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Transcriptional silencing by RNAi paradoxically relies on transcription, but how the transition from transcription to silencing is achieved has remained unclear. The Cryptic Loci Regulator complex (CLRC) in Schizosaccharomyces pombe is a cullin-ring E3 ligase required for silencing that is recruited by RNAi. We found that the E2 ubiquitin conjugating enzyme Ubc4 interacts with CLRC and mono-ubiquitinates the histone H3K9 methyltransferase Clr4 SUV39H1 , promoting the transition from co-transcriptional gene silencing (H3K9me2) to transcriptional gene silencing (H3K9me3). Ubiquitination of Clr4 occurs in an intrinsically disordered region (Clr4 IDR ), which undergoes liquid droplet formation in vitro, along with Swi6 HP1 the effector of transcriptional gene silencing. Our data suggests that phase separation is exquisitely sensitive to non-coding RNA (ncRNA) which promotes self-association of Clr4, chromatin association, and di-, but not tri- methylation instead. Ubc4-CLRC also targets the transcriptional co-activator Bdf2 BRD4 , down-regulating centromeric transcription and small RNA (sRNA) production. The deubiquitinase Ubp3 counteracts both activities., (© 2024. The Author(s).)

Pancreatic Cystic Neoplasms (PCN) represent a diverse group of tumors, some of which may progress to pancreatic cancer. Considering their high prevalence in the general population, the development of reliable biomarkers is crucial. The ideal biomarker will accurately diagnose the subtype of PCN and assess the risk of high-grade dysplasia or invasive cancer. Cyst fluid analysis has emerged as a promising approach to accomplish this goal, yet no single marker has yet gained unanimous support for routine inclusion in PCN evaluation., Competing Interests: Disclosure A.V. Maker is an inventor of record on the following pending or issued patent: WO2018183603A1 (PCT/US2018/025,027). T. Pollini and L. Todeschini have no conflict of interest. Funding Authors acknowledge the support of the Inner Child Foundation and the Shorenstein Foundation., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: This study comprehensively compared laparoscopic liver resection (LLR) to open liver resection (OLR) in treating colorectal cancer liver metastasis (CRLM)., Methods: A systematic review of relevant literature was conducted to assess a range of crucial surgical and oncological outcomes., Results: Findings indicate that minimally invasive surgery (MIS) did not significantly prolong the duration of surgery compared to open liver resection and notably demonstrated lower blood transfusion rates and reduced intraoperative blood loss. While some studies favored MIS for its lower complication rates, others did not establish a statistically significant difference. One study identified a lower post-operative mortality rate in the MIS group. Furthermore, MIS consistently correlated with shorter hospital stays, indicative of expedited post-operative recovery. Concerning oncological outcomes, while certain meta-analyses reported a lower rate of cancer recurrence in the MIS group, others found no significant disparity. Overall survival and disease-free survival remained comparable between the MIS and open liver resection groups., Conclusion: The analysis emphasizes the potential advantages of LLR in terms of surgical outcomes and aligns with existing literature findings in this field., Systematic Review Registration: [website], identifier [registration number]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pinto, Pangrazio, Martinino, Todeschini, Toti, Cristin, Caimano, Mattia, Bianco, Spoletini and Giovinazzo.)

Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al. , Genetics 215 , 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2 , as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH . We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43., Competing Interests: Competing interests statement:The authors declare no competing interest.

Surgical resection is the gold standard for treating synchronous colorectal liver metastases (CRLM). The resection of the primary tumor and metastatic lesions can follow different sequences: "simultaneous", "bowel-first", and "liver-first". Conservative approaches, such as parenchymal-sparing surgery and segmentectomy, may serve as alternatives to major hepatectomy. A comprehensive search of Medline, Epistemonikos, Scopus, and the Cochrane Library was conducted. Studies evaluating patients who underwent surgery for CRLM and reported survival results were included. Other secondary outcomes were analyzed, including disease-free survival, perioperative complications and mortality, and recurrence rates. Quality assessment was performed using the AMSTAR-2 method. No significant differences in overall survival, disease-free survival, and secondary outcomes were observed when comparing simultaneous to "bowel-first" resections, despite a higher rate of perioperative mortality in the former group. The 5-year OS was significantly higher for simultaneous resection compared to "liver-first" resection. No significant differences in OS and DFS were noted when comparing "liver-first" to "bowel-first" resection, or anatomic to non-anatomic resection. Our umbrella review validates simultaneous surgery as an effective oncological approach for treating SCRLM, though the increased risk of perioperative morbidity highlights the importance of selecting suitable patients. Non-anatomic resections might be favored to preserve liver function and enable future surgical interventions.

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

Proteinopathies are a large group of neurodegenerative diseases caused by both genetic and sporadic mutations in particular genes which can lead to alterations of the protein structure and to the formation of aggregates, especially toxic for neurons. Autophagy is a key mechanism for clearing those aggregates and its function has been strongly associated with the ubiquitin-proteasome system (UPS), hence mutations in both pathways have been associated with the onset of neurodegenerative diseases, particularly those induced by protein misfolding and accumulation of aggregates. Many crucial discoveries regarding the molecular and cellular events underlying the role of autophagy in these diseases have come from studies using Drosophila models. Indeed, despite the physiological and morphological differences between the fly and the human brain, most of the biochemical and molecular aspects regulating protein homeostasis, including autophagy, are conserved between the two species.In this review, we will provide an overview of the most common neurodegenerative proteinopathies, which include PolyQ diseases (Huntington's disease, Spinocerebellar ataxia 1, 2, and 3), Amyotrophic Lateral Sclerosis (C9orf72, SOD1, TDP-43, FUS), Alzheimer's disease (APP, Tau) Parkinson's disease (a-syn, parkin and PINK1, LRRK2) and prion diseases, highlighting the studies using Drosophila that have contributed to understanding the conserved mechanisms and elucidating the role of autophagy in these diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Santarelli, Londero, Soldano, Candelaresi, Todeschini, Vernizzi and Bellosta.)

Introduction: Hearing loss etiology depends on the population studied as well as on the ethnicity and the socio-economic condition of the analyzed region. Etiological diagnosis contributes to the improvement of preventive measures and to the early identification of this deficiency., Objective: To identify the etiological factors of hearing loss and its prevalence in a tertiary hospital in southern Brazil, to verify the frequency of mutations in GJB2 and GJB6 genes, and to correlate the degree of hearing loss with the etiological factors of deafness., Methods: This prevalence study involved 140 children with bilateral sensorineural or mixed hearing loss. Medical history, physical examination, audiometry, and evoked auditory brainstem response were conducted. Imaging and genetic examinations were also performed., Results: Etiologies and their prevalence were as follows: (a) indeterminate causes, 31.4%; (b) conditions related to neonatal period, 22.1%; (c) genetic, 22.1%; (d) auditory neuropathy, 10%; (e) other factors (cortical malformation, intracranial hemorrhage, and internal ear malformations), 7.9% and (f) congenital infections, 6.4%. Within the genetic cases, ten homozygous and seven heterozygotes of the 35delG mutation were identified, besides two cases of rare variants of GJB2: p.Try172* and p.Arg184Pro. One case with homozygosis of del(GJB6-D13S1830) was found. Regarding severity of hearing loss, in 78.6% of the cases the degree of hearing loss was profound and there were no significant differences when comparing between etiologies., Conclusion: The number of indeterminate etiologies is still high and congenital CMV infection may be a possible cause of undiagnosed etiology for hearing loss. The predominance of etiologies related to neonatal conditions and infectious causes are characteristic of developing countries. The most prevalent mutation was 35delG, the main GJB2 gene, probably because of the European influence in the genotype of our population., (Copyright © 2021 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

New cyanines were prepared by an efficient and practical route with satisfactory overall yield from low-cost starting materials. The photophysical behavior of the cyanines was investigated using UV-vis and steady-state fluorescence in solution, as well as their association with bovine serum albumin (BSA) in phosphate buffer solution (PBS). No cyanine aggregation was observed in organic solvents or in phosphate buffer solution. The alkyl chain length in the quaternized nitrogen was shown to be fundamental for BSA detection in PBS in these dyes.

This research investigated a new method to measure momentary affective clarity indirectly, which is based on latencies of responses to state affect items. Three studies revealed that this indirect measure of momentary clarity demonstrated high reliability and stability as well as convergent and predictive validity. The indirect measure was associated with dispositional clarity when the concept of clarity was activated before measuring response latencies (Studies 1 and 2) and was related to self-reports of momentary clarity (Study 3). Furthermore, Study 3 demonstrated that indirectly measured clarity decreased after an affectively complex film. Indirectly, but not directly, measured momentary clarity predicted a more positive affective state at the end of the study. This effect was mediated by affect regulation., (Copyright (c) 2005 APA, all rights reserved.)