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• Estrogen receptor alpha is a critical regulator of liver physiology. • Misregulation of ER signaling results in non-alcoholic fatty liver disease. • Lifestyle, diet and pharmacological interventions, and medical procedures are used to manage NAFLD. The pursuit of studying this subject is driven by the urgency to address the increasing global prevalence of Non-Alcoholic Fatty Liver Disease (NAFLD) and its profound health implications. NAFLD represents a significant public health concern due to its association with metabolic disorders, cardiovascular complications, and the potential progression to more severe conditions like non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Liver estrogen signaling is important for maintaining liver function, and loss of estrogens increases the likelihood of NAFLD in postmenopausal women. Understanding the multifaceted mechanisms underlying NAFLD pathogenesis, its varied treatment strategies, and their effectiveness is crucial for devising comprehensive and targeted interventions. By unraveling the intricate interplay between genetics, lifestyle, hormonal regulation, and gut microbiota, we can unlock insights into risk stratification, early detection, and personalized therapeutic approaches. Furthermore, investigating the emerging pharmaceutical interventions and dietary modifications offers the potential to revolutionize disease management. This review reinforces the role of collaboration in refining NAFLD comprehension, unveiling novel therapeutic pathways, and ultimately improving patient outcomes for this intricate hepatic condition. [ABSTRACT FROM AUTHOR]

The study's objective was to determine whether orally ingested caffeine could help overcome excitation-contraction-coupling failure, which has been suggested to explain part of the strength loss associated with eccentric-contraction-induced muscle injury. A sample of 13 college students (4 men and 9 women) was used in a double-blind, repeated-measures experimental design. Each participant performed 2 experimental trials, 1 with each leg, with each trial lasting 4 consecutive days. On a given day, each participant was randomly assigned to ingest a capsule containing 6 mg/kg of either caffeine or flour (placebo). On the day of and the first 2 days after a bout of 50 injurious eccentric contractions done by the knee extensors, the interpolated-twitch technique was used to assess electrically evoked strength, maximal voluntary isometric contraction (MVIC) strength, and percent muscle activation during MVIC both before and after capsule ingestion. These variables were also measured before and after capsule ingestion the day before the eccentric-contraction bout—when the muscle was uninjured. In injured muscle, caffeine had no effect on any variable. In uninjured muscle, caffeine also had no effect on electrically evoked strength but increased MVIC strength by 10.4% compared with placebo (p = .00002), and this was attributed to an increase in muscle activation (6.2%; p = .01). In conclusion, the data provide no evidence that caffeine ingestion can help overcome excitation-contraction-coupling failure, if it exists, in injured human muscle. The data do indicate that caffeine ingestion can increase MVIC strength and activation in uninjured muscle but not in injured muscle. [ABSTRACT FROM AUTHOR]

Abstract: Background: Cancer genomes accumulate frequent and diverse chromosomal abnormalities as well as gene mutations but must maintain the ability to survive in vivo. We hypothesize that genetic selection acts to maintain tumour survival by preserving copy number of specific genes and genomic regions. Genomic regions and genes that remain unaltered in copy number and expression, respectively, may be essential for maintaining tumour survival. Methods: We analyzed copy number data of 243 previously reported breast tumours and computationally derived stable copy number regions. To identify genes in stable copy number regions with nominal changes in expression, datasets for tumour and normal samples were compared. Results were replicated by analysis of a series of independent copy number, expression and genomic sequencing studies. A subset of stable regions, including stable paralogous regions, were confirmed by quantitative PCR and fluorescence in situ hybridization (FISH) in 5 breast cancer cell lines. We deduced a comprehensive set of dually stable genes (i.e. maintaining nominal copy number and expression) which were categorized according to pathway and ontology assignments. The stability of genes encoding therapeutic drug targets was also assessed. Results and Conclusion: Tumour genome analysis revealed 766 unstable (amplified and/or deleted) and 812 stable contiguous genomic regions. Replication analysis of an independent set of 171 breast tumours confirmed copy number stability of 1.3 Gb of the genome. We found that 5804 of these genes were dually stable. The composition of this gene set remained essentially unchanged (<2% reduction) after accounting for commonly mutated breast cancer genes found by sequencing and differential expression. The stable breast cancer genome is enriched for cellular metabolism, regulation of gene expression, DNA packaging (chromatin and nucleosome assembly), and regulation of apoptosis functions. Stable genes participating in multiple essential pathways were consistently found to be targets of chemotherapies. Preservation of stable, essential genes may be related to the effectiveness of certain chemotherapeutic agents that act on multiple gene products in this set. [Copyright &y& Elsevier]

The article discusses studies on the effect of caffeine ingestion on maximal voluntary contraction (MVC) strength and muscular endurance. It says that a systematic review and meta-analyses were conducted on 34 relevant studies within 1930 and 2008 wherein their effect sizes (ES) were calculated. These studies show that caffeine ingestion has small effect on MVC strength, particularly in the knee extensors. Meanwhile, a comparative study was also conducted between caffeine and placebo to determine its effects on muscular endurance where it reveals that caffeine is more beneficial though it can only be detected with open and end point tests. Moreover, the studies generally show that caffeine ingestion has negative effect, and can improve both MVC strength and muscular endurance.

Rehabilitation professionals have a major focus on competitive employment, which is a central component of adult life that provides not only economic benefits, but also a social network and enhanced self-esteem. The employment gap for individuals with disabilities has remained consistently high despite concerted efforts to provide access to quality job readiness training and a simultaneous increase in awareness of the value of diversity in the workforce. This study examined the outcomes of Project SEARCH, an employer-based transition program for young adults with disabilities that promotes partnerships among the school and community by utilizing a unique collaborative approach that brings the education system, employers, and rehabilitation services together to provide meaningful individualized employment experiences for students with disabilities. Findings suggest Project SEARCH appears to have the potential to address employment outcomes for young adults with various disabilities. Implications for practice and future research are also discussed. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) contains a subpopulation of cells, GBM stem cells (GSCs), that maintain the bulk tumor and represent a key therapeutic target. Norrin is a Wnt ligand that binds Frizzled class receptor 4 (FZD4) to activate canonical Wnt signaling. Although Norrin, encoded by NDP, has a well-described role in vascular development, its function in human tumorigenesis is largely unexplored. Here, we show that NDP expression is enriched in neurological cancers, including GBM, and its levels positively correlated with survival in a GBM subtype defined by low expression of ASCL1, a proneural factor. We investigated the function of Norrin and FZD4 in GSCs and found that it mediated opposing tumor-suppressive and -promoting effects on ASCL1lo and ASCL1hi GSCs. Consistent with a potential tumor-suppressive effect of Norrin suggested by the tumor outcome data, we found that Norrin signaling through FZD4 inhibited growth in ASCL1lo GSCs. In contrast, in ASCL1hi GSCs Norrin promoted Notch signaling, independently of WNT, to promote tumor progression. Forced ASCL1 expression reversed the tumor-suppressive effects of Norrin in ASCL1lo GSCs. Our results identify Norrin as a modulator of human brain cancer progression and reveal an unanticipated Notch-mediated function of Norrin in regulating cancer stem cell biology. This study identifies an unanticipated role of Norrin in human brain cancer progression. In addition, we provide preclinical evidence suggesting Norrin and canonical Wnt signaling as potential therapeutic targets for GBM subtype-restricted cancer stem cells. [ABSTRACT FROM AUTHOR]

Summary Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G 0 /G 1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM. [ABSTRACT FROM AUTHOR]

Summary Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM. [ABSTRACT FROM AUTHOR]