Changes of direction (CODs) are key manoeuvres linked to decisive moments in sport and are also key actions associated with lower limb injuries. During sport athletes perform a diverse range of CODs, ...from various approach velocities and angles, thus the ability to change direction safely and quickly is of great interest. To our knowledge, a comprehensive review examining the influence of angle and velocity on change of direction (COD) biomechanics does not exist. Findings of previous research indicate the biomechanical demands of CODs are ‘angle’ and ‘velocity’ dependent and are both critical factors that affect the technical execution of directional changes, deceleration and reacceleration requirements, knee joint loading, and lower limb muscle activity. Thus, these two factors regulate the progression and regression in COD intensity. Specifically, faster and sharper CODs elevate the relative risk of injury due to the greater associative knee joint loading; however, faster and sharper directional changes are key manoeuvres for successful performance in multidirectional sport, which subsequently creates a ‘performance-injury conflict’ for practitioners and athletes. This conflict, however, may be mediated by an athlete’s physical capacity (i.e. ability to rapidly produce force and neuromuscular control). Furthermore, an ‘angle-velocity trade-off’ exists during CODs, whereby faster approaches compromise the execution of the intended COD; this is influenced by an athlete’s physical capacity. Therefore, practitioners and researchers should acknowledge and understand the implications of angle and velocity on COD biomechanics when: (1) interpreting biomechanical research; (2) coaching COD technique; (3) designing and prescribing COD training and injury reduction programs; (4) conditioning athletes to tolerate the physical demands of directional changes; (5) screening COD technique; and (6) progressing and regressing COD intensity, specifically when working with novice or previously injured athletes rehabilitating from an injury.
For several decades, myths about the brain - neuromyths - have persisted in schools and colleges, often being used to justify ineffective approaches to teaching. Many of these myths are biased ...distortions of scientific fact. Cultural conditions, such as differences in terminology and language, have contributed to a 'gap' between neuroscience and education that has shielded these distortions from scrutiny. In recent years, scientific communications across this gap have increased, although the messages are often distorted by the same conditions and biases as those responsible for neuromyths. In the future, the establishment of a new field of inquiry that is dedicated to bridging neuroscience and education may help to inform and to improve these communications.
Hot spot mutations in the promoter region of telomerase reverse transcriptase (
TERT
) have recently been described in several human tumor entities. These mutations result in an upregulation of the ...telomerase complex activity and thus constitute a relevant mechanism for immortalization of tumor cells. Knowledge of the
TERT
promoter status in tumors is likely to be of interest for molecular classification and as a potential target for therapy. We, therefore, performed a systematic analysis of
TERT
promoter mutations in 1,515 tumors of the human nervous system and its coverings including 373 pediatric and 1,142 adult patients. We detected a total of 327 mutations.
TERT
promoter mutations were exceedingly rare in tumors typically encountered in pediatric patients. In entities typically encountered in adult patients
TERT
promoter mutations were strongly associated with older age (
p
< 0.0001). Highest mutation frequencies were detected in gliosarcomas (81 %), oligodendrogliomas (78 %), oligoastrocytomas (58 %), primary glioblastomas (54 %), and solitary fibrous tumors (50 %). Related to other molecular alterations,
TERT
promoter mutations were strongly associated with 1p/19q loss (
p
< 0.0001), but inversely associated with loss of ATRX expression (
p
< 0.0001) and
IDH1/IDH2
mutations (
p
< 0.0001).
TERT
promoter mutations are typically found in adult patients and occur in a highly tumor type-associated distribution.
Pediatric glioblastoma (pedGBM) is amongst the most common malignant brain tumors of childhood and carries a dismal prognosis. In contrast to adult GBM, few molecular prognostic markers for the ...pediatric counterpart have been established. We, therefore, investigated the prognostic significance of genomic and epigenetic alterations through molecular analysis of 202 pedGBM (1–18 years) with comprehensive clinical annotation. Routinely prepared formalin-fixed paraffin-embedded tumor samples were assessed for genome-wide DNA methylation profiles, with known candidate genes screened for alterations via direct sequencing or FISH. Unexpectedly, a subset of histologically diagnosed GBM (
n
= 40, 20 %) displayed methylation profiles similar to those of either low-grade gliomas or pleomorphic xanthoastrocytomas (PXA). These tumors showed a markedly better prognosis, with molecularly PXA-like tumors frequently harboring BRAF V600E mutations and 9p21 (
CDKN2A
) homozygous deletion. The remaining 162 tumors with pedGBM molecular signatures comprised four subgroups: H3.3 G34-mutant (15 %), H3.3/H3.1 K27-mutant (43 %), IDH1-mutant (6 %), and H3/IDH wild-type (wt) GBM (36 %). These subgroups were associated with specific cytogenetic aberrations,
MGMT
methylation patterns and clinical outcomes. Analysis of follow-up data identified a set of biomarkers feasible for use in risk stratification: pedGBM with any oncogene amplification and/or K27M mutation (
n
= 124) represents a particularly unfavorable group, with 3-year overall survival (OS) of 5 %, whereas tumors without these markers (
n
= 38) define a more favorable group (3-year OS ~70 %).Combined with the lower grade-like lesions, almost 40 % of pedGBM cases had distinct molecular features associated with a more favorable outcome. This refined prognostication method for pedGBM using a molecular risk algorithm may allow for improved therapeutic choices and better planning of clinical trial stratification for this otherwise devastating disease.
Summary
The Green Revolution successfully increased food production but in doing so created a legacy of inherently leaky and unsustainable agricultural systems. Central to this are the problems of ...excessive nutrient mining. If agriculture is to balance the needs of food security with the delivery of other ecosystem services, then current rates of soil nutrient stripping must be reduced and the use of synthetic fertilisers made more efficient.
We explore the global extent of the problem, with specific emphasis on the failure of macronutrient management (e.g. nitrogen, phosphorus) to deliver continued improvements in yield and the failure of agriculture to recognise the seriousness of micronutrient depletion (e.g. copper, zinc, selenium).
Nutrient removals associated with the relatively immature, nutrient‐rich soils of the UK are contrasted with the mature, nutrient‐poor soils of India gaining insight into the emerging issue of nutrient stripping and the long‐term implications for human health and soil quality. Whilst nutrient deficiencies are rare in developed countries, micronutrient deficiencies are commonly increasing in less‐developed countries. Increasing rates of micronutrient depletion are being inadvertently accomplished through increasing crop yield potential and nitrogen fertiliser applications.
Amongst other factors, the spatial disconnects caused by the segregation and industrialisation of livestock systems, between rural areas (where food is produced) and urban areas (where food is consumed and human waste treated) are identified as a major constraint to sustainable nutrient recycling.
Synthesis and applications. This study advocates that agricultural sustainability can only be accomplished using a whole‐systems approach that thoroughly considers nutrient stocks, removals, exports and recycling. Society needs to socially and environmentally re‐engineer agricultural systems at all scales. It is suggested that this will be best realised by national‐scale initiatives. Failure to do so will lead to an inevitable and rapid decline in the delivery of provisioning services within agricultural systems.
This study advocates that agricultural sustainability can only be accomplished using a whole‐systems approach that thoroughly considers nutrient stocks, removals, exports and recycling. Society needs to socially and environmentally re‐engineer agricultural systems at all scales. It is suggested that this will be best realised by national‐scale initiatives. Failure to do so will lead to an inevitable and rapid decline in the delivery of provisioning services within agricultural systems.
Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes. Polymorphic supergenes, in which specific ...combinations of traits are maintained within a single population, were first described for 'pin' and 'thrum' floral types in Primula and Fagopyrum, but classic examples are also found in insect mimicry and snail morphology. Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge. Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P. These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species, with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the P locus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow.
The division of medulloblastoma into different subgroups by microarray expression profiling has dramatically changed our perspective of this malignant childhood brain tumour. Now, the availability of ...next-generation sequencing and complementary high-density genomic technologies has unmasked novel driver mutations in each medulloblastoma subgroup. The implications of these findings for the management of patients are readily apparent, pinpointing previously unappreciated diagnostic and therapeutic targets. In this Review, we summarize the 'explosion' of data emerging from the application of modern genomics to medulloblastoma, and in particular the recurrent targets of mutation in medulloblastoma subgroups. These data are currently making their way into clinical trials as we seek to integrate conventional and molecularly targeted therapies.
pH–rate profiles for aqueous–organic protodeboronation of 18 boronic acids, many widely viewed as unstable, have been studied by NMR and DFT. Rates were pH-dependent, and varied substantially between ...the boronic acids, with rate maxima that varied over 6 orders of magnitude. A mechanistic model containing five general pathways (k 1–k 5) has been developed, and together with input of Btot, K W, K a, and K aH, the protodeboronation kinetics can be correlated as a function of pH (1–13) for all 18 species. Cyclopropyl and vinyl boronic acids undergo very slow protodeboronation, as do 3- and 4-pyridyl boronic acids (t 0.5 > 1 week, pH 12, 70 °C). In contrast, 2-pyridyl and 5-thiazolyl boronic acids undergo rapid protodeboronation (t 0.5 ≈ 25–50 s, pH 7, 70 °C), via fragmentation of zwitterionic intermediates. Lewis acid additives (e.g., Cu, Zn salts) can attenuate (2-pyridyl) or accelerate (5-thiazolyl and 5-pyrazolyl) fragmentation. Two additional processes compete when the boronic acid and the boronate are present in sufficient proportions (pH = pK a ± 1.6): (i) self-/autocatalysis and (ii) sequential disproportionations of boronic acid to borinic acid and borane.
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