Unbiased Drug Target Prediction Reveals Sensitivity to Ferroptosis Inducers, HDAC and RTK Inhibitors in Melanoma Subtypes.

Background: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem.

Objective: Here, we mine large-scale MM proteogenomic data to identify druggable targets and forecast treatment efficacy and resistance.

Covalent inhibition of the SARS-CoV-2 NiRAN domain via an active-site cysteine.

The kinase-like NiRAN domain of nsp12 in SARS-CoV-2 catalyzes the formation of the 5' RNA cap structure. This activity is required for viral replication, offering a new target for the development of antivirals. Here, we develop a high-throughput assay to screen for small molecule inhibitors targeting the SARS-CoV-2 NiRAN domain.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

Introduction: While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy.

Methods: Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders.

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts.

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders.

Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation.

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA.

Identifying Ferroptosis Inducers, HDAC, and RTK Inhibitor Sensitivity in Melanoma Subtypes through Unbiased Drug Target Prediction.

Unlabelled: The utilization of PD1 and CTLA4 inhibitors has revolutionized the treatment of malignant melanoma (MM). However, resistance to targeted and immune-checkpoint-based therapies still poses a significant problem. Here we mine large scale MM proteogenomic data integrating it with MM cell line dependency screen, and drug sensitivity data to identify druggable targets and forecast treatment efficacy and resistance.

Protein family neighborhood analyzer-ProFaNA.

Background: Functionally related genes are well known to be often grouped in close vicinity in the genomes, particularly in prokaryotes. Notwithstanding the diverse evolutionary mechanisms leading to this phenomenon, it can be used to predict functions of uncharacterized genes.

Methods: Here, we provide a simple but robust statistical approach that leverages the vast amounts of genomic data available today.

Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3.

PEAK pseudokinases are molecular scaffolds which dimerize to regulate cell migration, morphology, and proliferation, as well as cancer progression. The mechanistic role dimerization plays in PEAK scaffolding remains unclear, as there are no structures of PEAKs in complex with their interactors. Here, we report the cryo-EM structure of dimeric PEAK3 in complex with an endogenous 14-3-3 heterodimer.

Allnighter pseudokinase-mediated feedback links proteostasis and sleep in Drosophila.

In nervous systems, retrograde signals are key for organizing circuit activity and maintaining neuronal homeostasis. We identify the conserved Allnighter (Aln) pseudokinase as a cell non-autonomous regulator of proteostasis responses necessary for normal sleep and structural plasticity of Drosophila photoreceptors. In aln mutants exposed to extended ambient light, proteostasis is dysregulated and photoreceptors develop striking, but reversible, dysmorphology.

World Federation for Interventional Stroke Treatment (WIST) Multispecialty Training Guidelines for Endovascular Stroke Intervention.

Introduction: Today, endovascular treatment (EVT) is the therapy of choice for strokes due to acute large vessel occlusion, irrespective of prior thrombolysis. This necessitates fast, coordinated multi-specialty collaboration. Currently, in most countries, the number of physicians and centres with expertise in EVT is limited.

Thrombectomy-Capable Stroke Centre-A Key to Acute Stroke Care System Improvement? Retrospective Analysis of Safety and Efficacy of Endovascular Treatment in Cardiac Cathlab.

The optimal structure of the acute ischaemic stroke treatment network is unknown and eagerly sought. To make it most effective, different treatment and transportation strategies have been developed and investigated worldwide. Since only a fraction of acute stroke patients with large vessel occlusion are treated, a new entity-thrombectomy-capable stroke centre (TCSC)-was introduced to respond to the growing demand for timely endovascular treatment.

Ultrawide Dark Solitons and Droplet-Soliton Coexistence in a Dipolar Bose Gas with Strong Contact Interactions.

We look into dark solitons in a quasi-1D dipolar Bose gas and in a quantum droplet. We derive the analytical solitonic solution of a Gross-Pitaevskii-like equation accounting for beyond mean-field effects. The results show there is a certain critical value of the dipolar interactions, for which the width of a motionless soliton diverges.

Pan-kinome of Legionella expanded by a bioinformatics survey.

The pathogenic Legionella bacteria are notorious for delivering numerous effector proteins into the host cell with the aim of disturbing and hijacking cellular processes for their benefit. Despite intensive studies, many effectors remain uncharacterized. Motivated by the richness of Legionella effector repertoires and their oftentimes atypical biochemistry, also by several known atypical Legionella effector kinases and pseudokinases discovered recently, we undertook an in silico survey and exploration of the pan-kinome of the Legionella genus, i.

Neurointerventional tools and techniques for coronary thrombus removal. A case-based review.

Unlabelled: Due to the negative results of randomized aspiration thrombectomy studies, its role in myocardial infarction has been limited to high thrombus burden and/or failed vessel recanalization, with little technological advancement over the last years. In contrast, there has been rapid progress in mechanical thrombectomy in stroke, which is understandable as most ischemic cerebrovascular accidents have an embolic etiology.We present three transradial procedures wherein neurointerventional catheters were used as a first-line device for removal of large clots lodged distally in tortuous coronary anatomy.

Acute ischemic stroke treatment model for Poland in the mechanical thrombectomy era - which way to go?

The interventional treatment of acute ischemic stroke with large vessel occlusion has revolutionized patient care in recent years. The Mechanical Thrombectomy Pilot Program in Poland is due to end soon. It seems the right time to summarize the achievements and name the problems of a centralized stroke care system and decide what future model of treatment and transportation to implement.

The mechanism of RNA capping by SARS-CoV-2.

The RNA genome of SARS-CoV-2 contains a 5' cap that facilitates the translation of viral proteins, protection from exonucleases and evasion of the host immune response. How this cap is made in SARS-CoV-2 is not completely understood. Here we reconstitute the N7- and 2'-O-methylated SARS-CoV-2 RNA cap (GpppA) using virally encoded non-structural proteins (nsps).

Catheter-induced coronary artery and aortic dissections. A study of mechanisms, risk factors and propagation causes.

Background: Only the incidence, management, and prognosis of catheter-induced coronary artery and aortic dissections have been systematically studied until now. We sought to evaluate their mechanisms, risk factors, and propagation causes.

Methods: Electronic databases containing 76,104 procedures and complication registries from 2000-2020 were searched and relevant cineangiographic studies adjudicated.

Methods for discovering catalytic activities for pseudokinases.

Pseudoenzymes resemble active enzymes, but lack key catalytic residues believed to be required for activity. Many pseudoenzymes appear to be inactive in conventional enzyme assays. However, an alternative explanation for their apparent lack of activity is that pseudoenzymes are being assayed for the wrong reaction.

Labeling of heterochronic ribosomes reveals C1ORF109 and SPATA5 control a late step in human ribosome assembly.

Although features of ribosome assembly are shared between species, our understanding of the diversity, complexity, dynamics, and regulation of ribosome production in multicellular organisms remains incomplete. To gain insights into ribosome biogenesis in human cells, we perform a genome-wide loss-of-function screen combined with differential labeling of pre-existing and newly assembled ribosomes. These efforts identify two functionally uncharacterized genes, C1orf109 and SPATA5.

Novel protein markers of androgen activity in humans: proteomic study of plasma from young chemically castrated men.

Background: Reliable biomarkers of androgen activity in humans are lacking. The aim of this study was, therefore, to identify new protein markers of biological androgen activity and test their predictive value in relation to low vs normal testosterone values and some androgen deficiency linked pathologies.

Methods: Blood samples from 30 healthy GnRH antagonist treated males were collected at three time points: (1) before GnRH antagonist administration; (2) 3 weeks later, just before testosterone undecanoate injection, and (3) after additional 2 weeks.