135 research outputs found
Eigenvalues and Singular Values of Products of Rectangular Gaussian Random Matrices
We derive exact analytic expressions for the distributions of eigenvalues and
singular values for the product of an arbitrary number of independent
rectangular Gaussian random matrices in the limit of large matrix dimensions.
We show that they both have power-law behavior at zero and determine the
corresponding powers. We also propose a heuristic form of finite size
corrections to these expressions which very well approximates the distributions
for matrices of finite dimensions.Comment: 13 pages, 3 figure
Experimental and economic evaluation of different culture systems for mesenchymal stromal/stem cell expansion for clinical applications
The translation of cell therapies into clinical practice requires a scalable, efficient and cost-effective manufacturing process. This study presents an integrated experimental and cost analysis of different cell culture technologies for commercial manufacture of a novel umbilical cord-derived cell therapy, currently in early phase clinical trials for the treatment of acute graft-versus-host disease (aGvHD). The experimental analysis assessed the expansion and harvest potential of mesenchymal stromal cells (MSCs), derived from umbilical cord matrix (UCM-MSCs), in different scalable cell culture technologies: a multi-layer vessel (ML), a stirred tank bioreactor with microcarrriers (STR), a hollow fiber bioreactor (HF) and a packed-bed bioreactor (PB). The presentation will highlight differences in cell proliferation rate, expansion fold and harvesting efficiency across the technologies. The cells retained their functional properties post culture in all the technologies evaluated. The experimental results were incorporated into a bioprocess economics tool comprising a stochastic cost of goods (COG) and sizing model to evaluate the commercial economic feasibility and robustness of the technologies. The financial and risk rank orders predicted by the tool will be presented, as well as their sensitivity to the reimbursement scenario selected. The model determined industrially relevant scenarios for which no technology will yield a satisfactory gross margin, indicating that many studies are still needed to establish an optimized manufacturing process
Um método evolucionário para sintonia de controladores PI/PID em processos multivariáveis
Effect of Dietary Zinc Oxide on Morphological Characteristics, Mucin Composition and Gene Expression in the Colon of Weaned Piglets
The trace element zinc is often used in the diet of weaned piglets, as high
doses have resulted in positive effects on intestinal health. However, the
majority of previous studies evaluated zinc supplementations for a short
period only and focused on the small intestine. The hypothesis of the present
study was that low, medium and high levels of dietary zinc (57, 164 and 2,425
mg Zn/kg from zinc oxide) would affect colonic morphology and innate host
defense mechanisms across 4 weeks post-weaning. Histological examinations were
conducted regarding the colonic morphology and neutral, acidic, sialylated and
sulphated mucins. The mRNA expression levels of mucin (MUC) 1, 2, 13, 20,
toll-like receptor (TLR) 2, 4, interleukin (IL)-1β, 8, 10, interferon-γ
(IFN-γ) and transforming growth factor-β (TGF-β) were also measured. The
colonic crypt area increased in an age-depending manner, and the greatest area
was found with medium concentration of dietary zinc. With the high
concentration of dietary zinc, the number of goblet cells containing mixed
neutral-acidic mucins and total mucins increased. Sialomucin containing goblet
cells increased age-dependently. The expression of MUC2 increased with age and
reached the highest level at 47 days of age. The expression levels of TLR2 and
4 decreased with age. The mRNA expression of TLR4 and the pro-inflammatory
cytokine IL-8 were down-regulated with high dietary zinc treatment, while
piglets fed with medium dietary zinc had the highest expression. It is
concluded that dietary zinc level had a clear impact on colonic morphology,
mucin profiles and immunological traits in piglets after weaning. Those
changes might support local defense mechanisms and affect colonic physiology
and contribute to the reported reduction of post-weaning diarrhea
Diet and Energy-Sensing Inputs Affect TorC1-Mediated Axon Misrouting but Not TorC2-Directed Synapse Growth in a Drosophila Model of Tuberous Sclerosis
The Target of Rapamycin (TOR) growth regulatory system is influenced by a number of different inputs, including growth factor signaling, nutrient availability, and cellular energy levels. While the effects of TOR on cell and organismal growth have been well characterized, this pathway also has profound effects on neural development and behavior. Hyperactivation of the TOR pathway by mutations in the upstream TOR inhibitors TSC1 (tuberous sclerosis complex 1) or TSC2 promotes benign tumors and neurological and behavioral deficits, a syndrome known as tuberous sclerosis (TS). In Drosophila, neuron-specific overexpression of Rheb, the direct downstream target inhibited by Tsc1/Tsc2, produced significant synapse overgrowth, axon misrouting, and phototaxis deficits. To understand how misregulation of Tor signaling affects neural and behavioral development, we examined the influence of growth factor, nutrient, and energy sensing inputs on these neurodevelopmental phenotypes. Neural expression of Pi3K, a principal mediator of growth factor inputs to Tor, caused synapse overgrowth similar to Rheb, but did not disrupt axon guidance or phototaxis. Dietary restriction rescued Rheb-mediated behavioral and axon guidance deficits, as did overexpression of AMPK, a component of the cellular energy sensing pathway, but neither was able to rescue synapse overgrowth. While axon guidance and behavioral phenotypes were affected by altering the function of a Tor complex 1 (TorC1) component, Raptor, or a TORC1 downstream element (S6k), synapse overgrowth was only suppressed by reducing the function of Tor complex 2 (TorC2) components (Rictor, Sin1). These findings demonstrate that different inputs to Tor signaling have distinct activities in nervous system development, and that Tor provides an important connection between nutrient-energy sensing systems and patterning of the nervous system
Mapping the Spatio-Temporal Pattern of the Mammalian Target of Rapamycin (mTOR) Activation in Temporal Lobe Epilepsy
Growing evidence from rodent models of temporal lobe epilepsy (TLE) indicates that dysregulation of the mammalian target of rapamycin (mTOR) pathway is involved in seizures and epileptogenesis. However, the role of the mTOR pathway in the epileptogenic process remains poorly understood. Here, we used an animal model of TLE and sclerotic hippocampus from patients with refractory TLE to determine whether cell-type specific activation of mTOR signaling occurs during each stage of epileptogenesis. In the TLE mouse model, we found that hyperactivation of the mTOR pathway is present in distinct hippocampal subfields at three different stages after kainate-induced seizures, and occurs in neurons of the granular and pyramidal cell layers, in reactive astrocytes, and in dispersed granule cells, respectively. In agreement with the findings in TLE mice, upregulated mTOR was observed in the sclerotic hippocampus of TLE patients. All sclerotic hippocampus (n = 13) exhibited widespread reactive astrocytes with overactivated mTOR, some of which invaded the dispersed granular layer. Moreover, two sclerotic hippocampus exhibited mTOR activation in some of the granule cells, which was accompanied by cell body hypertrophy. Taken together, our results indicate that mTOR activation is most prominent in reactive astrocytes in both an animal model of TLE and the sclerotic hippocampus from patients with drug resistant TLE
The Effect of Selenium Supplementation in the Prevention of DNA Damage in White Blood Cells of Hemodialyzed Patients: A Pilot Study
Patients with chronic kidney disease (CKD) have an increased incidence of cancer. It is well known that long periods of hemodialysis (HD) treatment are linked to DNA damage due to oxidative stress. In this study, we examined the effect of selenium (Se) supplementation to CKD patients on HD on the prevention of oxidative DNA damage in white blood cells. Blood samples were drawn from 42 CKD patients on HD (at the beginning of the study and after 1 and 3 months) and from 30 healthy controls. Twenty-two patients were supplemented with 200 μg Se (as Se-rich yeast) per day and 20 with placebo (baker's yeast) for 3 months. Se concentration in plasma and DNA damage in white blood cells expressed as the tail moment, including single-strand breaks (SSB) and oxidative bases lesion in DNA, using formamidopyrimidine glycosylase (FPG), were measured. Se concentration in patients was significantly lower than in healthy subjects (P < 0.0001) and increased significantly after 3 months of Se supplementation (P < 0.0001). Tail moment (SSB) in patients before the study was three times higher than in healthy subjects (P < 0.01). After 3 months of Se supplementation, it decreased significantly (P < 0.01) and was about 16% lower than in healthy subjects. The oxidative bases lesion in DNA (tail moment, FPG) of HD patients at the beginning of the study was significantly higher (P < 0.01) compared with controls, and 3 months after Se supplementation it was 2.6 times lower than in controls (P < 0.01). No changes in tail moment was observed in the placebo group. In conclusion, our study shows that in CKD patients on HD, DNA damage in white blood cells is higher than in healthy controls, and Se supplementation prevents the damage of DNA
The Interaction between Early Life Epilepsy and Autistic-Like Behavioral Consequences: A Role for the Mammalian Target of Rapamycin (mTOR) Pathway
Early life seizures can result in chronic epilepsy, cognitive deficits and behavioral changes such as autism, and conversely epilepsy is common in autistic children. We hypothesized that during early brain development, seizures could alter regulators of synaptic development and underlie the interaction between epilepsy and autism. The mammalian Target of Rapamycin (mTOR) modulates protein translation and is dysregulated in Tuberous Sclerosis Complex, a disorder characterized by epilepsy and autism. We used a rodent model of acute hypoxia-induced neonatal seizures that results in long term increases in neuronal excitability, seizure susceptibility, and spontaneous seizures, to determine how seizures alter mTOR Complex 1 (mTORC1) signaling. We hypothesized that seizures occurring at a developmental stage coinciding with a critical period of synaptogenesis will activate mTORC1, contributing to epileptic networks and autistic-like behavior in later life. Here we show that in the rat, baseline mTORC1 activation peaks during the first three postnatal weeks, and induction of seizures at postnatal day 10 results in further transient activation of its downstream targets phospho-4E-BP1 (Thr37/46), phospho-p70S6K (Thr389) and phospho-S6 (Ser235/236), as well as rapid induction of activity-dependent upstream signaling molecules, including BDNF, phospho-Akt (Thr308) and phospho-ERK (Thr202/Tyr204). Furthermore, treatment with the mTORC1 inhibitor rapamycin immediately before and after seizures reversed early increases in glutamatergic neurotransmission and seizure susceptibility and attenuated later life epilepsy and autistic-like behavior. Together, these findings suggest that in the developing brain the mTORC1 signaling pathway is involved in epileptogenesis and altered social behavior, and that it may be a target for development of novel therapies that eliminate the progressive effects of neonatal seizures
- …