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Surgical resection, when combined with chemotherapy, has been shown to significantly improve the survival rate of patients with pancreatic ductal adenocarcinoma (PDAC). However, this treatment option is only feasible for a fraction of patients, as more than 50% of cases are diagnosed with metastasis. The multifaceted process of metastasis is still not fully understood, but recent data suggest that transcriptional and epigenetic plasticity play significant roles. Interfering with epigenetic reprogramming can potentially control the adaptive processes responsible for metastatic progression and therapy resistance, thereby enhancing treatment responses and preventing recurrence. This review will focus on the relevance of histone-modifying enzymes in pancreatic cancer, specifically on their impact on the metastatic cascade. Additionally, it will also provide a brief update on the current clinical developments in epigenetic therapies.

Arginine methylation of histones is one mechanism of epigenetic regulation in eukaryotic cells. Methylarginines can also be found in non-histone proteins involved in various different processes in a cell. An enzyme family of nine protein arginine methyltransferases catalyses the addition of methyl groups on arginines of histone and non-histone proteins, resulting in either mono- or dimethylated-arginine residues. The reversibility of histone modifications is an essential feature of epigenetic regulation to respond to changes in environmental factors, signalling events, or metabolic alterations. Prominent histone modifications like lysine acetylation and lysine methylation are reversible. Enzyme family pairs have been identified, with each pair of lysine acetyltransferases/deacetylases and lysine methyltransferases/demethylases operating complementarily to generate or erase lysine modifications. Several analyses also indicate a reversible nature of arginine methylation, but the enzymes facilitating direct removal of methyl moieties from arginine residues in proteins have been discussed controversially. Differing reports have been seen for initially characterized putative candidates, like peptidyl arginine deiminase 4 or Jumonji-domain containing protein 6. Here, we review the most recent cellular, biochemical, and mass spectrometry work on arginine methylation and its reversible nature with a special focus on putative arginine demethylases, including the enzyme superfamily of Fe(II) and 2-oxoglutarate-dependent oxygenases.

Post-translational modifications (PTMs) are implicated in many biological processes including receptor activation, signal transduction, transcriptional regulation and protein turnover. Lysine’s side chain is particularly notable, as it can undergo methylation, acetylation, SUMOylation and ubiquitination. Methylation affects not only lysine but also arginine residues, both of which are implicated in epigenetic regulation. Beyond histone-tails as substrates, dynamic methylation of transcription factors has been described. The focus of this review is on these non-histone substrates providing a detailed discussion of what is currently known about methylation of hypoxia-inducible factor (HIF), P53, nuclear receptors (NRs) and RELA. The role of methylation in regulating protein stability and function by acting as docking sites for methyl-reader proteins and via their crosstalk with other PTMs is explored.

Trimethylated lysine 27 on histone H3 (H3K27me3) is present in Drosophila, Arabidopsis. worms, and mammals, but is absent from yeasts that have been examined. We identified and analyzed H3K27me3 in the filamentous fungus Neurospora crassa and in other Neurospora species. H3K27me3 covers 6.8% of the N. crassa genome, encompassing 223 domains, including 774 genes, all of which are transcriptionally silent N. crassa H3K27me3-marked genes are less conserved than unmarked genes and only ~35% of genes marked by H3K27me3 in N. crassa are also H3K27me3-marked in Neurospora discreta and Neurospora tetrasperma. We found that three components of the Neurospora Polycomb repressive complex 2 (PRC2)—[Su-(var) 3-9; E(z); Trrthorax] (SET)-7, embryonic ectoderm development (EED), and SU(Z)12 (suppressor of zeste12)—are required for H3K27me3, whereas the fourth component Neurospora protein 55 (an N. crassa homolog of p55/RbAp48), is critical for H3K27me3 only at subtelomeric domains. Loss of H3K27me3, caused by deletion of the gene encoding the catalytic PRC2 subunit, set-7, resulted in up-regulation of 130 genes, including genes in both H3K27me3-marked and unmarked regions.

SMYD3 is a member of the SMYD lysine methylase family and plays an important role in the methylation of various histone and non-histone targets. Aberrant SMYD3 expression contributes to carcinogenesis and SMYD3 upregulation was proposed as a prognostic marker in various solid cancers. Here we summarize SMYD3-mediated regulatory mechanisms, which are implicated in the pathophysiology of cancer, as drivers of distinct oncogenic pathways. We describe SMYD3-dependent mechanisms affecting cancer progression, highlighting SMYD3 interplay with proteins and RNAs involved in the regulation of cancer cell proliferation, migration and invasion. We also address the effectiveness and mechanisms of action for the currently available SMYD3 inhibitors. The findings analyzed herein demonstrate that a complex network of SMYD3-mediated cytoplasmic and nuclear interactions promote oncogenesis across different cancer types. These evidences depict SMYD3 as a modulator of the transcriptional response and of key signaling pathways, orchestrating multiple oncogenic inputs and ultimately, promoting transcriptional reprogramming and tumor transformation. Further insights into the oncogenic role of SMYD3 and its targeting of different synergistic oncogenic signals may be beneficial for effective cancer treatment.

We prove the one-dimensional almost sure invariance principle with essentially optimal rates for slowly (polynomially) mixing deterministic dynamical systems, such as Pomeau–Manneville intermittent maps, with Hölder continuous observables. Our rates have form $o(n^{\\unicode[STIX]{x1D6FE}}L(n))$, where $L(n)$ is a slowly varying function and $\\unicode[STIX]{x1D6FE}$ is determined by the speed of mixing. We strongly improve previous results where the best available rates did not exceed $O(n^{1/4})$. To break the $O(n^{1/4})$ barrier, we represent the dynamics as a Young-tower-like Markov chain and adapt the methods of Berkes–Liu–Wu and Cuny–Dedecker–Merlevède on the Komlós–Major–Tusnády approximation for dependent processes.

China heightened its military pressure on Taiwan, but president Tsai In-wen defiantly resisted Beijing’s coercion and overcame domestic criticism. With a cooperative public and international support, Taipei quelled an unexpected COVID-19 outbreak. The bullish economy continues to be fueled by global demand for Taiwan’s technology products as the Taipei–Washington relationship progresses advantageously.

The celebrated results of Komlós, Major and Tusnády [Z. Wahrsch. Verw. Gebiete32 (1975) 111–131;Z. Wahrsch. Verw. Gebiete34 (1976) 33–58] give optimal Wiener approximation for the partial sums of i.i.d. random variables and provide a powerful tool in probability and statistics. In this paper we extend KMT approximation for a large class of dependent stationary processes, solving a long standing open problem in probability theory. Under the framework of stationary causal processes and functional dependence measures of Wu [Proc. Natl. Acad. Sci. USA102 (2005) 14150–14154], we show that, under natural moment conditions, the partial sum processes can be approximated by Wiener process with an optimal rate. Our dependence conditions are mild and easily verifiable. The results are applied to ergodic sums, as well as to nonlinear time series and Volterra processes, an important class of nonlinear processes.

Schizophrenia is a chronic psychiatric disorder marked by significant cognitive and functional impairments. Current antipsychotic treatments offer limited benefit for negative symptoms and cognitive dysfunction while often exacerbating metabolic comorbidities. Emerging evidence implicates impaired glucose metabolism and mitochondrial dysfunction in the pathophysiology of schizophrenia, suggesting a role for metabolic interventions. This article reviews and synthesizes clinical, preclinical, and mechanistic evidence supporting the use of ketogenic therapy-a high-fat, low-carbohydrate intervention that induces ketosis-as a potential adjunctive treatment in schizophrenia. Preliminary clinical findings, including case reports and small trials, suggest that ketogenic therapy may improve positive and negative symptoms, cognitive performance, and metabolic outcomes in individuals with schizophrenia spectrum disorders. Preclinical studies using NMDA antagonist models demonstrate that ketogenic interventions can normalize behavioral and neurophysiological deficits. Mechanistically, ketone bodies enhance mitochondrial function, modulate neurotransmitter systems (GABA, glutamate, dopamine), and reduce inflammation and oxidative stress. These effects may address core dysfunctions in schizophrenia that are unresponsive to dopamine-targeting pharmacotherapies. Ketogenic therapy holds potential for addressing unmet clinical needs in schizophrenia, including negative and cognitive symptoms, treatment-resistant cases, and antipsychotic-induced metabolic syndrome. It may also be explored as a preventive strategy in high-risk populations. However, larger controlled trials are needed to establish efficacy, safety, and feasibility in psychiatric settings. Ketogenic therapy offers a novel, mechanistically informed intervention that targets metabolic and neurochemical pathways implicated in schizophrenia. If validated, it could pave the way for more integrative and personalized treatment strategies.

Taiwan saw a series of crucial developments at home and abroad in 2020. Externally, the massive confrontations in Hong Kong were taken as justifying the ruling DPP’s anti-China cross-Strait policy. The impacts of the intense US–China trade war reshaped relations in the US–China–Taiwan triangle. Internally, the results of the 2020 general election strengthened the DPP’s political dominance. Likewise, the successful fight against COVID-19 buttressed the government’s popular support. Still, there are old and new socio-economic issues that will continue to challenge the governing capability of the DPP in 2021.