Regulation of stem cell dynamics through volume exclusion

Maintenance and regeneration of adult tissues rely on the self-renewal of stem cells. Regeneration without over-proliferation requires precise regulation of the stem cell proliferation and differentiation rates. The nature of such regulatory mechanisms in different tissues, and how to incorporate them in models of stem cell population dynamics, is incompletely understood. The critical birth-death (CBD) process is widely used to model stem cell populations, capturing key phenomena, such as population asymmetry and scaling laws in clone size distributions. However, the CBD process neglects regulatory mechanisms. Here, we propose the birth-death process with volume exclusion (vBD), a variation of the birth-death process that takes into account crowding effects, such as may arise due to limited space in a stem cell niche. While the deterministic rate equations predict a single non-trivial attracting steady state, the master equation predicts extinction and a transient distribution of stem cell numbers that can be bimodal. We investigate the accuracy of the system-size expansion (including finite size corrections to the linear-noise approximation), the quasi-steady state approximation, and the WKB method to approximate the probability distribution solution of the vBD master equation, as well as the mean extinction time. Our study suggests that the size distribution of a stem cell population and its extinction dynamics bear signatures that may be useful to detect negative feedback mediated via volume exclusion.Comment: 15 pages, 5 figure

Coupled oscillations of the Wilberforce pendulum unveiled by smartphones

Publicado en: American Journal of Physics, 2023, 91(11): 873-878. DOI: doi.org/10.1119/5.0138680The Wilberforce pendulum is a great experience for illustrating important properties of coupled oscillatory systems, such as normal modes and beat phenomena, in physics courses. A helical spring attached to a mass comprises this simple but colorful device that features longitudinal and torsional oscillations, catching the eye of students and teachers, and offering a fantastic environment to study coupled oscillations at qualitative and quantitative levels. However, the experimental setups that are commonly used to simultaneously acquire both oscillation types can be cumbersome and/or costly, often requiring two synchronised cameras, or motion sensors and photo-gates integrated by an expensive analog-to-digital converter. Here, we show that a smartphone can be the perfect device for recording the oscillations of a Wilberforce pendulum composed of just an educational helical spring and a can. Our setup employs a smartphone’s accelerator and gyroscope to acquire data from the longitudinal and torsional oscillations, respectively. This setup can successfully record both normal modes and beats. Furthermore, we show that our experimentally obtained time-series and power spectra are in great agreement with simulations of the motion equations. In addition, we critically analyse how to set the initial conditions to observe both normal modes and beats. We believe our study contributes to bring the striking physics of the Wilberforce pendulum closer to undergraduate classrooms with low-cost, highly-accessible materials

Improving the reporting quality of intervention trials addressing the inter-individual variability in response to the consumption of plant bioactives: quality index and recommendations

PURPOSE: The quality of the study design and data reporting in human trials dealing with the inter-individual variability in response to the consumption of plant bioactives is, in general, low. There is a lack of recommendations supporting the scientific community on this topic. This study aimed at developing a quality index to assist the assessment of the reporting quality of intervention trials addressing the inter-individual variability in response to plant bioactive consumption. Recommendations for better designing and reporting studies were discussed. METHODS: The selection of the parameters used for the development of the quality index was carried out in agreement with the scientific community through a survey. Parameters were defined, grouped into categories, and scored for different quality levels. The applicability of the scoring system was tested in terms of consistency and effort, and its validity was assessed by comparison with a simultaneous evaluation by experts' criteria. RESULTS: The "POSITIVe quality index" included 11 reporting criteria grouped into four categories (Statistics, Reporting, Data presentation, and Individual data availability). It was supported by detailed definitions and guidance for their scoring. The quality index score was tested, and the index demonstrated to be valid, reliable, and responsive. CONCLUSIONS: The evaluation of the reporting quality of studies addressing inter-individual variability in response to plant bioactives highlighted the aspects requiring major improvements. Specific tools and recommendations favoring a complete and transparent reporting on inter-individual variability have been provided to support the scientific community on this field

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C : A prospective observational study

Niemann-Pick disease type C (NP-C) is a rare, autosomal recessive neurodegenerative disease caused by mutations in either the NPC1 or NPC2 genes. The diagnosis of NP-C remains challenging due to the non-specific, heterogeneous nature of signs/symptoms. This study assessed the utility of plasma chitotriosidase (ChT) and Chemokine (C-C motif) ligand 18 (CCL18)/pulmonary and activation-regulated chemokine (PARC) in conjunction with the NP-C suspicion index (NP-C SI) for guiding confirmatory laboratory testing in patients with suspected NP-C. In a prospective observational cohort study, incorporating a retrospective determination of NP-C SI scores, two different diagnostic approaches were applied in two separate groups of unrelated patients from 51 Spanish medical centers (n = 118 in both groups). From Jan 2010 to Apr 2012 (Period 1), patients with ≥2 clinical signs/symptoms of NP-C were considered 'suspected NP-C' cases, and NPC1/NPC2 sequencing, plasma chitotriosidase (ChT), CCL18/PARC and sphingomyelinase levels were assessed. Based on findings in Period 1, plasma ChT and CCL18/PARC, and NP-C SI prediction scores were determined in a second group of patients between May 2012 and Apr 2014 (Period 2), and NPC1 and NPC2 were sequenced only in those with elevated ChT and/or elevated CCL18/PARC and/or NP-C SI ≥70. Filipin staining and 7-ketocholesterol (7-KC) measurements were performed in all patients with NP-C gene mutations, where possible. In total across Periods 1 and 2, 10/236 (4%) patients had a confirmed diagnosis o NP-C based on gene sequencing (5/118 [4.2%] in each Period): all of these patients had two causal NPC1 mutations. Single mutant NPC1 alleles were detected in 8/236 (3%) patients, overall. Positive filipin staining results comprised three classical and five variant biochemical phenotypes. No NPC2 mutations were detected. All patients with NPC1 mutations had high ChT activity, high CCL18/PARC concentrations and/or NP-C SI scores ≥70. Plasma 7-KC was higher than control cut-off values in all patients with two NPC1 mutations, and in the majority of patients with single mutations. Family studies identified three further NP-C patients. This approach may be very useful for laboratories that do not have mass spectrometry facilities and therefore, they cannot use other NP-C biomarkers for diagnosis

Analysis of clinical characteristics and outcomes in patients with COVID-19 based on a series of 1000 patients treated in Spanish emergency departments

Objetivo: Describir las características clínicas de los pacientes con COVID-19 atendidos en los servicios de urgencias hospitalarios (SUH) españoles y evaluar su asociación con los resultados de su evolución. Métodos: Estudio multicéntrico, anidado en una cohorte prospectiva. Participaron 61 SUH que incluyeron pacientes seleccionados aleatoriamente de todos los diagnosticados de COVID-19 entre el 1 de m Se recogieron características basales, clínicas, de exploraciones complementarias y terapéuticas del episodio en los SUH. Se calcularon las odds ratio (OR) asociadas a la mortalidad intrahospitalaria y al evento combinado formado por el ingreso en unidad de cuidados intensivos (UCI), la intubación orotraqueal o ventilación mecánica invasiva (IOT/ VMI), crudas y ajustadas con modelos de regresión logística para tres grupos de variables independientes: basales, clínicas y de exploraciones complementarias. Resultados: La edad media fue de 62 años (DE 18). La mayoría manifestaron fiebre, tos seca, disnea, febrícula y diarrea. Las comorbilidades más frecuentes fueron las enfermedades cardiovasculares, seguidas de las respiratorias y el cáncer. Las variables basales que se asociaron independientemente y de forma directa a peores resultados evolutivos (tanto a mortalidad como a evento combinado) fueron edad y obesidad; las variables clínicas fueron disminución de consciencia y crepitantes a la auscultación pulmonar, y de forma inversa cefalea; y las variables de resultados de exploraciones complementarias fueron infiltrados pulmonares bilaterales y cardiomegalia radiológicos, y linfopenia, hiperplaquetosis, dímero-D > 500 mg/dL y lactato-deshidrogenasa > 250 UI/L en la analítica. Conclusiones: Conocer las características clínicas y la comorbilidad de los pacientes con COVID-19 atendidos en urgencias permite identificar precozmente a la población más susceptible de empeorar, para prever y mejorar los resultado

Subcutaneous anti-COVID-19 hyperimmune immunoglobulin for prevention of disease in asymptomatic individuals with SARS-CoV-2 infection: a double-blind, placebo-controlled, randomised clinical trialResearch in context

Summary: Background: Anti-COVID-19 hyperimmune immunoglobulin (hIG) can provide standardized and controlled antibody content. Data from controlled clinical trials using hIG for the prevention or treatment of COVID-19 outpatients have not been reported. We assessed the safety and efficacy of subcutaneous anti-COVID-19 hyperimmune immunoglobulin 20% (C19-IG20%) compared to placebo in preventing development of symptomatic COVID-19 in asymptomatic individuals with SARS-CoV-2 infection. Methods: We did a multicentre, randomized, double-blind, placebo-controlled trial, in asymptomatic unvaccinated adults (≥18 years of age) with confirmed SARS-CoV-2 infection within 5 days between April 28 and December 27, 2021. Participants were randomly assigned (1:1:1) to receive a blinded subcutaneous infusion of 10 mL with 1 g or 2 g of C19-IG20%, or an equivalent volume of saline as placebo. The primary endpoint was the proportion of participants who remained asymptomatic through day 14 after infusion. Secondary endpoints included the proportion of individuals who required oxygen supplementation, any medically attended visit, hospitalisation, or ICU, and viral load reduction and viral clearance in nasopharyngeal swabs. Safety was assessed as the proportion of patients with adverse events. The trial was terminated early due to a lack of potential benefit in the target population in a planned interim analysis conducted in December 2021. ClinicalTrials.gov registry: NCT04847141. Findings: 461 individuals (mean age 39.6 years [SD 12.8]) were randomized and received the intervention within a mean of 3.1 (SD 1.27) days from a positive SARS-CoV-2 test. In the prespecified modified intention-to-treat analysis that included only participants who received a subcutaneous infusion, the primary outcome occurred in 59.9% (91/152) of participants receiving 1 g C19-IG20%, 64.7% (99/153) receiving 2 g, and 63.5% (99/156) receiving placebo (difference in proportions 1 g C19-IG20% vs. placebo, −3.6%; 95% CI -14.6% to 7.3%, p = 0.53; 2 g C19-IG20% vs placebo, 1.1%; −9.6% to 11.9%, p = 0.85). None of the secondary clinical efficacy endpoints or virological endpoints were significantly different between study groups. Adverse event rate was similar between groups, and no severe or life-threatening adverse events related to investigational product infusion were reported. Interpretation: Our findings suggested that administration of subcutaneous human hyperimmune immunoglobulin C19-IG20% to asymptomatic individuals with SARS-CoV-2 infection was safe but did not prevent development of symptomatic COVID-19. Funding: Grifols