Miracle-dz/UniFAR-FTUs huggingface dataset:
CMR Measures of Left Atrial Volume Index and Right Ventricular Function Have Prognostic Value in Chronic Thromboembolic Pulmonary Hypertension

Providing prognostic information is important when counseling patients and planning treatment strategies in chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to assess the prognostic value of gold standard imaging of cardiac structure and function using cardiac magnetic resonance imaging (CMR) in CTEPH. Consecutive treatment-naive patients with CTEPH who underwent right heart catheterization and CMR between 2011 and 2017 were identified from the ASPIRE (Assessing-the-Specturm-of-Pulmonary-hypertensIon-at-a-REferral-center) registry. CMR metrics were corrected for age and sex where appropriate. Univariate and multivariate regression models were generated to assess the prognostic ability of CMR metrics in CTEPH. Three hundred and seventy-five patients (mean+/-standard deviation: age 64+/-14 years, 49% female) were identified and 181 (48%) had pulmonary endarterectomy (PEA). For all patients with CTEPH, left-ventricular-stroke-volume-index-%predicted (LVSVI%predicted) (p = 0.040), left-atrial-volume-index (LAVI) (p = 0.030), the presence of comorbidities, incremental shuttle walking test distance (ISWD), mixed venous oxygen saturation and undergoing PEA were independent predictors of mortality at multivariate analysis. In patients undergoing PEA, LAVI (p < 0.010), ISWD and comorbidities and in patients not undergoing surgery, right-ventricular-ejection-fraction-%predicted (RVEF%pred) (p = 0.040), age and ISWD were independent predictors of mortality. CMR metrics reflecting cardiac function and left heart disease have prognostic value in CTEPH. In those undergoing PEA, LAVI predicts outcome whereas in patients not undergoing PEA RVEF%pred predicts outcome. This study highlights the prognostic value of imaging cardiac structure and function in CTEPH and the importance of considering left heart disease in patients considered for PEA.
Effects of Receptor Specificity and Conformational Stability of Influenza A Virus Hemagglutinin on Infection and Activation of Different Cell Types in Human PBMCs

Humans can be infected by zoonotic avian, pandemic and seasonal influenza A viruses (IAVs), which differ by receptor specificity and conformational stability of their envelope glycoprotein hemagglutinin (HA). It was shown that receptor specificity of the HA determines the tropism of IAVs to human airway epithelial cells, the primary target of IAVs in humans. Less is known about potential effects of the HA properties on viral attachment, infection and activation of human immune cells. To address this question, we studied the infection of total human peripheral blood mononuclear cells (PBMCs) and subpopulations of human PBMCs with well characterized recombinant IAVs differing by the HA and the neuraminidase (NA) but sharing all other viral proteins. Monocytes and all subpopulations of lymphocytes were significantly less susceptible to infection by IAVs with avian-like receptor specificity as compared to human-like IAVs, whereas plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells were equally susceptible to IAVs with avian-like and human-like receptor specificity. This tropism correlated with the surface expression of 2-3-linked sialic acids (avian-type receptors) and 2-6-linked sialic acids (human-type receptors). Despite a reduced infectivity of avian-like IAVs for PBMCs, these viruses were not less efficient than human-like IAVs in terms of cell activation as judged by the induction of cellular mRNA of IFN-α, CCL5, RIG-I, and IL-6. Elevated levels of IFN-α mRNA were accompanied by elevated IFN-α protein secretion in primary human pDC. We found that high basal expression in monocytes of antiviral interferon-induced transmembrane protein 3 (IFITM3) limited viral infection in these cells. siRNA-mediated knockdown of IFITM3 in monocytes demonstrated that viral sensitivity to inhibition by IFITM3 correlated with the conformational stability of the HA. Our study provides new insights into the role of host- and strain-specific differences of HA in the interaction of IAVs with human immune cells and advances current understanding of the mechanisms of viral cell tropism, pathogenesis and markers of virulence.
Interleukin-17a Induces Neuronal Differentiation of Induced-Pluripotent Stem Cell-Derived Neural Progenitors From Autistic and Control Subjects

Prenatal exposure to maternal immune activation (MIA) has been suggested to increase the probability of autism spectrum disorder (ASD). Recent evidence from animal studies indicates a key role for interleukin-17a (IL-17a) in promoting MIA-induced behavioral and brain abnormalities reminiscent of ASD. However, it is still unclear how IL-17a acts on the human developing brain and the cell types directly affected by IL-17a signaling. In this study, we used iPSC-derived neural progenitor cells (NPCs) from individuals with ASD of known and unknown genetic cause as well as from neurotypical controls to examine the effects of exogenous IL-17a on NPC proliferation, migration and neuronal differentiation, and whether IL-17a and genetic risk factors for ASD interact exacerbating alterations in NPC function. We observed that ASD and control NPCs endogenously express IL-17a receptor (IL17RA), and that IL-17a/IL17RA activation modulates downstream ERK1/2 and mTORC1 signaling pathways. Exogenous IL-17a did not induce abnormal proliferation and migration of ASD and control NPCs but, on the other hand, it significantly increased the expression of synaptic (Synaptophysin-1, Synapsin-1) and neuronal polarity (MAP2) proteins in these cells. Also, as we observed that ASD and control NPCs exhibited similar responses to exogenous IL-17a, it is possible that a more inflammatory environment containing other immune molecules besides IL-17a may be needed to trigger gene-environment interactions during neurodevelopment. In conclusion, our results suggest that exogenous IL-17a positively regulates the neuronal differentiation of human NPCs, which may disturb normal neuronal and synaptic development and contribute to MIA-related changes in brain function and behavior.
Transcutaneous Electrical Acupoint Stimulation Decreases the Incidence of Postoperative Nausea and Vomiting After Laparoscopic Non-gastrointestinal Surgery: A Multi-Center Randomized Controlled Trial

Importance Postoperative nausea and vomiting (PONV) gives patients a bad experience and negates their good recovery from surgery. Objective This trial aims to assess the preventive effectiveness of transcutaneous electrical acupoint stimulation (TEAS) on the incidence of PONV in high-risk surgical patients. Design The large sample size, multicenter, evaluator-blinded, and randomized controlled study was conducted between September 3, 2019 to February 6, 2021. Setting The 12 hospitals were from different Chinese provinces. Participants After obtaining ethics approval and written informed consent, 1,655 patients with Apfel score ≥ 3 points were enrolled for selective laparoscopic non-gastrointestinal surgery under general anesthesia. Interventions Patients were randomly allocated into the TEAS and Sham group with a 1:1 ratio. The TEAS group was stimulated on bilateral Neiguan and Zusanli acupoints after recovery from anesthesia on the surgical day and the next morning for 30 min, while the Sham group received an identical setting as TEAS but without currents delivered. Electronic patient self-reported scale was used to evaluate and record the occurrence of PONV. Main Outcomes and Measures Primary clinical end point is the incidence of PONV which was defined as at least one incidence of nausea, retching, or vomiting after operation within postoperative 24 h. Results Compared with the Sham treatment, the TEAS lowered the PONV incidence by 4.8% (29.4 vs. 34.2%, P = 0.036) and vomiting incidence by 7.4% (10.4 vs. 17.8%, P < 0.001). TEAS also lowered persistent nausea incidence and PONV scores and decreased PONV related complications and Quality of Recovery−40 scores (P < 0.05). TEAS lowered the 24 h PONV risk by 20% (OR, 0.80, 95% CI, 0.65 −0.98; P = 0.032), and lowered hazard ratio by 17% (HR, 0.83, 95% CI, 0.70–0.99; P = 0.035). Both TEAS and palonosetron were the independent PONV risk protective factors for 24 h PONV incidence and cumulative PONV incidence. The combination of TEAS and palonosetron was the most effective strategy to reduce the PONV incidence (P < 0.001). Conclusions and Relevance TEAS attenuated the PONV incidence and severity in high-risk surgical patients and may be applied clinically as a complement therapy to prevent PONV. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT04043247, identifier: NCT04043247.
Design and Characterization of Paclitaxel-Loaded Polymeric Nanoparticles Decorated With Trastuzumab for the Effective Treatment of Breast Cancer

The aim of the study was to design and formulate an antibody-mediated targeted, biodegradable polymeric drug delivery system releasing drug in a controlled manner to achieve a therapeutic goal for the effective treatment of breast cancer. Antibody-mediated paclitaxel-loaded PLGA polymeric nanoformulations were prepared by the solvent evaporation method using different experimental parameters and compatibility studies. The optimized formulations were selected for in vitro and in vivo evaluation and cytotoxicity studies. The in vitro drug release studies show a biphasic release pattern for the paclitaxel-loaded PLGA nanoparticles showing a burst release for 24 h followed by an extended release for 14 days; however, a more controlled and sustained release was observed for antibody-conjugated polymeric nanoparticles. The cytotoxicity of reference drug and paclitaxel-loaded PLGA nanoparticles with and without antibody was determined by performing MTT assay against MCF-7 cells. Rabbits were used as experimental animals for the assessment of various in vivo pharmacokinetic parameters of selected formulations. The pharmacokinetic parameters such as Cmax (1.18–1.33 folds), AUC0-t (39.38–46.55 folds), MRT (10.04–12.79 folds), t1/2 (3.06–4.6 folds), and Vd (6.96–8.38 folds) have been increased significantly while clearance (4.34–4.61 folds) has been decreased significantly for the selected nanoformulations as compared to commercially available paclitaxel formulation (Paclixil®). The surface conjugation of nanoparticles with trastuzumab resulted in an increase in in vitro cytotoxicity as compared to plain nanoformulations and commercially available conventional brand (Paclixil®). The developed PLGA-paclitaxel nanoformulations conjugated with trastuzumab have the desired physiochemical characteristics, surface morphology, sustained release kinetics, and enhanced targeting.
Dietary Nitrate Supplementation Is Not Helpful for Endurance Performance at Simulated Altitude Even When Combined With Intermittent Normobaric Hypoxic Training

Introduction Training intensity and nutrition may influence adaptations to training performed in hypoxia and consequently performance outcomes at altitude. This study investigates if performance at simulated altitude is improved to a larger extent when high-intensity interval training is performed in normobaric hypoxia and if this is potentiated when combined with chronic dietary nitrate (NO3−) supplementation. Methods Thirty endurance-trained male participants were allocated to one of three groups: hypoxia (13% FiO2) + NO3−; hypoxia + placebo; and normoxia (20.9% FiO2) + placebo. All performed 12 cycling sessions (eight sessions of 2*6 × 1 min at severe intensity with 1 min recovery and four sessions of 4*6*10 s all-out with 20 s recovery) during a 4-week period (three sessions/week) with supplementation administered 3–2.5 h before each session. An incremental exhaustion test, a severe intensity exercise bout to exhaustion (Tlim) and a 3 min all-out test (3AOT) in hypoxia (FiO2 = 13%) with pulmonary oxygen uptake ( V ˙ O2), V ˙ O2 kinetics, and changes in vastus lateralis local O2 saturation (SmO2) measured were completed by each participant before and after training. Results In all tests, performance improved to the same extent in hypoxia and normoxia, except for SmO2 after Tlim (p = 0.04, d = 0.82) and 3AOT (p = 0.03, d = 1.43) which were lower in the two hypoxic groups compared with the normoxic one. Dietary NO3− supplementation did not bring any additional benefits. Conclusion Performance at simulated altitude was not improved to a larger extent when high-intensity interval training was undertaken in normobaric hypoxic conditions, when compared with normoxic training. Additionally, dietary NO3− supplementation was ineffective in further enhancing endurance performance at simulated altitude.
The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

Transplantation of allogenic hematopoietic stem and progenitor cells (HSPCs) with C-C chemokine receptor type 5 (CCR5) Δ32 genotype generates HIV-1 resistant immune cells. CCR5 gene edited autologous HSPCs can be a potential alternative to hematopoietic stem cell transplantation (HSCT) from HLA-matched CCR5 null donor. However, the clinical application of gene edited autologous HSPCs is critically limited by the quality of the graft, as HIV also infects the HSPCs. In this study, by using mobilized HSPCs from healthy donors, we show that the CD34+CD90+ hematopoietic stem cells (HSCs) express 7-fold lower CD4/CCR5 HIV receptors, higher levels of SAMHD1 anti-viral restriction factor, and possess lower susceptibility to HIV infection than the CD34+CD90- hematopoietic progenitor cells. Further, the treatment with small molecule cocktail of Resveratrol, UM729 and SR1(RUS) improved the in vivo engraftment potential of CD34+CD90+ HSCs. To demonstrate that CD34+CD90+ HSC population as an ideal graft for HIV gene therapy, we sort purified CD34+CD90+ HSCs, treated with RUS and then gene edited the CCR5 with single sgRNA. On transplantation, 100,000 CD34+CD90+ HSCs were sufficient for long-term repopulation of the entire bone marrow of NBSGW mice. Importantly, the gene editing efficiency of ~90% in the infused product was maintained in vivo, facilitating the generation of CCR5 null immune cells, resistant to HIV infection. Altogether, CCR5 gene editing of CD34+CD90+ HSCs provide an ideal gene manipulation strategy for autologous HSCT based gene therapy for HIV infection.
Editorial: Improving Wellbeing in Patients With Chronic Conditions: Theory, Evidence, and Opportunities

1 School of Psychology, Faculty of Medicine, Health & Life Science, Swansea University, Swansea, United Kingdom, 2 Regional Neuropsychology and Community Brain Injury Service, Morriston Hospital, Swansea, United Kingdom, Department of Clinical Psychology and Psychological Therapies, Norwich Medical School, Univeristy of East Anglia, Norwich, United Kingdom, Health and Wellbeing Academy, Faculty of Medicine, Health and Life Science, Swansea University, Swansea, United Kingdom
Effect of Seasonal Variation on Relapse Rate in Patients With Relapsing-Remitting Multiple Sclerosis in Saudi Arabia

Multiple sclerosis (MS) is becoming a global subject of study in which some demographic variations are thought to be correlated with its activity. Relapsing-remitting multiple sclerosis (RRMS) is the most common demyelinating disorder, characterized by periods of exacerbating attacks, followed by partial or complete remission. Several factors might play a role in disease progression and relapse frequency, such as vitamin D, ultraviolet B radiation, estrogen levels, smoking, obesity, and unhealthy lifestyles. In this study, we identified the relationship between seasonal variation and relapse rate and correlated the latter with sex, age, and vitamin D levels in patients with RRMS in Jeddah, Saudi Arabia. We retrospectively collected data from 182 RRMS patients between 2016 and 2021. A total of 219 relapses were documented in 106 patients (58.2 %). The relapse per patient ratio showed a sinusoidal pattern, peaking in January at a rate of 0.49 and troughed in June at a rate of 0.18. There was no difference in relapse rates between men and women (p =0.280). There was a significant negative correlation between vitamin D levels and relapse rate (r = −0.312, p =0.024). Therefore, the relapse rate was higher during the winter and was correlated with low vitamin D levels. However, relapses are likely multifactorial, and more population-based studies are needed to understand the role of environmental variables in MS exacerbation. A better understanding of this relationship will allow for improved treatment and possibly better prevention of relapse.
Isolation of Extracellular Vesicles From Microalgae: A Renewable and Scalable Bioprocess

Extracellular vesicles (EVs) play a crucial role as potent signal transducers among cells, with the potential to operate cross-species and cross-kingdom communication. Nanoalgosomes are a subtype of EVs recently identified and isolated from microalgae. Microalgae represent a natural bioresource with the capacity to produce several secondary metabolites with a broad range of biological activities and commercial applications. The present study highlights the upstream and downstream processes required for the scalable production of nanoalgosomes from cultures of the marine microalgae Tetraselmis chuii. Different technical parameters, protocols, and conditions were assessed to improve EVs isolation by tangential flow filtration (TFF), aiming to enhance sample purity and yield. The optimization of the overall bioprocess was enhanced by quality control checks operated through robust biophysical and biochemical characterizations. Further, we showed the possibility of recycling by TFF microalgae cells post-EVs isolation for multiple EV production cycles. The present results highlight the potential of nanoalgosome production as a scalable, cost-effective bioprocess suitable for diverse scientific and industrial exploitations.
Isoforms of the Papillomavirus Major Capsid Protein Differ in Their Ability to Block Viral Spread and Tumor Formation

Notably, the majority of papillomaviruses associated with a high cancer risk have the potential to translate different isoforms of the L1 major capsid protein. In an infection model, the cutaneous Mastomys natalensis papillomavirus (MnPV) circumvents the humoral immune response of its natural host by first expressing a 30 amino acid extended L1 isoform (L1LONG). Although inducing a robust seroconversion, the raised antibodies are not neutralizing in vitro. In contrast, neutralizing antibodies induced by the capsid-forming isoform (L1SHORT) appear delayed by several months. We now provide evidence that, although L1LONG vaccination showed a strong seroconversion, these antibodies were not protective. As a consequence, virus-free animals subsequently infected with MnPV still accumulated high numbers of transcriptionally active viral genomes, ultimately leading to skin tumor formation. In contrast, vaccination with L1SHORT was completely protective. This shows that papillomavirus L1LONG expression is a unique strategy to escape from antiviral immune surveillance.
Mitochondrial Protein Akap1 Deletion Exacerbates Endoplasmic Reticulum Stress in Mice Exposed to Hyperoxia

Acute lung injury (ALI) and its severe manifestation, acute respiratory distress syndrome (ARDS), are treated with high concentrations of supplementary oxygen. However, prolonged exposure to high oxygen concentrations stimulates the production of reactive oxygen species (ROS), which damages the mitochondria and accumulates misfolded proteins in the endoplasmic reticulum (ER). The mitochondrial protein A-kinase anchoring protein 1 (Akap1) is critical for mitochondrial homeostasis. It is known that Akap1 deficiency results in heart damage, neuronal development impairment, and mitochondrial malfunction in preclinical studies. Our laboratory recently revealed that deleting Akap1 increases the severity of hyperoxia-induced ALI in mice. To assess the role of Akap1 deletion in ER stress in lung injury, wild-type and Akap1 −/− mice were exposed to hyperoxia for 48 h. This study indicates that Akap1 −/− mice exposed to hyperoxia undergo ER stress, which is associated with an increased expression of BiP, JNK phosphorylation, eIF2α phosphorylation, ER stress-induced cell death, and autophagy. This work demonstrates that deleting Akap1 results in increased ER stress in the lungs of mice and that hyperoxia exacerbates ER stress-related consequences.
Notochordal Cell-Based Treatment Strategies and Their Potential in Intervertebral Disc Regeneration

Chronic low back pain is the number one cause of years lived with disability. In about 40% of patients, chronic lower back pain is related to intervertebral disc (IVD) degeneration. The standard-of-care focuses on symptomatic relief, while surgery is the last resort. Emerging therapeutic strategies target the underlying cause of IVD degeneration and increasingly focus on the relatively overlooked notochordal cells (NCs). NCs are derived from the notochord and once the notochord regresses they remain in the core of the developing IVD, the nucleus pulposus. The large vacuolated NCs rapidly decline after birth and are replaced by the smaller nucleus pulposus cells with maturation, ageing, and degeneration. Here, we provide an update on the journey of NCs and discuss the cell markers and tools that can be used to study their fate and regenerative capacity. We review the therapeutic potential of NCs for the treatment of IVD-related lower back pain and outline important future directions in this area. Promising studies indicate that NCs and their secretome exerts regenerative effects, via increased proliferation, extracellular matrix production, and anti-inflammatory effects. Reports on NC-like cells derived from embryonic- or induced pluripotent-stem cells claim to have successfully generated NC-like cells but did not compare them with native NCs for phenotypic markers or in terms of their regenerative capacity. Altogether, this is an emerging and active field of research with exciting possibilities. NC-based studies demonstrate that cues from developmental biology can pave the path for future clinical therapies focused on regenerating the diseased IVD.
Isogeometric Analysis and Shape Optimal Design of Shell Structures

Isogeometric analysis is a new method of computational analysis with the goal of merging design and analysis into one common model. In this thesis, the isogeometric concept is applied to the analysis and shape optimization of shell structures. With the developed formulation it is possible to directly integrate analysis into a CAD design model. For shape optimization, this new approach offers large flexibility in defining the optimization model. The application to dynamic analyses of a wind turbine rotor blade shows the relevance of this method for industrial applications.