. The review invites considerable interest in elevating the appeal of eIF4E beyond its role in regulating translation viz a viz cancer genesis, attributed to its phosphorylation state that improves the prospect for the growth of the cancerous cell. This review highlights the latest studies that have envisioned to target these pathways and ultimately the translational machinery for therapeutic intervention. The review also brings forward the prospect of eIF4E to act as a converging juncture for signaling pathways like mTOR/PI3K and Mnk/MAPK to promote tumorigenesis.

TAK1 mediates convergence of cellular signals for death and survival.

TGF-ß activated kinase 1, a MAPK kinase kinase family serine threonine kinase has been implicated in regulating diverse range of cellular processes that include embryonic development, differentiation, autophagy, apoptosis and cell survival. TAK1 along with its binding partners TAB1, TAB2 and TAB3 displays a complex pattern of regulation that includes serious crosstalk with major signaling pathways including the C-Jun N-terminal kinase (JNK), p38 MAPK, and I-kappa B kinase complex (IKK) involved in establishing cellular commitments for death and survival. This review also highlights how TAK1 orchestrates regulation of energy homeostasis via AMPK and its emerging role in influencing mTORC1 pathway to regulate death or survival in tandem.

Eukaryotic Initiation Factor 4E (eIF4E) sequestration mediates 4E-BP1 response to rapamycin.

The cap dependent translation initiation is a tightly controlled process of cooperative ternary complex formation by 4E-BP1, eIF4E and the 5' cap of eukaryotic mRNA in response to environmental cues like glucose, nutrients and growth factor levels. Based on the well-described effects of mTORC1/rapamycin complex on 4E-BP1 phosphorylation/s, it is generally accepted that rapamycin is a global inhibitor of cap-dependent translation. We have previously shown that 4E-BP1 resistance to rapamycin was overcome by the stoichiometric abundance of S6K1. Now we present evidence that the TOS-bearing amino terminal domain of S6K1 is sufficient to relieve the rapamycin resistance of 4E-BP1 as TOS deleted variants of S6K1, active or inactive with regard to S6K1 activity failed to bring about relief of 4E-BP1 resistance to rapamycin. We also show that the reciprocal inactivation of S6K1 by abundance of 4E-BP1 gets accomplished only with intact TOS motif in the protein. The data presented in this study identifies eIF4E and not Raptor as a cellular factor responsible to regulate rapamycin sensitivity of 4E-BP1 suggesting that the phosphorylation dynamics and rapamycin sensitivity of 4E-BP1 and S6K1 are regulated independently.

Necrotizing Crescentic Glomerulonephritis Complicating Bivalvular Bacterial Endocarditis.

In the setting of an increasing incidence of endocarditis in the United States, we report a patient with necrotizing crescentic glomerulonephritis (GN) associated with native valve bacterial endocarditis due to Streptococcus parasanguinis. He was started on appropriate antibiotic treatment and subsequent blood cultures showed no growth. However, due to continuing decline in kidney function, immunosuppressive therapy was started. Despite immunosuppressive therapy and antibiotics, renal function did not improve and chronic hemodialysis was required. Due to rarity of condition, there are no definite treatment guidelines available. Antibiotics, steroids, immunosuppressive agents can be of help in most cases. Further research in this regard may help with early diagnosis and better treatment modalities.

Solitary Fibrous Tumor of Pleura Invading into the Left Atrium via Pulmonary Vein.

A 67-year-old woman came to the hospital because of difficulty in breathing. After an initial clinical assessment, contrast-enhanced computerized tomography (CT) of the chest revealed a well-circumscribed heterogeneous mass arising from the pleura adjacent to the superior and medial left pulmonary artery. The mass was invading the pulmonary vein and entering the left atrium. Histopathology of the biopsy of the mass was suggestive of solitary fibrous tumor (SFT) of the pleura. The patient underwent pneumonectomy and resection of the left atrial mass with pericardial patch repair of the left atrium.

Reappraisal to the study of 4E-BP1 as an mTOR substrate - A normative critique.

mTOR-4E-BP1 axis is regarded as the best oncogenic circuitry impinging on translational control whereby mTORC1 dictates post-translational regulation of 4E-BP1. This review provides new insights into the molecular network of signalling pathways highlighting the recent explosion of studies in respect to the deviant behaviour of 4E-BP1 towards mTORC1. Despite the striking conservation of mTOR nexus, the eccentric phosphorylation dynamics of 4E-BP1 negate the apparent linear architecture of mTORC1 attesting the importance of other kinases that may evoke cross-talks with the conventional frame, most of which are enlisted in the manuscript. We also throw light on the tenuous role of rapamycin in 4E-BP1 regulation, which further necessitates the evaluation of 4E-BP1 to envisage the underlying molecular mechanisms in the discovery of novel drugs of 4E-BP1 for new treatment strategies. Finally, the review brings forward comprehensive studies delineating the redundancy of 4E-BP isoforms in regulating translational control.

Phosphorylation dynamics of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) is discordant with its potential to interact with eukaryotic initiation factor 4E (eIF4E).

Mammalian target of rapamycin (mTOR) controls cellular growth and proliferation by virtue of its ability to regulate protein translation. Eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) - a key mTOR substrate, binds and sequesters eIF4E to impede translation initiation that is supposedly overcome upon 4E-BP1 phosphorylation by mTOR. Ambiguity surrounding the precise identity of mTOR regulated sites in 4E-BP1 and their invariable resistance to mTOR inactivation raises concerns about phospho-regulated model proposed for 4E:4E-BP1 interaction. Our attempt to mimic dephosphorylation associated with rapamycin response by introducing phospho deficient mutants for sites implicated in regulating 4E:4E-BP1 interaction individually or globally highlighted no obvious difference in the quantum of their association with CAP bound 4E when compared with their phosphomimicked counterparts or the wild type 4E-BP1. TOS or RAIP motif deletion variants compromised for raptor binding and resultant phosphodeficiency did little to influence their association with CAP bound 4E. Interestingly ectopic expression of ribosomal protein S6 kinase 1 (S6K1) that restored 4E-BP1 sensitivity to rapamycin/Torin reflected by instant loss of 4E-BP1 phosphorylation, failed to bring about any obvious change in 4E:4E-BP1 stoichiometry. Our data clearly demonstrate a potential disconnect between rapamycin response of 4E-BP1 and its association with CAP bound 4E.