Hybrid modeling of an ultracentrifugation process for separation of full and empty adeno-associated virus particles.

Ultracentrifugation is an attractive method for separating full and empty capsids, exploiting their density difference. Changes of the serotype/capsid, density of loading material, or the genetic information contained in the adeno-associated viruses (AAVs) require the adaptation of the harvesting parameters and the density gradient loaded onto the centrifuge. To streamline these adaptations, a mathematical model could support the design and testing of operating conditions.Here, hybrid models, which combine empirical functions with artificial neural networks, are proposed to describe the separation of full and empty capsids as a function of material and operational parameters, i.e., the harvest model. In addition, critical quality attributes are estimated by a quality model which is operating on top of the harvest model. The performance of these models was evaluated using test data and two additional blind runs. Also, a "what-if" analysis was conducted to investigate whether the models' predictions align with expectations.It is concluded that the models are sufficiently accurate to support the design of operating conditions, though the accuracy and applicability of the models can further be increased by training them on more specific data with higher variability.

Heterogeneity of determining disease severity, clinical course and outcomes in systemic sclerosis-associated interstitial lung disease: a systematic literature review.

Objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable and different from continuously progressive idiopathic pulmonary fibrosis (IPF). Most proposed definitions of progressive pulmonary fibrosis or SSc-ILD severity are based on the research data from patients with IPF and are not validated for patients with SSc-ILD. Our study aimed to gather the current evidence for severity, progression and outcomes of SSc-ILD.Methods A systematic literature review to search for definitions of severity, progression and outcomes recorded for SSc-ILD was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in Medline, Embase, Web of Science and Cochrane Library up to 1 August 2023.Results A total of 9054 papers were reviewed and 342 were finally included. The most frequent tools used for the definition of SSc-ILD progression and severity were combined changes of carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC), isolated FVC or DLCO changes, high-resolution CT (HRCT) extension and composite algorithms including pulmonary function test, clinical signs and HRCT data. Mortality was the most frequently reported long-term event, both from all causes or ILD related.Conclusions The studies presenting definitions of SSc-ILD 'progression', 'severity' and 'outcome' show a large heterogeneity. These results emphasise the need for developing a standardised, consensus definition of severe SSc-ILD, to link a disease specific definition of progression as a surrogate outcome for clinical trials and clinical practice.PROSPERO registration number CRD42022379254.Cite Now.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Autoimmune Rheumatic and Non Rheumatic Diseases.

The soluble urokinase plasminogen activator receptor (suPAR) is the bioactive form of uPAR, a membrane-bound glycoprotein, and it is primarily expressed on the surface of immunologically active cells. Mirroring local inflammation and immune activation, suPAR has gained interest as a potential prognostic biomarker in several inflammatory diseases. Indeed, in many diseases, including cancer, diabetes, cardiovascular diseases, kidney diseases, and inflammatory disorders, higher suPAR concentrations have been associated with disease severity, disease relapse, and mortality. Our review describes and discusses the supporting literature concerning the promising role of suPAR as a biomarker in different autoimmune rheumatic and non-rheumatic diseases.

Circulating Calprotectin (cCLP) in autoimmune diseases.

BACKGROUND AND AIM: Calprotectin (CLP) is a heterodimeric complex formed by two S100 proteins (S100A8/A9), which plays a pivotal role in innate immunity. Due to its intrinsic cytotoxic and proinflammatory properties, CLP controls cell differentiation, proliferation and NETosis and has been associated with a wide range of rheumatic diseases. Our review summarizes the widespread interest in circulating CLP (cCLP) as a biomarker of neutrophil-related inflammation, in autoimmune rheumatic disease (ARD) and non-ARD. METHODS: A thorough literature review was performed using PubMed and EMBASE databases searching for circulating calprotectin and synonyms S100A8/A9, myeloid-related protein 8/14 (MRP8/MRP14), calgranulin A/B and L1 protein in addition to specific ARDs and autoimmune non-rheumatic diseases. We selected only English-language articles and excluded abstracts without the main text. RESULTS: High cCLP serum levels are associated with worse structural outcomes in rheumatoid arthritis and to a lesser extent, in spondyloarthritis. In addition, cCLP can predict disease relapse in some autoimmune diseases including systemic lupus erythematosus (SLE), anti-neutrophil cytoplasmic antibodies-associated vasculitis (AAV) and some severe manifestations of connective tissue diseases, such as glomerulonephritis in SLE, AAV, juvenile idiopathic arthritis, adult-onset Still's disease and lung fibrosis in systemic sclerosis. Therefore, cCLP levels enable the identification of patients who need an accurate and tight follow-up. The clinical usefulness of cCLP as an inflammatory marker has been suggested for inflammatory/autoimmune non-rheumatic diseases, and especially for the monitoring of the inflammatory bowel diseases patients. Currently, there are only a few studies that evaluated the cCLP efficacy as a clinical biomarker in inflammatory/autoimmune non-rheumatic diseases with controversial results. Future studies are warranted to better clarify the role of cCLP in relation to the disease severity in myasthenia gravis, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, Graves' orbitopathy, autoimmune bullous diseases and uveitis. CONCLUSION: Our literature review supports a relevant role of cCLP as potential prognostic biomarker mirroring local or systemic inflammation, especially in chronic inflammatory rheumatic diseases.

JAK inhibitors and autoimmune rheumatic diseases.

The four Janus kinase (JAK) proteins and the seven Signal Transducers of Activated Transcription (STAT) mediate intracellular signal transduction downstream of cytokine receptors, which are involved in the pathology of allergic, autoimmune, and inflammatory diseases. The development of targeted small-molecule treatments with diverse selective inhibitory profiles, such as JAK inhibitors (JAKi), has supported an important change in the treatment of multiple disorders. Indeed, JAKi inhibit intracellular signalling controlled by numerous cytokines implicated in the disease process of rheumatoid arthritis and several other inflammatory and immune diseases. Therefore, JAKi have the capacity to target multiple pathways of those diseases. Other autoimmune diseases treated with JAKi include systemic sclerosis, systemic lupus erythematosus, dermatomyositis, primary Sjogren's syndrome, and vasculitis. In all of these cases, innate immunity stimulation activates adaptive immunity, resulting in the production of autoreactive T cells as well as the stimulation and differentiation of B cells. Mechanism-based treatments that target JAK-STAT pathways have the possibility of improving outcomes by reducing the consumption of glucocorticoids and/or non-specific immunosuppressive drugs in the management of systemic immune-mediated inflammatory diseases.

May a Nonlocalized Postactivation Performance Enhancement Exist Between the Upper and Lower Body in Trained Men?

ABSTRACT: Bartolomei, S, De Luca, R, and Marcora, SM. May a nonlocalized postactivation performance enhancement exist between the upper and lower body in trained men? J Strength Cond Res 37(1): 68-73, 2023-The aim of this study was to establish whether a resistance exercise for the upper body may generate a postactivation performance enhancement (PAPE) in the lower body. Thirteen resistance-trained men (age = 26.4 ± 3.3 years, body mass = 76.9 ± 6.3 kg, and height = 177.6 ± 5.2 cm) participated in the present investigation and were tested for upper-body and lower-body power (bench press throw and countermovement jump power [CMJP] tests). Subjects were also tested for maximum force and electromyographic (EMG) activation of quadriceps muscles while performing an isometric leg extension. All assessments were performed before and 8 minutes after a high-intensity (HI: 5 sets of 1 rep at 90% of 1 repetition maximum [1RM]) bench press protocol, a high-power protocol (POW: 5 sets of 1 rep at 30% of 1RM with maximum explosive intent), and a control trial (CON). Subjects performed all trials in a randomized order and on different days. A significant trial × time interaction was detected for CMJP ( p = 0.049). This parameter was significantly increased following the HI protocol only ( p = 0.024). A significant interaction was also noted for EMG with a significant improvement following the HI protocol ( p = 0.032) and a significant decrease following the POW protocol ( p = 0.020). No other significant effects were detected ( p > 0.05). The results of this investigation indicate that a HI bench press protocol may produce a PAPE in the lower-body power and increase the neuromuscular activation of leg extensor muscles. The POW bench press protocol did not show any positive effects on lower-body performance. Athletes and practitioners may take advantage from the inclusion of upper-body HI resistance exercises throughout complex resistance workouts to improve lower-body power output.

Empirical mode decomposition analysis of near-infrared spectroscopy muscular signals to assess the effect of physical activity in type 2 diabetic patients.

Type 2 diabetes is a metabolic disorder that may cause major problems to several physiological systems. Exercise has proven to be very effective in the prevention, management and improvement of this pathology in patients. Muscle metabolism is often studied with near-infrared spectroscopy (NIRS), a noninvasive technique that can measure changes in the concentration of oxygenated (O2Hb) and reduced hemoglobin (HHb) of tissues. These NIRS signals are highly non-stationary, non-Gaussian and nonlinear in nature. The empirical mode decomposition (EMD) is used as a nonlinear adaptive model to extract information present in the NIRS signals. NIRS signals acquired from the tibialis anterior muscle of controls and type 2 diabetic patients are processed by EMD to yield three intrinsic mode functions (IMF). The sample entropy (SE), fractal dimension (FD), and Hurst exponent (HE) are computed from these IMFs. Subjects are monitored at the beginning of the study and after one year of a physical training programme. Following the exercise programme, we observed an increase in the SE and FD and a decrease in the HE in all diabetic subjects. Our results show the influence of physical exercise program in improving muscle performance and muscle drive by the central nervous system in the patients. A multivariate analysis of variance performed at the end of the training programme also indicated that the NIRS metabolic patterns of controls and diabetic subjects are more similar than at the beginning of the study. Hence, the proposed EMD technique applied to NIRS signals may be very useful to gain a non-invasive understanding of the neuromuscular and vascular impairment in diabetic subjects.

Entropy analysis of muscular near-infrared spectroscopy (NIRS) signals during exercise programme of type 2 diabetic patients: quantitative assessment of muscle metabolic pattern.

Diabetes mellitus (DM) is a metabolic disorder that is widely rampant throughout the world population these days. The uncontrolled DM may lead to complications of eye, heart, kidney and nerves. The most common type of diabetes is the type 2 diabetes or insulin-resistant DM. Near-infrared spectroscopy (NIRS) technology is widely used in non-invasive monitoring of physiological signals. Three types of NIRS signals are used in this work: (i) variation in the oxygenated haemoglobin (O2Hb) concentration, (ii) deoxygenated haemoglobin (HHb), and (iii) ratio of oxygenated over the sum of the oxygenated and deoxygenated haemoglobin which is defined as: tissue oxygenation index (TOI) to analyze the effect of exercise on diabetes subjects. The NIRS signal has the characteristics of non-linearity and non-stationarity. Hence, the very small changes in this time series can be efficiently extracted using higher order statistics (HOS) method. Hence, in this work, we have used sample and HOS entropies to analyze these NIRS signals. These computer aided techniques will assist the clinicians to diagnose and monitor the health accurately and easily without any inter or intra observer variability. Results showed that after a one-year of physical exercise programme, all diabetic subjects increased the sample entropy of the NIRS signals, thus revealing a better muscle performance and an improved recruitment by the central nervous system. Moreover, after one year of physical therapy, diabetic subjects showed a NIRS muscular metabolic pattern that was not distinguished from that of controls. We believe that sample and bispectral entropy analysis is need when the aim is to compare the inner structure of the NIRS signals during muscle contraction, particularly when dealing with neuromuscular impairments.