Notes

Pressurised Water Extraction Along with Enzymatic-Assisted Removal to have Bioactive Non-Extractable Polyphenols through Special Cherry (Prunus avium T.) Pomace.
Pharmacological combinations using immune checkpoint inhibition (ICI), tyrosine kinase inhibition (TKIs), and mammalian target of rapamycin inhibitors (mTOR) have improved survival in metastatic clear cell renal cell cancer (mccRCC). read more Despite improvements in survival, complete durable responses are rare.

Molecular pathways involved in mccRCC and drugs targets are highlighted. The background and rationale for combination therapy are covered. Results from combination trials are reviewed and potential approaches with biomarker-stratified treatment and novel experimental agents are examined. PubMed Central and ClinicalTrials.gov were searched. Search terms used to identify clinical trials were '(metastatic renal cell cancer OR renal cell carcinoma OR mccRCC OR mRCC OR RCC OR kidney cancer) AND (combination OR combined).'

First-line standard of care has moved to combination therapy with ICI-ICI and TKI-ICI combinations; VEGF-mTORi is available in subsequent lines. Combining targeted treatments without validatr directed.Skeletal muscle possesses a remarkable regenerative capacity that relies on the activity of muscle stem cells, also known as satellite cells. The presence of non-myogenic cells also plays a key role in the coordination of skeletal muscle regeneration. Particularly, fibro-adipogenic progenitors (FAPs) emerged as master regulators of muscle stem cell function and skeletal muscle regeneration. This population of muscle resident mesenchymal stromal cells has been initially characterized based on its bi-potent ability to differentiate into fibroblasts or adipocytes. New technologies such as single-cell RNAseq revealed the cellular heterogeneity of FAPs and their complex regulatory network during muscle regeneration. In acute injury, FAPs rapidly enter the cell cycle and secrete trophic factors that support the myogenic activity of muscle stem cells. Conversely, deregulation of FAP cell activity is associated with the accumulation of fibrofatty tissue in pathological conditions such as muscular dystrophies and ageing. Considering their central role in skeletal muscle pathophysiology, the regulatory mechanisms of FAPs and their cellular and molecular crosstalk with muscle stem cells are highly investigated in the field. In this review, we summarize the current knowledge on FAP cell characteristics, heterogeneity and the cellular crosstalk during skeletal muscle homeostasis and regeneration. We further describe their role in muscular disorders, as well as different therapeutic strategies targeting these cells to restore muscle regeneration.Sound is an essential source of information in many taxa and can notably be used by embryos to programme their phenotypes for postnatal environments. While underlying mechanisms are mostly unknown, there is growing evidence for the involvement of mitochondria-main source of cellular energy (i.e. ATP)-in developmental programming processes. Here, we tested whether prenatal sound programmes mitochondrial metabolism. In the arid-adapted zebra finch, prenatal exposure to 'heat-calls'-produced by parents incubating at high temperatures-adaptively alters nestling growth in the heat. We measured red blood cell mitochondrial function, in nestlings exposed prenatally to heat- or control-calls, and reared in contrasting thermal environments. Exposure to high temperatures always reduced mitochondrial ATP production efficiency. However, as expected to reduce heat production, prenatal exposure to heat-calls improved mitochondrial efficiency under mild heat conditions. In addition, when exposed to an acute heat-challenge, LEAK respiration was higher in heat-call nestlings, and mitochondrial efficiency low across temperatures. Consistent with its role in reducing oxidative damage, LEAK under extreme heat was also higher in fast growing nestlings. Our study therefore provides the first demonstration of mitochondrial acoustic sensitivity, and brings us closer to understanding the underpinning of acoustic developmental programming and avian strategies for heat adaptation.In freshwater ecosystems, water temperature and discharge are two intrinsically associated triggers of key events in the life cycle of aquatic organisms such as the migration of diadromous fishes. However, global changes have already profoundly altered the thermal and hydrological regimes of rivers, affecting the timing of fish migration as well as the environmental conditions under which it occurs. In this study, we focused on Atlantic salmon (Salmo salar), an iconic diadromous species whose individuals migrate between marine nursery areas and continental spawning grounds. An innovative multivariate method was developed to analyse long-term datasets of daily water temperature, discharge and both salmon juvenile downstream and adult upstream migrations in three French rivers (the Bresle, Oir and Nivelle rivers). While all three rivers have gradually warmed over the last 35 years, changes in discharge have been very heterogeneous. Juveniles more frequently used warmer temperatures to migrate. Adults migrating a few weeks before spawning more frequently used warm temperatures associated with high discharges. This has already led to modifications in preferential niches of both life stages and suggests a potential mismatch between these populations' ecological preference and changes in their local environment due to global change.Uniparental inheritance (UPI) of mitochondria predominates over biparental inheritance (BPI) in most eukaryotes. link2 However, examples of BPI of mitochondria, or paternal leakage, are becoming increasingly prevalent. Most reported cases of BPI occur in hybrids of distantly related sub-populations. It is thought that BPI in these cases is maladaptive; caused by a failure of female or zygotic autophagy machinery to recognize divergent male-mitochondrial DNA 'tags'. Yet recent theory has put forward examples in which BPI can evolve under adaptive selection, and empirical studies across numerous metazoan taxa have demonstrated outbreeding depression in hybrids attributable to disruption of population-specific mitochondrial and nuclear genotypes (mitonuclear mismatch). Based on these developments, we hypothesize that BPI may be favoured by selection in hybridizing populations when fitness is shaped by mitonuclear interactions. We test this idea using a deterministic, simulation-based population genetic model and demonstrate that BPI is favoured over strict UPI under moderate levels of gene flow typical of hybridizing populations. Our model suggests that BPI may be stable, rather than a transient phenomenon, in hybridizing populations.Conflict between rival groups is rife in nature. While recent work has begun exploring the behavioural consequences of this intergroup conflict, studies have primarily considered just the 1-2 h immediately after single interactions with rivals or their cues. Using a habituated population of wild dwarf mongooses (Helogale parvula), we conducted week-long manipulations to investigate longer-term impacts of intergroup conflict. Compared to a single presentation of control herbivore faeces, one rival-group faecal presentation (simulating a territorial intrusion) resulted in more within-group grooming the following day, beyond the likely period of conflict-induced stress. Repeated presentations of outsider cues led to further changes in baseline behaviour by the end of the week compared to control weeks, mongooses spent less time foraging and foraged closer to their groupmates, even when there had been no recent simulated intrusion. Moreover, there was more baseline territorial scent-marking and a higher likelihood of group fissioning in intrusion weeks. Consequently, individuals gained less body mass at the end of weeks with repeated simulated intrusions. Our experimental findings provide evidence for longer-term, extended and cumulative, effects of an elevated intergroup threat, which may lead to fitness consequences and underpin this powerful selective pressure.Knowledge of adaptive potential is crucial to predicting the impacts of ocean acidification (OA) on marine organisms. In the spiny damselfish, Acanthochromis polyacanthus, individual variation in behavioural tolerance to elevated pCO2 has been observed and is associated with offspring gene expression patterns in the brain. However, the maternal and paternal contributions of this variation are unknown. To investigate parental influence of behavioural pCO2 tolerance, we crossed pCO2-tolerant fathers with pCO2-sensitive mothers and vice versa, reared their offspring at control and elevated pCO2 levels, and compared the juveniles' brain transcriptional programme. We identified a large influence of parental phenotype on expression patterns of offspring, irrespective of environmental conditions. Circadian rhythm genes, associated with a tolerant parental phenotype, were uniquely expressed in tolerant mother offspring, while tolerant fathers had a greater role in expression of genes associated with histone binding. Expression changes in genes associated with neural plasticity were identified in both offspring types the maternal line had a greater effect on genes related to neuron growth while paternal influence impacted the expression of synaptic development genes. Our results confirm cellular mechanisms involved in responses to varying lengths of OA exposure, while highlighting the parental phenotype's influence on offspring molecular phenotype.The length ratio between the second and the fourth digit (2D 4D) is a retrospective, non-invasive biomarker for prenatal androgen exposure. It was found to be negatively correlated with handgrip strength (HGS) in men, but the evidence for women is mixed. Such studies in women call for increased detection sensitivity. The present study was designed to reduce potential confounding factors, especially age and ethnicity variation. link3 We measured the digit ratios and HGS of 125 healthy women between 19 and 31 years of age from a remote region in Austria. 2D 4D of both hands was significantly and negatively correlated with HGS (n = 125, right hand r = -0.255, p = 0.002, left hand r = -0.206, p = 0.011). Size, direction and significance of correlation coefficients remained stable when statistically controlling for age, body weight, body height, body mass index or hours of exercise per week. This yields theory-consistent evidence that HGS and 2D 4D are clearly associated in women-when sufficiently reducing genetic variation (confounding 2D 4D), the ontogenetic environment and age ranges (confounding HGS) in the study population. This finding implies similar organizing effects of prenatal androgens as in men, pointing to a more parsimonious developmental mechanism and a new look into its proximate and ultimate causes.Many social groups are made up of complex social networks in which each individual associates with a distinct subset of its groupmates. If social groups become larger over time, competition often leads to a permanent group fission. During such fissions, complex social networks present a collective decision problem and a multidimensional optimization problem it is advantageous for each individual to remain with their closest allies after a fission, but impossible for every individual to do so. Here, we develop computational algorithms designed to simulate group fissions in a network-theoretic framework. We focus on three fission algorithms (democracy, community and despotism) that fall on a spectrum from a democratic to a dictatorial collective decision. We parameterize our social networks with data from wild baboons (Papio cynocephalus) and compare our simulated fissions with actual baboon fission events. We find that the democracy and community algorithms (egalitarian decisions where each individual influences the outcome) better maintain social networks during simulated fissions than despotic decisions (driven primarily by a single individual).
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