The astrovirus N-terminal nonstructural protein anchors replication complexes to the perinuclear ER membranes.

An essential aspect of positive-sense RNA virus replication is anchoring the replication complex (RC) to cellular membranes. Positive-sense RNA viruses employ diverse strategies, including co-translational membrane targeting through signal peptides and co-opting cellular membrane trafficking components. Often, N-terminal nonstructural proteins play a crucial role in linking the RC to membranes, facilitating the early association of the replication machinery. Astroviruses utilize a polyprotein strategy to synthesize nonstructural proteins, relying on subsequent processing to form replication-competent complexes. This study provides evidence for the perinuclear ER membrane association of RCs in five distinct human astrovirus strains. Using tagged recombinant classical human astrovirus 1 and neurotropic MLB2 strains, we establish that the N-terminal domain guides the ER membrane association. We identified di-arginine motifs responsible for the perinuclear ER retention and formation of functional RCs through mutational analysis of the N-terminal domain in replicon and reverse genetics systems. In addition, we demonstrate the association of key components of the astrovirus replication complex: double-stranded RNA, RNA-dependent RNA polymerase, protease, and N-terminal protein. Our findings highlight the intricate virus-ER interaction mechanism employed by astroviruses, potentially leading to the development of novel antiviral intervention strategies.

Artificial intelligence in cancer diagnosis: Opportunities and challenges.

Since cancer is one of the world's top causes of death, early diagnosis is critical to improving patient outcomes. Artificial intelligence (AI) has become a viable technique for cancer diagnosis by using machine learning algorithms to examine large volumes of data for accurate and efficient diagnosis. AI has the potential to alter the way cancer is detected fundamentally. Still, it has several disadvantages, such as requiring a large amount of data, technological limitations, and ethical concerns. This overview looks at the possibilities and restrictions of AI in cancer detection, as well as current applications and possible future developments. We can better understand how to use AI to improve patient outcomes and reduce cancer mortality rates by looking at its potential for cancer detection.

SARS-CoV-2 RNAemia and proteomic trajectories inform prognostication in COVID-19 patients admitted to intensive care.

Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia is associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22-2.77] adjusted for age and sex). RNAemia is comparable in performance to the best protein predictors. Mannose binding lectin 2 and pentraxin-3 (PTX3), two activators of the complement pathway of the innate immune system, are positively associated with mortality. Machine learning identified 'Age, RNAemia' and 'Age, PTX3' as the best binary signatures associated with 28-day ICU mortality. In longitudinal comparisons, COVID-19 ICU patients have a distinct proteomic trajectory associated with mortality, with recovery of many liver-derived proteins indicating survival. Finally, proteins of the complement system and galectin-3-binding protein (LGALS3BP) are identified as interaction partners of SARS-CoV-2 spike glycoprotein. LGALS3BP overexpression inhibits spike-pseudoparticle uptake and spike-induced cell-cell fusion in vitro.

Non-coding RNA therapeutics for cardiac regeneration.

A growing body of evidence indicates that cardiac regeneration after myocardial infarction can be achieved by stimulating the endogenous capacity of cardiomyocytes (CMs) to replicate. This process is controlled, both positively and negatively, by a large set of non-coding RNAs (ncRNAs). Some of the microRNAs (miRNAs) that can stimulate CM proliferation is expressed in embryonic stem cells and is required to maintain pluripotency (e.g. the miR-302∼367 cluster). Others also govern the proliferation of different cell types, including cancer cells (e.g. the miR-17∼92 cluster). Additional miRNAs were discovered through systematic screenings (e.g. miR-199a-3p and miR-590-3p). Several miRNAs instead suppress CM proliferation and are involved in the withdrawal of CMs from the cell cycle after birth (e.g. the let-7 and miR-15 families). Similar regulatory roles on CM proliferation are also exerted by a few long ncRNAs. This body of information has obvious therapeutic implications, as miRNAs with activator function or short antisense oligonucleotides against inhibitory miRNAs or lncRNAs can be administered to stimulate cardiac regeneration. Expression of miRNAs can be achieved by gene therapy using adeno-associated vectors, which transduce CMs with high efficiency. More effective and safer for therapeutic purposes, small nucleic acid therapeutics can be obtained as chemically modified, synthetic molecules, which can be administered through lipofection or inclusion in lipid or polymer nanoparticles for efficient cardiac delivery. The notion that it is possible to reprogramme CMs into a regenerative state and that this property can be enhanced by ncRNA therapeutics remains exciting, however extensive experimentation in large mammals and rigorous assessment of safety are required to advance towards clinical application.

Melanoma Detection and Classification using Computerized Analysis of Dermoscopic Systems: A Review.

Malignant melanoma is considered as one of the most deadly cancers, which has broadly increased worldwide since the last decade. In 2018, around 91,270 cases of melanoma were reported and 9,320 people died in the US. However, diagnosis at the initial stage indicates a high survival rate. The conventional diagnostic methods are expensive, inconvenient and subject to the dermatologist's expertise as well as a highly equipped environment. Recent achievements in computerized based systems are highly promising with improved accuracy and efficiency. Several measures such as irregularity, contrast stretching, change in origin, feature extraction and feature selection are considered for accurate melanoma detection and classification. Typically, digital dermoscopy comprises four fundamental image processing steps including preprocessing, segmentation, feature extraction and reduction, and lesion classification. Our survey is compared with the existing surveys in terms of preprocessing techniques (hair removal, contrast stretching) and their challenges, lesion segmentation methods, feature extraction methods with their challenges, features selection techniques, datasets for the validation of the digital system, classification methods and performance measure. Also, a brief summary of each step is presented in the tables. The challenges for each step are also described in detail, which clearly indicate why the digital systems are not performing well. Future directions are also given in this survey.

Review of Automated Computerized Methods for Brain Tumor Segmentation and Classification.

Recently, medical imaging and machine learning gained significant attention in the early detection of brain tumor. Compound structure and tumor variations, such as change of size, make brain tumor segmentation and classification a challenging task. In this review, we survey existing work on brain tumor, their stages, survival rate of patients after each stage, and computerized diagnosis methods. We discuss existing image processing techniques with a special focus on preprocessing techniques and their importance for tumor enhancement, tumor segmentation, feature extraction and features reduction techniques. We also provide the corresponding mathematical modeling, classification, performance matrices, and finally important datasets. Last but not least, a detailed analysis of existing techniques is provided which is followed by future directions in this domain.

MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs.

Prompt coronary catheterization and revascularization have markedly improved the outcomes of myocardial infarction, but have also resulted in a growing number of surviving patients with permanent structural damage of the heart, which frequently leads to heart failure. There is an unmet clinical need for treatments for this condition1, particularly given the inability of cardiomyocytes to replicate and thereby regenerate the lost contractile tissue2. Here we show that expression of human microRNA-199a in infarcted pig hearts can stimulate cardiac repair. One month after myocardial infarction and delivery of this microRNA through an adeno-associated viral vector, treated animals showed marked improvements in both global and regional contractility, increased muscle mass and reduced scar size. These functional and morphological findings correlated with cardiomyocyte de-differentiation and proliferation. However, subsequent persistent and uncontrolled expression of the microRNA resulted in sudden arrhythmic death of most of the treated pigs. Such events were concurrent with myocardial infiltration of proliferating cells displaying a poorly differentiated myoblastic phenotype. These results show that achieving cardiac repair through the stimulation of endogenous cardiomyocyte proliferation is attainable in large mammals, however dosage of this therapy needs to be tightly controlled.

Inhibition of Non Canonical HIV-1 Tat Secretion Through the Cellular Na+,K+-ATPase Blocks HIV-1 Infection.

Besides its essential role in the activation of HIV-1 gene expression, the viral Tat protein has the unusual property of trafficking in and out of cells. In contrast to Tat internalization, the mechanism involved in extracellular Tat release has so far remained elusive. Here we show that Tat secretion occurs through a Golgi-independent pathway requiring binding of Tat with three short, non-consecutive intracytoplasmic loops at the C-terminus of the cellular Na+,K+-ATPase pump alpha subunit. Ouabain, a pump inhibitor, blocked this interaction and prevented Tat secretion; virions produced in the presence of this drug were less infectious, consistent the capacity of virion-associated Tat to increase HIV-1 infectivity. Treatment of CD4+ T-cells with short peptides corresponding to the Tat-binding regions of the pump alpha subunit impaired extracellular Tat release and blocked HIV-1 replication. Thus, non canonical, extracellular Tat secretion is essential for viral infectivity.

Right wire in orthodontics: a review

Quality of orthodontic wire such as stiffness, hardness, resiliency, elasticity and working range are important determinants of the effectivenes of tooth movement. Commonly used types of orthodontic arch wire:1) stainless steel(ss) wire, 2) conventional nickel- titanium (NiTi)alloy wire,3) improved super elastic NiTi- alloy wire( also called low hysteresis(LH)wire), and titanium molybdenum alloy(TMA) wire.

Proximity to PML nuclear bodies regulates HIV-1 latency in CD4+ T cells.

Nuclear bodies (NBs), characterized by the presence of the promyelocytic leukemia (PML) protein, are important components of the nuclear architecture, contributing to genetic and epigenetic control of gene expression. In investigating the mechanisms mediating HIV-1 latency, we determined that silenced but transcriptionally competent HIV-1 proviruses reside in close proximity to PML NBs and that this association inhibits HIV-1 gene expression. PML binds to the latent HIV-1 promoter, which coincides with transcriptionally inactive facultative heterochromatic marks, notably H3K9me2, at the viral genome. PML degradation and NB disruption result in strong activation of viral transcription as well as release of G9a, the major methyltransferase responsible for H3K9me2, and loss of facultative heterochromatin marks from the proviral DNA. Additionally, HIV-1 transcriptional activation requires proviral displacement from PML NBs by active nuclear actin polymerization. Thus, nuclear topology and active gene movement mediate HIV-1 transcriptional regulation and have implications for controlling HIV-1 latency and eradication.

Impact of surgeon selection on access placement and survival following preoperative mapping in the "Fistula First" era.

According to the "Fistula First Initiative" surgeon selection should be based on best outcomes, willingness, and ability to provide access services. This analysis presents arteriovenous access placement and outcomes in 75 patients when surgery was performed by one of two dedicated high-volume vascular access surgeons (community [surgeon I] and academic medical center [surgeon II]). Preoperative vascular mapping was performed in all the patients. Demographic characteristics were similar except that patients referred to surgeon I (n = 40) were older (52.7 +/- 16.2 years vs. 45.4 +/- 13.7 years; p = 0.04) and tended to have more previously failed accesses (50% vs. 29%; p = 0.06) and black race (65% vs. 43%; p = 0.055) including a history of previously failed accesses (50% for surgeon I and 29% for surgeon II; p = 0.06). Similarly, there was no significant difference in the size of forearm ([surgeon I: 2.0 +/- 1.0 mm], [surgeon II: 1.9 +/- 0.8 mm]; p = 0.45) or upper arm veins (cephalic vein: surgeon I = 3.2 +/- 1.4 mm, surgeon II = 2.9 +/- 1.2 mm, p = 0.34; basilic vein: surgeon I = 5.0 +/- 1.2 mm, surgeon II = 4.7 +/- 1.3 mm, p = 0.25). Fistulae placement occurred in 98% vs. 71% (p = 0.001) for surgeon I and II, respectively. Characteristics predictive of fistula placement over an arteriovenous graft were surgeon selection (odds ratio [OR] = 19.52; p = 0.01) and no history of diabetes (OR = 7.61; p = 0.016). Kaplan-Meier analysis revealed 6 and 12 months overall access survival rates of 82%, 58% and 82% and 47% for surgeon I and II, respectively (p = 0.007). This analysis demonstrates that surgeon selection can have a significant impact on the rate of fistula placement and its overall survival despite similar findings on preoperative vascular mapping.