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Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.
The commercialization of medical devices and biotechnology products is characterized by high failure rates and long development lead times particularly among start-up enterprises. To increase the success rate of these high-risk ventures, the University of Massachusetts Lowell (UML) and University of Massachusetts Medical School (UMMS) partnered to create key academic support centers with programs to accelerate entrepreneurship and innovation in this industry. In 2008, UML and UMMS founded the Massachusetts Medical Device Development Center (M2D2), which is a business and technology incubator that provides business planning, product prototyping, laboratory services, access to clinical testing, and ecosystem networking to medical device and biotech start-up firms. M2D2 has three physical locations that encompass approximately 40,000 square feet. Recently, M2D2 leveraged these resources to expand into new areas such as health security, point of care technologies for heart, lung, blood, and sleep disorders, and rapid diagnostics to detect SARS-CoV-2. Since its inception, M2D2 has vetted approximately 260 medical device and biotech start-up companies for inclusion in its programs and provided active support to more than 80 firms. This manuscript describes how two UMass campuses leveraged institutional, state, and Federal resources to create a thriving entrepreneurial environment for medical device and biotech companies.
Intramuscular connective tissue (IMCT) is mainly composed of several fibrils (known as total collagen (TCol)) linked between each other by different chemical cross-links (CLs), the whole being embedded in a matrix of proteoglycans (PGs). In the field of beef quality, there is limited information on the role of CLs and PGs. Accordingly, several authors suggest that, to investigate the role of IMCT, it is important to investigate them just like TCol and insoluble collagen (ICol). In muscle, there are two other components, the muscle fibres and intramuscular fat (IMF) content. There are limited data on the relationships between these three components of muscle and then on possibility to independently manipulate these characteristics in order to control the final quality of meat. The present study aimed to investigate whether consistent relationships exist between these different components of muscle. Therefore, the present study compared four muscles of two cattle types (dairy and beef) to determine associations between TCol, ICol, CLs and PGs. Data were analysed across and within muscle (M) and animal type (AT) based on residuals. There was a strong M and AT effect for all muscle characteristics and an interaction M × AT for type I muscle fibres and IMF. Correlations between TCol, ICol and their CLs were M- and AT-independent. Total proteoglycans were positively correlated with TCol and ICol in a muscle-dependent manner irrespective of AT, but no correlation was found with CLs. On the contrary, CLs were negatively correlated with the ratio TPGs : TCol in an M-dependent manner, irrespective of AT. TCol, ICol and CLs were positively and negatively correlated with type IIA and IIB+X muscle fibres only in longissimus thoracis (LT) muscle, regardless the AT. Insoluble collagen was the only parameter of IMCT to be correlated with type I muscle fibres but only in LT muscle, irrespective of AT. There was no correlation between PGs and muscle fibre types, but PGs were the only IMCT component to be related with IMF in an M-dependent manner, irrespective of AT. Finally, there was no correlation between muscle fibre types and IMF content within M and AT. This study revealed that there is a strong relationship between IMCT components irrespective of M, an M-dependent relationship between the IMCT components and muscle fibre types and few (only with PGs) or no relationship between IMF and IMCT and muscle fibres.
Band ogives are a striking and enigmatic feature of Mer de Glace glacier flow. The surface mass balances (SMBs) of these ogives have been thoroughly investigated over a period of 12 years. We find similar cumulative SMBs over this period, ranging between −64.1 and −66.2 m w.e., on the dark and light ogives even though the dark ogive albedo is ~40% lower than that of the light ogives. We, therefore, looked for another process that could compensate for the large difference of absorbed short-wave radiation between dark and light ogives. Based on in situ roughness measurements, our numerical modeling experiments demonstrate that a significant difference in turbulent flux over the dark and light ogives due to different surface roughnesses could compensate for the difference in radiative forcing. Our results discard theories for the genesis of band ogives that are based on the assumption of a strong ice ablation contrast between dark and light ogives. More generally, our study demonstrates that future roughness changes are as important to analyze as the radiative impacts of a potential increase of aerosols or debris at the surface of glaciers.
In practice cattle may be slaughtered at different combinations of age and weight. As each of these factors could affect meat quality traits, the present work aimed to identify which combination can be expected to increase overall meat quality of m. rectus abdominis of Charolais heifers. Totally, 40 heifers were slaughtered either at 26±1 or at 36±1 months of age. Young heifers were sampled at two different carcass weights (349±12 and 394±8 kg). Old heifers were also sampled at two different carcass weights (397±6 and 451±9 kg). The m. rectus abdominis was excised 24 h postmortem to determine metabolic enzyme activities, myosin heavy-chain isoform proportions, lipid contents, collagen content and collagen solubility. Shear force measurements were evaluated on raw and broiled meat after 14 days of ageing. Meat quality traits scored between 0 and 10 by sensory analysis. Increasing slaughter age from 26 to 36 months had no impact on either raw/broiled shear force (0.31⩽P⩽0.47) and/or meat quality traits (0.62⩽P⩽0.91) or on physicochemical properties of heifer’s meat samples. Increasing carcass weight for a similar slaughter age of 26 months had also impact neither on meat quality traits (0.52⩽P⩽0.91) nor on muscular properties. On the contrary, increasing carcass weight for a similar slaughter age of 36 months had induced a decrease of muscular shear force (raw muscle; P=0.009) and a concomitant decrease of total collagen content (P=0.03). Nevertheless, no significant impact on meat quality traits was revealed by the sensorial panel (0.13⩽P⩽0.49). Metabolic enzyme activities (0.13⩽P⩽0.86) and myosin heavy-chain proportions (0.13⩽P⩽0.96) were not significantly impacted by slaughter age and carcass weight. Thus, the impact of increasing carcass weight and/or slaughter age in young Charolais heifers has a limited impact on meat quality traits and associated muscular characteristics. Modulating heifer’s cycles (age and/or carcass weight in the studied range) appears to be a way to answer to the numerous marketing chains, without penalising meat quality traits.
A health emergency situation occurred in Bulgaria in 2007 when positive rabies cases were notified in Sofia district in the central-western part of the country, suggesting a southward spread of the disease for the first time in the last 10 years. Phylogenetic analysis on 49 isolates sampled between 2009 and 2011 showed, for the first time, evidence of the existence of NEE and D clustered lineages in Bulgaria. Their geographical distribution clearly reveals the permeability of natural barriers, as already suggested by the disease spread that occurred across the Balkan mountain range in 2007. The monitoring and passive surveillance programmes conducted since the first 2009 oral vaccination campaign, the spatio-temporal evolution of the disease in the country since 2007, and the need for further investigation of the role of jackals in virus dispersion are discussed.
The aim of this paper was to identify pre-slaughter factors that modify total and insoluble collagen contents in bovine muscle to construct a model of collagen dynamics. The meta-analyses were performed with primary data of total (n = 1165) and insoluble (n = 1145) collagen contents from INRA experiments obtained from different muscles in young bulls, cows and steers. According to both the bibliography and meta-analyses, total collagen content and solubility were greatly affected by the muscle (type). Moreover, the pattern of the evolution of collagen characteristics was similar among Longissimus, Semitendinosus and Triceps brachii muscles in young bulls. In cows, collagen contents in the Triceps brachii muscle had delayed dynamics compared with the other muscles. Collagen characteristics differed among breeds because of variation in the maturity of the breed. Similarly, according to the meta-analyses, total and insoluble collagen content evolutions with the degree of maturity (DOM; proportion of adult weight reached at slaughter) were different in dairy and rustic breeds from those of beef breeds, especially in bulls. Although the relationships between collagen content and DOM were quantified in different muscles and sexes, the precision of the fitted equations was not sufficient for prediction. Consequently, relying on the hypotheses raised by the meta-analysis and the literature, an approach to further develop a dynamic mechanistic model of soluble and insoluble collagen content is proposed.
The objective of this study was to characterize the condensed tannins (CTs) in wrapped silage bales of sainfoin (Onobrychis viciifolia) and examine their potential action on in vivo and in situ digestive characteristics in sheep. Silage was made from sainfoin, cut at two phenological stages. The first phenological stage, at which silage was made, was from the first vegetation cycle at the end of flowering and the second stage silage was made from regrowth, 5 weeks after the first cut, but before flowering. The silages made from the two phenological stages were fed to 12 rumen-fistulated sheep in a crossover design. Of the 12 sheep, six received polyethylene glycol (PEG) to bind with and remove the effects of CT, whereas the other six were dosed with water. Organic matter digestibility, total-tract N digestibility and N (N) balance were measured over 6 days. Kinetic studies were performed on total N, ammonia N (NH3-N) and volatile fatty acids (VFAs) in rumen fluid before and 1.5, 3 and 6 h after feeding. The kinetics of degradation of dry matter and N from Dacron bags suspended in the rumen were also determined. Biological activity of CT (protein-binding capacity) and CT concentration were greater for the silage made from sainfoin at the early flowering stage. Total-tract N digestibility was increased by the addition of PEG (P < 0.001) to the sainfoin silage before flowering (P < 0.001). CTs decreased N excretion in urine (P < 0.05) and increased faecal N excretion (P < 0.001), but had no effect on body N retention, which is beneficial for the animal. Ruminal N degradability was smaller in the presence of active CT (P < 0.001) at both phenological stages; however, soluble N (P = 0.2060) and NH3-N (P = 0.5225) concentrations in rumen fluid remained unchanged. The results of this experiment indicate that CT in the sainfoin retain their ability to affect the nutritive value of preserved forage legumes.
The ‘Organic’ product label guarantees a production process that avoids the use of synthetic fertilisers, pesticides and hormones and minimises recourse to pharmaceuticals or veterinary drugs; however, the product's quality remains an issue that needs to be addressed in response to consumer demand. Consequently, this study was conducted to compare the sensory and nutritional qualities of meat and carcasses from pasture-fed lambs reared organically (O) or conventionally (C). Mean lamb growth profile was kept similar between the two treatments to avoid confounding effects with lamb age or weight at slaughter. The experiment was conducted over 3 years (2005 to 2007) with 12 O and 12 C lambs each year. The O and C treatments differed in the level of on-pasture mineral N fertilisation inducing a higher proportion of white clover in the organic pasture than the conventional pasture. Lambs were slaughtered when they attained a fat class of 2 to 3, and carcass and meat quality were evaluated. Lambs were slaughtered at an average weight and age of 35.3 kg and 156 days in the O treatment, respectively, and 35.2 kg and 155 days in the C treatment, respectively. Sensory evaluation indicated that loin chops from the O treatment had a higher level of abnormal fat odour compared with the C treatment. Carcasses from the O treatment had a softer subcutaneous fat one among 3 years (2007) compared to the C treatment. These results are probably due to a higher proportion of white clover in the diet. Organically reared lambs did offer the slight advantage of muscle fatty acid containing a higher level of stearic acid, which may have positive effects in the prevention of cardiovascular disease in humans. This may be the result of a higher rumen bio-hydrogenation of C18:3n-3 due to differences in the botanical composition between the O and the C pasture. Production system had no effect on the colour characteristics of the meat and subcutaneous fat, except lightness of subcutaneous dorsal fat, which was slightly higher in the O lambs. There were no differences between O and C lambs in terms of colour stability and lipid oxidation of the meat during the 6-day refrigerated storage under gas-permeable film.
Near infrared reflectance spectroscopy (NIRS) of 924 fresh temperate forages were used to develop calibration models for chemical composition – crude ash (CA) and crude protein (CP) – organic matter digestibility (OMD) and voluntary intake (VI). We used 110 samples to assess the models. Four calibration strategies for determining forage quality were compared: (i) species-specific calibration, (ii) family-specific calibration, (iii) a global procedure and (iv) a local approach. Forage calibration data sets displayed CA values ranging from 52 to 205 g/kg of dry matter (DM), CP values from 50 to 280 g/kg DM, OMD values from 0.48 to 0.85 g/g and VI values from 22.5 to 115.2 g DM/kg metabolic body weight (BW0.75). The calibration models performed well for all the variables except for VI. For CA, local procedure showed lower standard error of prediction (SEP) than species-specific, family-specific or global models. For CP, the calibration models all showed similar SEP values (11.13, 11.08, 11.38 and 11.34 g/kg DM for species-specific, family-specific, global and local approaches). For OMD, the local procedure gave a similar SEP (0.024 g/g) to specific species and global procedures (0.027 g/g) and a lower SEP than the family-specific approach (0.028 g/g). For VI, the local approach and species-specific calibration showed lower SEP (7.08 and 7.16 g/kg BW0.75) than the broad-based calibrations (8.09 and 8.34 g/kg BW0.75 for family-specific model and global procedure, respectively). Local calibration may thus offer a practical way to develop robust universal equations for animal response determinations.
We have recently shown that the expression of the DNAJA1 gene encoding a heat shock protein (Hsp40) is a negative marker of meat tenderness in Charolais bulls. To acquire knowledge on the regulation of DNAJA1 expression, we analysed the abundance of DNAJA1 transcripts and protein during development and according to management factors (e.g. feeding treatments, growth path and stress status) in different bovine muscles during postnatal life. We report here a developmental expression profile for DNAJA1 with decreased levels of transcript and protein during the progression of myogenesis. During postnatal life, we found the highest expression of DNAJA1 in the most oxidative muscles. No effect was detected for dietary treatment (pasture v. maize-based diet), growth path (compensatory growth after a restriction period) or pre-slaughter stress status. Therefore, the genetic background and muscle type could be considered as the main factors regarding the level of DNAJA1. Integration of the knowledge gained from this study should help to predict muscle metabolic properties and the ability of the live animals to give high sensory quality meat.
Selective breeding is an effective tool to improve livestock. Several selection experiments have been conducted to study direct selection responses as well as correlated responses in traits of skeletal muscle growth and function. Moreover, comparisons of domestic with wild-type species and of extreme breeds provide information on the genetic background of the skeletal muscle phenotype. Structural muscular components that differed with increasing distance in lean growth or meat quality in mammals were found to be myofibre number, myofibre size, proportions of fibre types as well as the numbers and proportions of secondary and primary fibres. Furthermore, markers of satellite cell proliferation, metabolic enzyme activities, glycogen and fat contents, the expression of myosin heavy chain isoforms, of activated AMPKα and other proteins in skeletal muscle tissue and circulating IGF1 and IGF-binding proteins have been identified to be involved in selection responses observed in pigs, cattle and/or chicken. The use of molecular methods for selective breeding of fish has only recently been adopted in aquaculture and studies of the genetic basis of growth and flesh quality traits are scarce. Some of the molecular markers of muscle structure/metabolism in livestock have also been identified in fish, but so far no studies have linked them with selection response. Genome scans have been applied to identify genomic regions exhibiting quantitative trait loci that control traits of interest, for example, muscle structure and meat quality in pigs and growth rate in chicken. As another approach, polymorphisms in candidate genes reveal the relationship between genetic variation and target traits. Thus, in large-scale studies with pigs’ associations of polymorphisms in the HMGA2, CA3, EPOR, NME1 and TTN genes with traits of carcass and meat quality were detected. Other studies revealed the significance of mutations in the IGF2 and RYR1 genes for carcass lean and muscle fibre traits in pigs. Mutations in the myostatin (MSTN) gene in fish were also examined. Advances in research of the genetic and environmental control of traits related to meat quality and growth have been made by the application of holistic ‘omics’ techniques that studied the whole muscle-specific genome, transcriptome and proteome in relation to muscle and meat traits, the development of new methods for muscle fibre typing and the adaptation of biophysical measures to develop parameters of muscle fibre traits as well as the application of in vitro studies. Finally, future research priorities in the field are defined.
Skeletal muscle development in vertebrates – also termed myogenesis – is a highly integrated process. Evidence to date indicates that the processes are very similar across mammals, poultry and fish, although the timings of the various steps differ considerably. Myogenesis is regulated by the myogenic regulatory factors and consists of two to three distinct phases when different fibre populations appear. The critical times when myogenesis is prone to hormonal or environmental influences depend largely on the developmental stage. One of the main mechanisms for both genetic and environmental effects on muscle fibre development is via the direct action of the growth hormone–insulin-like growth factor (GH–IGF) axis. In mammals and poultry, postnatal growth and function of muscles relate mainly to the hypertrophy of the fibres formed during myogenesis and to their fibre-type composition in terms of metabolic and contractile properties, whereas in fish hyperplasia still plays a major role. Candidate genes that are important in skeletal muscle development, for instance, encode for IGFs and IGF-binding proteins, myosin heavy chain isoforms, troponin T, myosin light chain and others have been identified. In mammals, nutritional supply in utero affects myogenesis and the GH–IGF axis may have an indirect action through the partitioning of nutrients towards the gravid uterus. Impaired myogenesis resulting in low skeletal myofibre numbers is considered one of the main reasons for negative long-term consequences of intrauterine growth retardation. Severe undernutrition in utero due to natural variation in litter or twin-bearing species or insufficient maternal nutrient supply may impair myogenesis and adversely affect carcass quality later in terms of reduced lean and increased fat deposition in the progeny. On the other hand, increases in maternal feed intake above standard requirement seem to have no beneficial effects on the growth of the progeny with myogenesis not or only slightly affected. Initial studies on low and high maternal protein feeding are published. Although there are only a few studies, first results also reveal an influence of nutrition on skeletal muscle development in fish and poultry. Finally, environmental temperature has been identified as a critical factor for growth and development of skeletal muscle in both fish and poultry.
The cracking behaviour of the oxide layer formed during hot rolling was studied together
with different combinations of process parameters in order to find their single influence
on the surface quality and formation of oxide defects. Several trials were performed on
the CRM pilot line to study in detail the impact of strip reduction, strip temperature,
entry scale thickness, roll degradation, lubrication, skin cooling, chemical composition
and humidity on the scale behaviour. In general, the degree of deformation, entry scale
thickness and rolling temperatures are the most important parameters and the importance
decreases in that order.
The cracking behaviour of the oxide layer formed during
hot rolling has been studied together with different
combinations of process parameters in order to find their
single influence on the surface quality and formation of
oxide defects. Several trials have been performed on the
CRM pilot line to study in detail the impact of strip reduction,
strip temperature, entry scale thickness, roll degradation,
lubrication, skin cooling, chemical composition and
humidity on the scale behaviour. In general the degree of
deformation, entry scale thickness and rolling temperatures
are the more important parameters and the importance
decreases in that order.