Mitochondrial Sequencing Identifies Long Non-Coding RNA Features that Promote Binding to PNPase.

Extranuclear localization of long non-coding RNAs (lncRNAs) is poorly understood. Based on machine learning evaluations, we propose a lncRNA-mitochondrial interaction pathway where Polynucleotide Phosphorylase (PNPase), through domains that provide specificity for primary sequence and secondary structure, binds nuclear-encoded lncRNAs to facilitate mitochondrial import. Using FVB/NJ mouse and human cardiac tissues, RNA from isolated subcellular compartments (cytoplasmic and mitochondrial) and crosslinked immunoprecipitate (CLIP) with PNPase within the mitochondrion were sequenced on the Illumina HiSeq and MiSeq, respectively. LncRNA sequence and structure were evaluated through supervised (Classification and Regression Trees (CART) and Support Vector Machines, (SVM)) machine learning algorithms. In HL-1 cells, qPCR of PNPase CLIP knockout mutants (KH and S1) were performed. In vitro fluorescence assays assessed PNPase RNA binding capacity and verified with PNPase CLIP. 112 (mouse) and 1,548 (human) lncRNAs were identified in the mitochondrion with Malat1 being the most highly expressed. Most non-coding RNAs binding PNPase were lncRNAs, including Malat1. LncRNA fragments bound to PNPase compared against randomly generated sequences of similar length showed stratification with SVM and CART algorithms. The lncRNAs bound to PNPase were used to create a criterion for binding, with experimental validation revealing increased binding affinity of RNA designed to bind PNPase compared to control RNA. Binding of lncRNAs to PNPase was decreased through knockout of RNA binding domains KH and S1. In conclusion, sequence and secondary structural features identified by machine learning enhance the likelihood of nuclear-encoded lncRNAs to bind to PNPase and undergo import into the mitochondrion.

Bridging frontiers: The role of a Global Breast Research Working Group.

Breast cancer remains a significant cause of death for women globally, despite advancements in detection and treatment, low- and middle-income countries face unique obstacles. Role of Research Working Group (RWG) can expedite research progress by fostering collaboration between scientists, clinicians, and stakeholders. Benefits of a Global RWG include pooling resources and expertise to develop new research ideas, addressing disparities, and building local research capacity, with the potential to improve breast cancer research and outcomes.

The Youth Anxiety Measure for DSM-5 (YAM-5): An Updated Systematic Review of its Psychometric Properties.

The Youth Anxiety Measure for DSM-5 (YAM-5) is a self- and parent-report scale specifically developed to assess symptoms of major anxiety disorders (part 1 or YAM-5-I) and specific phobias/agoraphobia (part 2 or YAM-5-II) in children and adolescents in terms of the contemporary psychiatric classification system. Since its introduction, the measure has been increasingly used in research, making it feasible to provide a summary of its psychometric properties. The present article presents a systematic review of 20 studies that employed the YAM-5, involving 5325 young participants. Overall, the results supported the hypothesized factor structure of both parts of the measure, although there were also some studies that could not fully replicate the original five-factor model of YAM-5-I. The internal consistency of the YAM-5 was generally high for the total scores of both parts, while reliability coefficients for the subscales were more variable across studies. Research also obtained evidence for other psychometric properties, such as test-retest reliability, parent-child agreement, convergent/divergent validity, and discriminant validity. Results further revealed that girls tend to show significantly higher anxiety levels on the YAM-5 than boys. Overall, these findings indicate that the YAM-5 is a promising tool for assessing symptoms of anxiety disorders including specific phobias in young people. Some directions for future research with the YAM-5 and recommendations regarding the use of the measure are given.

Evaluating Antibody Mediated Protection against Alpha, Beta, and Delta SARS-CoV-2 Variants of Concern in K18-hACE2 Transgenic Mice.

SARS-CoV-2 variants of concern (VoC) are impacting responses to the COVID-19 pandemic. Here, we utilized passive immunization using human convalescent plasma (HCP) obtained from a critically ill COVID-19 patient in the early pandemic to study the efficacy of polyclonal antibodies generated to ancestral SARS-CoV-2 against the Alpha, Beta, and Delta VoC in the K18 human angiotensin converting enzyme 2 (hACE2) transgenic mouse model. HCP protected mice from challenge with the original WA-1 SARS-CoV-2 strain; however, only partially protected mice challenged with the Alpha VoC (60% survival) and failed to save Beta challenged mice from succumbing to disease. HCP treatment groups had elevated receptor binding domain (RBD) and nucleocapsid IgG titers in the serum; however, Beta VoC viral RNA burden in the lung and brain was not decreased due to HCP treatment. While mice could be protected from WA-1 or Alpha challenge with a single dose of HCP, six doses of HCP could not decrease mortality of Delta challenged mice. Overall, these data demonstrate that VoC have enhanced immune evasion and this work underscores the need for in vivo models to evaluate future emerging strains. IMPORTANCE Emerging SARS-CoV-2 VoC are posing new problems regarding vaccine and monoclonal antibody efficacy. To better understand immune evasion tactics of the VoC, we utilized passive immunization to study the effect of early-pandemic SARS-CoV-2 HCP against, Alpha, Beta, and Delta VoC. We observed that HCP from a human infected with the original SARS-CoV-2 was unable to control lethality of Alpha, Beta, or Delta VoC in the K18-hACE2 transgenic mouse model of SARS-CoV-2 infection. Our findings demonstrate that passive immunization can be used as a model to evaluate immune evasion of emerging VoC strains.

Small regulatory RNAs: from bench to bedside - a keystone symposia meeting report.

The Keystone Symposium 'Small Regulatory RNAs: From Bench to Bedside' was held in Santa Fe, New Mexico from May 1-4, 2022. The symposium was organized by Frank J. Slack, Jörg Vogel, Ivan Martinez and Karyn Schmidt, and brought together scientists working in noncoding RNA biology, therapeutics, and technologies to address mechanistic questions about small regulatory RNAs and facilitate translation of these findings into clinical applications. The conference addressed four specific aims: Aim 1. Focus on the exciting biology of small regulatory RNAs, highlighting the best current research into the role that small RNAs play in fundamental biological processes; Aim 2. Focus on the latest efforts to harness the power of these RNAs as agents in the fight against disease and provide the basic understanding that will drive the invention of powerful clinical tools; Aim 3. Attract leaders from both academia and industry working in small RNAs to one place for critical discussions that will advance the field and accelerate the bench to bedside use of this technology; Aim 4. Provide a stimulating environment where students, postdoctoral researchers and junior investigators, along with scientists from Biotechnology and Pharmaceutical companies specializing in small regulatory RNAs, can present and discuss their research with the best minds in the field.

Yet Another Compact Time Series Data Representation Using CBOR Templates (YACTS).

The Internet of Things (IoT) technology is growing rapidly, while the IoT devices are being deployed massively. However, interoperability with information systems remains a major challenge for this accelerated device deployment. Furthermore, most of the time, IoT information is presented as Time Series (TS), and while the majority of the studies in the literature focus on the prediction, compression, or processing of TS, no standardized representation format has emerged. Moreover, apart from interoperability, IoT networks contain multiple constrained devices which are designed with limitations, e.g., processing power, memory, or battery life. Therefore, in order to reduce the interoperability challenges and increase the lifetime of IoT devices, this article introduces a new format for TS based on CBOR. The format exploits the compactness of CBOR by leveraging delta values to represent measurements, employing tags to represent variables, and utilizing templates to convert the TS data representation into the appropriate format for the cloud-based application. Moreover, we introduce a new refined and structured metadata to represent additional information for the measurements, then we provide a Concise Data Definition Language (CDDL) code to validate the CBOR structures against our proposal, and finally, we present a detailed performance evaluation to validate the adaptability and the extensibility of our approach. Our performance evaluation results show that the actual data sent by IoT devices can be reduced by between 88% and 94% compared to JavaScript Object Notation (JSON), between 82% and 91% compared to Concise Binary Object Representation (CBOR) and ASN.1, and between 60% and 88% compared to Protocol buffers. At the same time, it can reduce Time-on-Air by between 84% and 94% when a Low Power Wide Area Networks (LPWAN) technology such as LoRaWAN is employed, leading to a 12-fold increase in battery life compared to CBOR format or between a 9-fold and 16-fold increase when compared to Protocol buffers and ASN.1, respectively. In addition, the proposed metadata represent an additional 0.5% of the overall data transmitted in cases where networks such as LPWAN or Wi-Fi are employed. Finally, the proposed template and data format provide a compact representation of TS that can significantly reduce the amount of data transmitted containing the same information, extend the battery life of IoT devices, and improve their lifetime. Moreover, the results show that the proposed approach is effective for different data types and it can be integrated seamlessly into existing IoT systems.

Bilateral facial nerve palsy as a presentation of coexisting neuroborreliosis and post-acute COVID-19 syndrome.

Bilateral simultaneous facial nerve palsy is an extremely rare condition that may be induced by infection (bacterial, viral, or fungal) or noninfective causes (autoimmune, traumatic, or structural). The treatment depends on the underlying disorder, and, if it is introduced on time, the disease is in most cases completely reversible. We report on a patient with bilateral simultaneous facial nerve palsy without an obvious cause. The possible causes were SARS-CoV-2 infection and postvaccination syndrome. After we excluded the SARS-CoV-2 infection, a wide range of diagnostic tests were conducted. Magnetic resonance imaging after gadolinium intravenous application showed bilateral facial nerve enhancement. Serological tests revealed Borrelia burgdorferi, and the result was confirmed by an enzyme-linked immunosorbent assay (IgM positivity). After 14 days of antibiotic therapy, the symptoms resolved completely without sequelae. This report shows that the symptoms of bilateral simultaneous facial nerve palsy may completely resolve if thorough clinical investigation and an appropriate early treatment are applied.

The Role of B Cell and T Cell Glycosylation in Systemic Lupus Erythematosus.

Glycosylation is a post-translational modification that affects the stability, structure, antigenicity and charge of proteins. In the immune system, glycosylation is involved in the regulation of ligand-receptor interactions, such as in B-cell and T-cell activating receptors. Alterations in glycosylation have been described in several autoimmune diseases, such as systemic lupus erythematosus (SLE), in which alterations have been found mainly in the glycosylation of B lymphocytes, T lymphocytes and immunoglobulins. In immunoglobulin G of lupus patients, a decrease in galactosylation, sialylation, and nucleotide fucose, as well as an increase in the N-acetylglucosamine bisector, are observed. These changes in glycoisolation affect the interactions of immunoglobulins with Fc receptors and are associated with pericarditis, proteinuria, nephritis, and the presence of antinuclear antibodies. In T cells, alterations have been described in the glycosylation of receptors involved in activation, such as the T cell receptor; these changes affect the affinity with their ligands and modulate the binding to endogenous lectins such as galectins. In T cells from lupus patients, a decrease in galectin 1 binding is observed, which could favor activation and reduce apoptosis. Furthermore, these alterations in glycosylation correlate with disease activity and clinical manifestations, and thus have potential use as biomarkers. In this review, we summarize findings on glycosylation alterations in SLE and how they relate to immune system defects and their clinical manifestations.

Effect of Adipose-Derived Mesenchymal Stem Cells (ADMSCs) Application in Achilles-Tendon Injury in an Animal Model.

Background: Achilles-tendon rupture prevails as a common tendon pathology. Adipose-derived mesenchymal stem cells (ADMSCs) are multipotent stem cells derived from adipose tissue with attractive regeneration properties; thus, their application in tendinopathies could be beneficial. Methods: Male rabbit ADMSCs were obtained from the falciform ligament according to previously established methods. After tenotomy and suture of the Achilles tendon, 1 × 106 flow-cytometry-characterized male ADMSCs were injected in four female New Zealand white rabbits in the experimental group (ADMSC group), whereas four rabbits were left untreated (lesion group). Confirmation of ADMSC presence in the injured site after 12 weeks was performed with quantitative sex-determining region Y (SRY)-gene RT-PCR. At Week 12, histochemical analysis was performed to evaluate tissue regeneration along with quantitative RT-PCR of collagen I and collagen III mRNA. Results: Presence of male ADMSCs was confirmed at Week 12. No statistically significant differences were found in the histochemical analysis; however, statistically significant differences between ADMSC and lesion group expression of collagen I and collagen III were evidenced, with 36.6% and 24.1% GAPDH-normalized mean expression, respectively, for collagen I (p < 0.05) and 26.3% and 11.9% GAPDH-normalized mean expression, respectively, for collagen III (p < 0.05). The expression ratio between the ADMSC and lesion group was 1.5 and 2.2 for collagen I and collagen III, respectively. Conclusion: Our results make an important contribution to the understanding and effect of ADMSCs in Achilles-tendon rupture.

Heparan Sulfate and Sialic Acid in Viral Attachment: Two Sides of the Same Coin?

Sialic acids and heparan sulfates make up the outermost part of the cell membrane and the extracellular matrix. Both structures are characterized by being negatively charged, serving as receptors for various pathogens, and are highly expressed in the respiratory and digestive tracts. Numerous viruses use heparan sulfates as receptors to infect cells; in this group are HSV, HPV, and SARS-CoV-2. Other viruses require the cell to express sialic acids, as is the case in influenza A viruses and adenoviruses. This review aims to present, in a general way, the participation of glycoconjugates in viral entry, and therapeutic strategies focused on inhibiting the interaction between the virus and the glycoconjugates. Interestingly, there are few studies that suggest the participation of both glycoconjugates in the viruses addressed here. Considering the biological redundancy that exists between heparan sulfates and sialic acids, we propose that it is important to jointly evaluate and design strategies that contemplate inhibiting the interactions of both glycoconjugates. This approach will allow identifying new receptors and lead to a deeper understanding of interspecies transmission.

Neuroplasticity vs. cognitive prediction models in acute ischaemic stroke: limitations must be remembered.

Not applicable.

Impact of the droplet size of canola oil-in-water emulsions on the rheology and sensory acceptability of reduced-milk fat stirred yogurt.

A coarse canola oil-in-water (O/W) emulsion (dispersed mass fraction 0.1) was prepared by adding oil to whey protein hydrolysate (WPH)-citric pectin (CP) soluble complex (1% total biopolymer weight; WPH to CP mass ratio 6:1; pH 4.25) aqueous phase using a high shear homogenizer (4000 rpm, 2 min). The coarse O/W emulsion was further homogenized to obtain emulsions (Ex) with different mean droplet sizes (4000, 3000, 120 and 60 nm). A full-fat yogurt (YC; 26 ± 0.3 g milk fat L-1) was prepared from reconstituted whole milk powder (WMP, 3% milk fat) and skim milk powder (SMP, 0.01% milk fat). Reduced-milk fat yogurt (YEx 13 ± 0.3 g milk fat L-1) variations were prepared from WMP + SMP + Ex, where Ex substituted 50% of the milk-fat contained in YC. The viscosity and viscoelastic moduli were lower for YEx than for YC; the effect was more pronounced for E60 and E120. Aroma was non-significantly different between YC and YEx. A multivariate analysis showed that YEx overall acceptability was linked to taste and after taste attributes and to the viscosity perceived in mouth. The loss modulus showed anti-correlation directionality with the overall acceptance. The smaller mean droplet sized YEx exhibited the highest overall acceptability. Supplementary Information: The online version contains supplementary material available at 10.1007/s13197-022-05573-3.

Role of the Cholinergic Anti-Inflammatory Reflex in Central Nervous System Diseases.

In several central nervous system diseases, it has been reported that inflammation may be related to the etiologic process, therefore, therapeutic strategies are being implemented to control inflammation. As the nervous system and the immune system maintain close bidirectional communication in physiological and pathological conditions, the modulation of inflammation through the cholinergic anti-inflammatory reflex has been proposed. In this review, we summarized the evidence supporting chemical stimulation with cholinergic agonists and vagus nerve stimulation as therapeutic strategies in the treatment of various central nervous system pathologies, and their effect on inflammation.

Rumination, Catastrophizing, and Other-Blame: The Cognitive-Emotional Regulation Strategies Involved in Anxiety-Related Life Interference in Anxious Children.

Childhood anxiety problems have a great impact on the daily functioning of children and their families. The first objective of this study was to compare whether the use of cognitive-emotional regulation strategies differs in children with and without anxious symptomatology. A second objective was to analyze the possible mediating role of regulation strategies in the relationship between the presence of anxious symptomatology and its subsequent interference in children's lives. In total, 315 children (53.7% boys) between 8 and 12 years old participated. Mann-Whitney-Wilcoxon U-test was used to analyze differences in the use of cognitive-emotional regulation strategies between children with and without anxious symptomatology. In order to identify the cognitive-emotional regulation strategies which mediate the relation between anxiety and the consequent interference in children's lives, mediation analyses were carried out. As expected, children with anxious symptomatology used more maladaptive regulatory strategies than those without such symptomatology. Multiple mediation models in parallel showed that catastrophizing, rumination, and other-blame mediated the relationship between anxiety problems and their consequent interference. The identification of functional or dysfunctional patterns of cognitive-emotion regulation may favor the inclusion of new components in the evidence-based interventions currently available, in an attempt to increase rates of remission of anxiety.

Soft Tissue Perivascular Epithelioid Cell Tumour: An Unusual Finding.

Perivascular epithelioid cell tumour (PEComa) is a rare mesenchymal tumour made up of clear perivascular cells with epithelioid characteristics, which co-expresses muscle and melanocytic markers with a component of spindle cells, like sarcoma and variety of other tissues. This time, we present the case of a young patient with a tumour in the dorsal region of progressive growth, compatible with PEComa of soft tissue after histopathological and immunohistochemical analysis.

Post-COVID 19 Neurological Syndrome: a fresh challenge in neurological management.

Not applicable.

Hypovascular pancreas head adenocarcinoma: CT texture analysis for assessment of resection margin status and high-risk features.

OBJECTIVES: To determine if CT texture analysis features are associated with hypovascular pancreas head adenocarcinoma (PHA) postoperative margin status, nodal status, grade, lymphovascular invasion (LVI), and perineural invasion (PNI). METHODS: This Research Ethics Board-approved retrospective cohort study included 131 consecutive patients with resected PHA. Tumors were segmented on preoperative contrast-enhanced CT. Tumor diameter and texture analysis features including mean, minimum and maximum Hounsfield units, standard deviation, skewness, kurtosis, and entropy and gray-level co-occurrence matrix (GLCM) features correlation and dissimilarity were extracted. Two-sample t test and logistic regression were used to compare parameters for prediction of margin status, nodal status, grade, LVI, and PNI. Diagnostic accuracy was assessed using receiver operating characteristic curves and Youden method was used to establish cutpoints. RESULTS: Margin status was associated with GLCM correlation (p = 0.012) and dissimilarity (p = 0.003); nodal status was associated with standard deviation (p = 0.026) and entropy (p = 0.031); grade was associated with kurtosis (p = 0.031); LVI was associated with standard deviation (p = 0.047), entropy (p = 0.026), and GLCM correlation (p = 0.033) and dissimilarity (p = 0.011). No associations were found for PNI (p > 0.05). Logistic regression yielded an area under the curve of 0.70 for nodal disease, 0.70 for LVI, 0.68 for grade, and 0.65 for margin status. Optimal sensitivity/specificity was as follows: nodal disease 73%/72%, LVI 72%/65%, grade 55%/83%, and margin status 63%/66%. CONCLUSIONS: CT texture analysis features demonstrate fair diagnostic accuracy for assessment of hypovascular PHA nodal disease, LVI, grade, and postoperative margin status. Additional research is rapidly needed to identify these high-risk features with better accuracy. KEY POINTS: • CT texture analysis features are associated with pancreas head adenocarcinoma postoperative margin status which may help inform treatment decisions as a negative resection margin is required for cure. • CT texture analysis features are associated with pancreas head adenocarcinoma nodal disease, a poor prognostic feature. • Indicators of more aggressive pancreas head adenocarcinoma biology including tumor grade and LVI can be diagnosed using CT texture analysis with fair accuracy.

Diagnostic Accuracy of Single-Phase Computed Tomography Texture Analysis for Prediction of LI-RADS v2018 Category.

OBJECTIVE: The aim of this study was to determine if texture analysis can classify liver observations likely to be hepatocellular carcinoma based on the Liver Imaging Reporting and Data System (LI-RADS) using single portal venous phase computed tomography. METHODS: This research ethics board-approved retrospective cohort study included 64 consecutive LI-RADS observations. Individual observation texture analysis features were compared using Kruskal-Wallis and 2 sample t tests. Logistic regression was used for prediction of LI-RADS group. Diagnostic accuracy was assessed using receiver operating characteristic curves and Youden method. RESULTS: Multiple texture features were associated with LI-RADS including the mean HU (P = 0.003), median (P = 0.002), minimum (P = 0.010), maximum (P = 0.013), standard deviation (P = 0.009), skewness (P = 0.007), and entropy (P < 0.001). On logistic regression, LI-RADS group could be predicted with area under the curve, sensitivity, and specificity of 0.98, 96%, and 100%, respectively. CONCLUSIONS: Texture analysis features on portal venous phase computed tomography can identify liver observations likely to be hepatocellular carcinoma, which may preclude the need to recall some patients for additional multiphase imaging.

An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence.

The reversible state of proliferative arrest known as "cellular quiescence" plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNA-processing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.