Miracle-dz/UniFAR-FTUs huggingface dataset:
Yeo and Darras: Extraneuronal Phenotypes of Spinal Muscular Atrophy

Recently, the splicing modulator risdiplam was approved by the US Food and Drug Administration (FDA) for spinal muscular atrophy (SMA) in adults and children 2 months of age and older. Risdiplam is the third disease modifying treatment for SMA and only the second for children above the age of 2 years and adults with SMA. Before the approval of the antisense oligonucleotide nusinersen in 2016 for all types of SMA, regardless of age, and adeno-associated virus serotype 9-mediated SMN1 gene replacement therapy onasemnogene abeparvovec-xioi in 2019 for children 2 years of age and younger, SMA was invariably fatal in the most severe form of SMA, SMA type 1. With intrathecal administration of nusinersen every 4 months after a loading regimen, a single dose intravenous administration of onasemnogene abeparvovecxioi, and now daily oral administration of risdiplam, infants and children below the age of 2 years with SMA type 1 can now survive to childhood and probably up to adulthood. Data are just emerging about treatment tolerability and efficacy in different clinical settings and age groups, and long-term adverse effects of treatment are yet unclear. Children above the age of 2 years and adults with SMA now have two FDA-approved therapies, nusinersen and risdiplam, for less severe but still significantly limiting forms of SMA. Treatment efficacy and expectations in adults, where the motor neuron pool is already severely depleted, is under debate. The exponential growth of precision medicine in SMA, and the significant costs of approved gene therapies, bring sharply into the forefront pressing questions related to treatment efficacy and iatrogenic phenotypes, which adult and pediatric neurologists have an ethical obligation to understand and counsel our patients on. In this timely two part ANA Highlights program, Dr. Basil Darras (Boston Children’s Hospital and Harvard Medical School) and Dr. Crystal Yeo (Boston Children’s Hospital, Harvard Medical School, LKC School of Medicine, EDDC, IMCB) explain the extraneuronal phenotypes of SMA, clinical implications in patients being treated with innovative therapies, and avenues for future research. In part 1 of the program, Dr. Basil Darras explains that SMA is a genetic disorder driven by degeneration and loss of motor neurons in the anterior horns of the spinal cord and brain stem of children and adults. SMA is typically characterized as a motor neuron disease; however, extraneuronal phenotypes have been noted in severely affected patients and animal models. Data from autopsies, case studies, and limited cohort studies in patients with severe SMA correspond with animal models of SMA, showing dysfunction in almost every peripheral organ system, including the skeletal muscle, heart, kidneys, liver, pancreas, spleen, bones, connective tissues, and immune systems, and providing evidence in support of SMA being a multisystem disorder. In part 2 of the program, Dr. Crystal Yeo explains why neurologists and neuroscientists need to be aware of the evolving therapeutic
GM-CSF and IL-33 Orchestrate Polynucleation and Polyploidy of Resident Murine Alveolar Macrophages in a Murine Model of Allergic Asthma

Allergic asthma is a chronical pulmonary disease with high prevalence. It manifests as a maladaptive immune response to common airborne allergens and is characterized by airway hyperresponsiveness, eosinophilia, type 2 cytokine-associated inflammation, and mucus overproduction. Alveolar macrophages (AMs), although contributing to lung homeostasis and tolerance to allergens at steady state, have attracted less attention compared to professional antigen-presenting and adaptive immune cells in their contributions. Using an acute model of house dust mite-driven allergic asthma in mice, we showed that a fraction of resident tissue-associated AMs, while polarizing to the alternatively activated M2 phenotype, exhibited signs of polynucleation and polyploidy. Mechanistically, in vitro assays showed that only Granulocyte-Macrophage Colony Stimulating Factor and interleukins IL-13 and IL-33, but not IL-4 or IL-5, participate in the establishment of this phenotype, which resulted from division defects and not cell-cell fusion as shown by microscopy. Intriguingly, mRNA analysis of AMs isolated from allergic asthmatic lungs failed to show changes in the expression of genes involved in DNA damage control except for MafB. Altogether, our data support the idea that upon allergic inflammation, AMs undergo DNA damage-induced stresses, which may provide new unconventional therapeutical approaches to treat allergic asthma.
Aptamers: Novel Therapeutics and Potential Role in Neuro-Oncology

Simple Summary Despite the remarkable effort of researchers to find more effective treatments for pediatric brain tumors, the prognosis continues to be poor. Forty percent of pediatric patients develop treatment resistance and relapse, and the morbidities and long-term side effects of systemic therapy remain concerning. Significant advances have been made by next-generation genomic profiling. Novel oncogenic drivers have been identified as potential targets for the treatment of pediatric brain tumors. Aptamers, which are synthetic single-strand oligonucleotides, specifically target, bind with high affinity, internalize, and deliver a wide range of therapeutic moieties inside the cells. Although several aptamers have been tested in preclinical and clinical studies for adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. Increased knowledge regarding the molecular mechanisms of the pathogenesis of pediatric brain tumors, as well as selection of novel aptamers and/or adaptation of aptamers currently used in adult glioblastoma, might open a novel research field. Abstract A relatively new paradigm in cancer therapeutics is the use of cancer cell–specific aptamers, both as therapeutic agents and for targeted delivery of anticancer drugs. After the first therapeutic aptamer was described nearly 25 years ago, and the subsequent first aptamer drug approved, many efforts have been made to translate preclinical research into clinical oncology settings. Studies of aptamer-based technology have unveiled the vast potential of aptamers in therapeutic and diagnostic applications. Among pediatric solid cancers, brain tumors are the leading cause of death. Although a few aptamer-related translational studies have been performed in adult glioblastoma, the use of aptamers in pediatric neuro-oncology remains unexplored. This review will discuss the biology of aptamers, including mechanisms of targeting cell surface proteins, various modifications of aptamer structure to enhance therapeutic efficacy, the current state and challenges of aptamer use in neuro-oncology, and the potential therapeutic role of aptamers in pediatric brain tumors.
Nicotinic Receptor Subunits Atlas in the Adult Human Lung

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AECs) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lungs of smokers and non-smokers using transcriptomic data for whole-lung tissues, isolated large AECs, and isolated small AECs. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified an nAChR transcriptomic print at the single-cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChR subunits to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases.
LOW TEMPERATURE HEAT-TREATMENT CYCLE ON AlSi10Mg_200C ALLOY FABRICATED BY DIRECT LASER METAL SINTERING: MICROSTRUCTURE EVOLUTION AND CORROSION RESISTIVITY

This study examines the impact of low-temperature heat-treatment cycles on microstructure and corrosion performance of Direct Metal Laser Sintered (DMLS) AlSi10Mg_200C alloy. It is known that the morphology and the size of eutectic silicon are the two most critical factors affecting mechanical properties of the AlSi10Mg alloy. Although high-temperature heat-treatment cycles are common practice for the strengthening of the cast Al-Si-Mg alloys, in the case of DMLS fabricated AlSi10Mg alloy, hightemperature solutionizing and low temperature annealing cycles result in mechanical properties degradation primarily due to a dramatic decrease in the solubility of Si in the super-saturated α-Al matrix of the as-printed alloy. In this study, low-temperature heat-treatment cycles that only promote precipitation of Mg2Si accompanied by the interruption of the silicon network were investigated. SEM and XRD analysis were utilized to observe the evolution of microstructure after different annealing heat-treatments at 200, 250, 300, and 350°C for 3 h. Increasing the heat-treatment temperature contributed to the Si networks interruption and an increased precipitation of Mg2Si phase. Low-temperature annealing from 200 to 350°C was found to promote the homogeneity of the microstructure characterized by a uniform distribution of eutectic Si in α-Al matrix. Additionally, in order to investigate the impact of different heat-treatment cycles on corrosion resistivity of DMLS-AlSi10Mg_200C, the potentiodynamic polarization testing and electrochemical impedance spectroscopy were performed in a 3.5 wt. % NaCl solution. The results revealed more uniformly distributed pitting attack on the corroded surface by further increase in the annealing temperature, which was attributed to the uniformity of Si dispersion. In comparison, low temperature annealing at 200°C led to a penetrating selective corrosion attack along the melt pool boundaries, resulting in a higher corrosion rate associated with the lower absolute value of impedance of the protective passive film on the surface.
“The structure of the Type III secretion system export gate with CdsO, an ATPase lever arm”

Type III protein secretion systems (T3SS) deliver effector proteins from the Gram-negative bacterial cytoplasm into a eukaryotic host cell through a syringe-like, multi-protein nanomachine. Cytosolic components of T3SS include a portion of the export apparatus, which traverses the inner membrane and features the opening of the secretion channel, and the sorting complex for substrate recognition and for providing the energetics required for protein secretion. Two components critical for efficient effector export are the export gate protein and the ATPase, which are proposed to be linked by the central stalk protein of the ATPase. We present the structure of the soluble export gate homo-nonamer, CdsV, in complex with the central stalk protein, CdsO, of its cognate ATPase, both derived from Chlamydia pneumoniae. This structure defines the interface between these essential T3S proteins and reveals that CdsO engages the periphery of the export gate that may allow the ATPase to catalyze an opening between export gate subunits to allow cargo to enter the export apparatus. We also demonstrate through structure-based mutagenesis of the homologous export gate in Pseudomonas aeruginosa that mutation of this interface disrupts effector secretion. These results provide novel insights into the molecular mechanisms governing active substrate recognition and translocation through a T3SS.
The β1 integrin plays a key role in lymphatic endothelial cell invasion in an optimized 3D Collagen matrix model.

Lymphangiogenesis or formation of new lymphatic vessels, is a tightly regulated process that is controlled by growth factor signaling and biomechanical cues. Lymphatic endothelial cells (LECs) undergo remodeling, migration and proliferation to invade the surrounding extracellular matrix (ECM) during both physiological and pathological lymphangiogenesis. This study optimized conditions for an in vitro 3D collagen-based model that induced LEC invasion and recapitulated physiological formation of lymphatic capillaries with lumens. Invasion of LECs was enhanced in the presence of Sphingosine 1-phosphate (S1P). Effects of various known lymphangiogenic factors, vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (bFGF), interleukin 8 (IL-8), and hepatocyte growth factor (HGF) were tested on LEC sprout formation synergistically with VEGF-C. Several of these growth factors significantly enhanced LEC invasion while synergistic effects of some of these further enhanced the sprouting density and lumen volume. To determine the contribution of specific ECM components, we analyzed the expression of different integrin subunits. Basal expression of the integrin α5 and integrin β1 subunits were high in LECs. The addition of fibronectin, which mediates cellular responses through these integrins, enhanced LEC sprouting density and sprout length dose-dependently. siRNA mediated knockdown of the integrin β1 subunit suppressed LEC invasion. Further, exposing LECs to the inflammatory mediator, LPS inhibited sprouting. This optimized model for LEC invasion, includes S1P, VEGF-C and fibronectin within a 3D collagen matrix, along with VEGF-C, VEGF-A, bFGF and HGF in the culture medium, providing a useful tool to investigate the effect of various lymphangiogenic factors and inhibitors.
The Multimodal Serotonergic Agent Vilazodone Inhibits L-DOPA-Induced Gene Regulation in Striatal Projection Neurons and Associated Dyskinesia in an Animal Model of Parkinson’s Disease

Levodopa (L-DOPA) treatment in Parkinson’s disease is limited by the emergence of L-DOPA-induced dyskinesia. Such dyskinesia is associated with aberrant gene regulation in neurons of the striatum, which is caused by abnormal dopamine release from serotonin terminals. Previous work showed that modulating the striatal serotonin innervation with selective serotonin reuptake inhibitors (SSRIs) or 5-HT1A receptor agonists could attenuate L-DOPA-induced dyskinesia. We investigated the effects of a novel serotonergic agent, vilazodone, which combines SSRI and 5-HT1A partial agonist properties, on L-DOPA-induced behavior and gene regulation in the striatum in an animal model of Parkinson’s disease. After unilateral dopamine depletion by 6-hydroxydopamine (6-OHDA), rats received repeated L-DOPA treatment (5 mg/kg) alone or in combination with vilazodone (10 mg/kg) for 3 weeks. Gene regulation was then mapped throughout the striatum using in situ hybridization histochemistry. Vilazodone suppressed the development of L-DOPA-induced dyskinesia and turning behavior but did not interfere with the prokinetic effects of L-DOPA (forelimb stepping). L-DOPA treatment drastically increased the expression of dynorphin (direct pathway), 5-HT1B, and zif268 mRNA in the striatum ipsilateral to the lesion. These effects were inhibited by vilazodone. In contrast, vilazodone had no effect on enkephalin expression (indirect pathway) or on gene expression in the intact striatum. Thus, vilazodone inhibited L-DOPA-induced gene regulation selectively in the direct pathway of the dopamine-depleted striatum, molecular changes that are considered critical for L-DOPA-induced dyskinesia. These findings position vilazodone, an approved antidepressant, as a potential adjunct medication for the treatment of L-DOPA-induced motor side effects.
Comparing Web-Based Mindfulness With Loving-Kindness and Compassion Training for Promoting Well-Being in Pregnancy: Protocol for a Three-Arm Pilot Randomized Controlled Trial

Background Promoting psychological well-being and preventing distress among pregnant women is an important public health goal. In addition to adversely impacting the mother’s health and well-being, psychological distress in pregnancy increases the risk of poor pregnancy outcomes, compromises infant socioemotional development and bonding, and heightens maternal and child vulnerability in the postpartum period. Mindfulness and compassion-based interventions show potential for prevention and early intervention for perinatal distress. As there is an established need for accessible, scalable, flexible, and low-cost interventions, there is increased interest in the delivery of these programs on the web. This project aims to pilot a three-arm randomized controlled trial (RCT) to determine the feasibility of a full-scale RCT comparing 2 web-based interventions (mindfulness vs loving-kindness and compassion) with a web-based active control condition (progressive muscle relaxation). Objective The primary objective of this study is to assess the feasibility of an RCT protocol comparing the 3 conditions delivered on the web as a series of instructional materials and brief daily practices over a course of 8 weeks. The second objective is to explore the experiences of women in the different intervention conditions. The third objective is to estimate SD values for the outcome measures to inform the design of an adequately powered trial to determine the comparative efficacy of the different conditions. Methods Pregnant women (n=75) participating in a longitudinal birth cohort study (the ORIGINS project) will be recruited to this study from 18 weeks of gestational age. We will assess the acceptability and feasibility of recruitment and retention strategies and the participants’ engagement and adherence to the interventions. We will also assess the experiences of women in each of the 3 intervention conditions by measuring weekly changes in their well-being and engagement with the program and by conducting a qualitative analysis of postprogram interviews. Results This project was funded in September 2019 and received ethics approval on July 8, 2020. Enrollment to the study will commence in September 2020. Feasibility of a full-scale RCT will be assessed using ADePT (a process for decision making after pilot and feasibility trials) criteria. Conclusions If the study is shown to be feasible, results will be used to inform future full-scale RCTs. Evidence for flexible, scalable, and low-cost interventions could inform population health strategies to promote well-being and reduce psychological distress among pregnant women. Trial Registration Australian New Zealand Clinical Trials Registry Number 12620000672954p; http://anzctr.org. au/ACTRN12620000672954p.aspx International Registered Report Identifier (IRRID) PRR1-10.2196/19803
Higher Social Anxiety Severity Predicts Better Cognitive Empathy Performance in Women but Not Men

Findings regarding relationships between social anxiety and subtypes of empathy have been mixed, and one study suggested that this may be due to moderation by biological sex. The present study examined whether accounting for general anxiety and biological sex clarifies these relationships. Undergraduates (N = 701, 76% female) completed online self-report measures of cognitive and affective empathy, social and general anxiety severity, and a behavioral measure of cognitive empathy (Reading the Mind in the Eyes Task; MIE). Path analysis examined relationships among social and general anxiety severity and affective and cognitive empathy. Model modification indices showed a significant influence of sex on the path from social anxiety severity to MIE accuracy. When the model was re-estimated with this path freed, more socially anxious women, but not men, showed greater MIE accuracy. Across both sexes, general anxiety severity related negatively to self-reported and behavioral (MIE) cognitive empathy. Affective empathy did not relate to either type of anxiety. The use of path analysis to simultaneously account for overlapping variance among measures of anxiety and empathy helps clarify earlier mixed findings on relationships between social anxiety and empathy subtypes.
Spinal cord stimulation using differential target multiplexed programming modulates neural cell-specific transcriptomes in an animal model of neuropathic pain

Spinal cord stimulation is a proven effective therapy for treating chronic neuropathic pain. Previous work in our laboratory demonstrated that spinal cord stimulation based on a differential target multiplexed programming approach provided significant relief of pain-like behavior in rodents subjected to the spared nerve injury model of neuropathic pain. The relief was significantly better than obtained using high rate and low rate programming. Furthermore, transcriptomics-based results implied that differential target multiplexed programming modulates neuronal–glial interactions that have been perturbed by the pain process. Although differential target multiplexed programming was developed to differentially target neurons and glial cells, our previous work did not address this. This work presents transcriptomes, specific to each of the main neural cell populations (neurons, microglia, astrocytes, and oligodendrocytes), obtained from spinal cord subjected to continuous spinal cord stimulation treatment with differential target multiplexed programming, high rate programming, or low rate programming compared with no spinal cord stimulation treatment, using the spared nerve injury model. To assess the effect of each spinal cord stimulation treatment on these cell-specific transcriptomes, gene expression levels were compared with that of healthy animals, naïve to injury and interventional procedures. Pearson correlations and cell population analysis indicate that differential target multiplexed programming yielded strong and significant correlations to expression levels found in the healthy animals across every evaluated cell-specific transcriptome. In contrast, high rate programming only yielded a strong correlation for the microglia-specific transcriptome, while low rate programming did not yield strong correlations with any cell types. This work provides evidence that differential target multiplexed programming distinctively targeted and modulated the expression of cell-specific genes in the direction of the healthy state thus supporting its previously established action on regulating neuronal–glial interaction processes in a pain model.