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Article ; Online: DNA damage and transcription stress.

Milano, Larissa / Gautam, Amit / Caldecott, Keith W

2023 Volume 84, Issue 1, Page(s) 70–79

Abstract: Genome damage and transcription are intimately linked. Tens to hundreds of thousands of DNA lesions arise in each cell each day, many of which can directly or indirectly impede transcription. Conversely, the process of gene expression is itself a source ... ...

Abstract	Genome damage and transcription are intimately linked. Tens to hundreds of thousands of DNA lesions arise in each cell each day, many of which can directly or indirectly impede transcription. Conversely, the process of gene expression is itself a source of endogenous DNA lesions as a result of the susceptibility of single-stranded DNA to damage, conflicts with the DNA replication machinery, and engagement by cells of topoisomerases and base excision repair enzymes to regulate the initiation and progression of gene transcription. Although such processes are tightly regulated and normally accurate, on occasion, they can become abortive and leave behind DNA breaks that can drive genome rearrangements, instability, or cell death.
MeSH term(s)	Humans ; DNA Damage ; DNA Replication ; DNA Repair ; DNA/genetics ; Genome ; Genomic Instability ; Transcription, Genetic
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2023-12-15
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.11.014
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Article ; Online: Hippocampus-to-amygdala pathway drives the separation of remote memories of related events.

Concina, Giulia / Milano, Luisella / Renna, Annamaria / Manassero, Eugenio / Stabile, Francesca / Sacchetti, Benedetto

Cell reports

2024 Volume 43, Issue 5, Page(s) 114151

Abstract: The mammalian brain can store and retrieve memories of related events as distinct memories and remember common features of those experiences. How it computes this function remains elusive. Here, we show in rats that recent memories of two closely timed ... ...

Abstract	The mammalian brain can store and retrieve memories of related events as distinct memories and remember common features of those experiences. How it computes this function remains elusive. Here, we show in rats that recent memories of two closely timed auditory fear events share overlapping neuronal ensembles in the basolateral amygdala (BLA) and are functionally linked. However, remote memories have reduced neuronal overlap and are functionally independent. The activity of parvalbumin (PV)-expressing neurons in the BLA plays a crucial role in forming separate remote memories. Chemogenetic blockade of PV preserves individual remote memories but prevents their segregation, resulting in reciprocal associations. The hippocampus drives this process through specific excitatory connections with BLA GABAergic interneurons. These findings provide insights into the neuronal mechanisms that minimize the overlap between distinct remote memories and enable the retrieval of related memories separately.
Language	English
Publishing date	2024-04-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.114151
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Article ; Online: Prior fear learning enables the rapid assimilation of new fear memories directly into cortical networks.

Concina, Giulia / Renna, Annamaria / Milano, Luisella / Sacchetti, Benedetto

PLoS biology

2022 Volume 20, Issue 9, Page(s) e3001789

Abstract: Long-term memory formation involves the reorganization of brain circuits, termed system consolidation. Whether and how a prior fear experience influences system consolidation of new memories is poorly understood. In rats, we found that prior auditory ... ...

Abstract	Long-term memory formation involves the reorganization of brain circuits, termed system consolidation. Whether and how a prior fear experience influences system consolidation of new memories is poorly understood. In rats, we found that prior auditory fear learning allows the secondary auditory cortex to immediately encode new auditory memories, with these new memories purely requiring the activation of cellular mechanisms of synaptic consolidation within secondary auditory cortex. Similar results were obtained in the anterior cingulate cortex for contextual fear memories. Moreover, prior learning enabled connections from these cortices to the basolateral amygdala (BLA) to support recent memory retention. We propose that the reorganization of circuits that characterizes system consolidation occurs only in the first instance that an event is learned, subsequently allowing the immediate assimilation of new analogous events in final storage sites.
MeSH term(s)	Animals ; Auditory Cortex/physiology ; Basolateral Nuclear Complex/physiology ; Fear/physiology ; Learning/physiology ; Memory/physiology ; Rats
Language	English
Publishing date	2022-09-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.3001789
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Article ; Online: Health Technology Assessment for the Prevention of Peri-Operative Hypothermia: Evaluation of the Correct Use of Forced-Air Warming Systems in an Italian Hospital.

Zucconi, Giulia / Marchello, Anna Maria / Demarco, Camilla / Fortina, Elisabetta / Milano, Ljdia

International journal of environmental research and public health

2022 Volume 20, Issue 1

Abstract: This study investigates the implications of using a system for the maintenance of normothermia in the treatment of patients undergoing surgery, determining whether the FAW (Forced-Air Warming) systems are more effective and efficient than the non- ... ...

Abstract	This study investigates the implications of using a system for the maintenance of normothermia in the treatment of patients undergoing surgery, determining whether the FAW (Forced-Air Warming) systems are more effective and efficient than the non-application of appropriate protocols (No Technology). We conducted Health Technology Assessment (HTA) analysis, using both real-world data and the data derived from literature, assuming the point of view of a medium-large hospital. The literature demonstrated that Inadvertent Perioperative Hypothermia (IPH) determines adverse events, such as surgical site infection (FAW: 3% vs. No Technology: 12%), cardiac events (FAW: 3.5% vs. No Technology: 7.6%) or the need for blood transfusions (FAW: 6.2% vs. No Technology: 7.4%). The correct use of FAW allows a medium saving of 16% per patient to be achieved, compared to the non-use of devices. The Cost Effectiveness Value (CEV) is lower in the hypothesis of FAW: it enables a higher efficacy level with a contextual optimization of patients' path costs. The social cost is reduced by around 30% and the overall hospital days are reduced by between 15% and 26%. The qualitative analyses confirmed the results. In conclusion, the evidence-based information underlines the advantages of the proper use of FAW systems in the prevention of accidental peri-operative hypothermia for patients undergoing surgery.
MeSH term(s)	Humans ; Hypothermia/prevention & control ; Technology Assessment, Biomedical ; Rewarming/methods ; Surgical Wound Infection/prevention & control ; Cost-Effectiveness Analysis ; Body Temperature
Language	English
Publishing date	2022-12-22
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2175195-X
ISSN	1660-4601 ; 1661-7827
ISSN (online)	1660-4601
ISSN	1661-7827
DOI	10.3390/ijerph20010133
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Article ; Online: Eating Disorders in Athletes: From Risk Management to Therapy.

Milano, Walter / Milano, Luca / Capasso, Anna

Endocrine, metabolic & immune disorders drug targets

2019 Volume 20, Issue 1, Page(s) 2–14

Abstract: Background: Balanced sporting activity should be considered a resource in the treatment of eating disorders (ED), in particular of the BED and in obesity and, if conducted and guided by expert preparers and rehabilitators, in some forms of anorexia and ... ...

Abstract	Background: Balanced sporting activity should be considered a resource in the treatment of eating disorders (ED), in particular of the BED and in obesity and, if conducted and guided by expert preparers and rehabilitators, in some forms of anorexia and in bulimia. Objective: To assess the role of excessive physical activity, predominantly interfering with daily activities by ultimately resulting in greater energy consumption leading to weight loss, and study the diagnostic criteria of bulimia and anorexia nervosa. Methods: A number of literature studies also report the presence of ED among athletes. A 2004 study reported that the prevalence of eating disorders in sports would be 13.5% compared to 4.5% of the control subjects. Results: In general, nutrition is used as a tool for improving performance not only of athletes but also of technicians and coaches. But in the presence of factors of vulnerability towards ED, the tendency to manipulate the weight can result in an eating disorder or the so-called athletic anorexia or the RED-S. Conclusion: It is important to emphasize that not only do professional athletes suffer from it, but also good-looking amateurs and laypersons.
MeSH term(s)	Athletes/psychology ; Energy Metabolism ; Exercise ; Feeding Behavior ; Feeding and Eating Disorders/epidemiology ; Feeding and Eating Disorders/physiopathology ; Feeding and Eating Disorders/psychology ; Feeding and Eating Disorders/therapy ; Female ; Health Knowledge, Attitudes, Practice ; Humans ; Male ; Nutritional Status ; Obesity/physiopathology ; Obesity/psychology ; Obesity/therapy ; Prognosis ; Risk Factors ; Weight Loss
Language	English
Publishing date	2019-11-04
Publishing country	United Arab Emirates
Document type	Journal Article ; Review
ZDB-ID	2228325-0
ISSN	2212-3873 ; 1871-5303
ISSN (online)	2212-3873
ISSN	1871-5303
DOI	10.2174/1871530319666190418121446
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Zs.A 5824: Show issues

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Article ; Online: Expression of IGF-2 Receptor in the Auditory Cortex Improves the Precision of Recent Fear Memories and Maintains Detailed Remote Fear Memories Over Time.

Concina, Giulia / Renna, Annamaria / Milano, Luisella / Manassero, Eugenio / Stabile, Francesca / Sacchetti, Benedetto

Cerebral cortex (New York, N.Y. : 1991)

2021 Volume 31, Issue 12, Page(s) 5381–5395

Abstract: Traumatic memories may become less precise over time and lead to the development of fear responses to novel stimuli, a process referred to as time-dependent fear generalization. The conditions that cause the growth of fear generalization over time are ... ...

Abstract	Traumatic memories may become less precise over time and lead to the development of fear responses to novel stimuli, a process referred to as time-dependent fear generalization. The conditions that cause the growth of fear generalization over time are poorly understood. Here, we found that, in male rats, the level of discrimination at the early time point contributes to determining whether fear generalization will develop with the passage of time or not, suggesting a link between the precision of recent memory and the stability of remote engrams. We also found that the expression of insulin-like growth factor 2 receptor in layer 2/3 of the auditory cortex is linked to the precision of recent memories and to the stability of remote engrams and the development of fear generalization over time. These findings provide new insights on the neural mechanisms that underlie the time-dependent development of fear generalization that may occur over time after a traumatic event.
MeSH term(s)	Animals ; Auditory Cortex/physiology ; Fear/physiology ; Male ; Memory/physiology ; Memory, Long-Term ; Rats ; Receptor, IGF Type 2
Chemical Substances	Receptor, IGF Type 2
Language	English
Publishing date	2021-06-18
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1077450-6
ISSN	1460-2199 ; 1047-3211
ISSN (online)	1460-2199
ISSN	1047-3211
DOI	10.1093/cercor/bhab165
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Zs.A 3235: Show issues

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Article ; Online: Lateral and Basal Amygdala Account for Opposite Behavioral Responses during the Long-Term Expression of Fearful Memories.

Manassero, Eugenio / Renna, Annamaria / Milano, Luisella / Sacchetti, Benedetto

Scientific reports

2018 Volume 8, Issue 1, Page(s) 518

Abstract: Memories of fearful events can be maintained throughout the lifetime of animals. Here we showed that lesions of the lateral nucleus (LA) performed shortly after training impaired the retention of long-term memories, assessed by the concomitant ... ...

Abstract	Memories of fearful events can be maintained throughout the lifetime of animals. Here we showed that lesions of the lateral nucleus (LA) performed shortly after training impaired the retention of long-term memories, assessed by the concomitant measurement of two dissociable defensive responses, freezing and avoidance in rats. Strikingly, when LA lesions were performed four weeks after training, rats did not show freezing to a learned threat stimulus, but they were able to direct their responses away from it. Similar results were found when the central nucleus (CeA) was lesioned four weeks after training, whereas lesions of the basal nucleus (BA) suppressed avoidance without affecting freezing. LA and BA receive parallel inputs from the auditory cortex, and optogenetic inhibition of these terminals hampered both freezing and avoidance. We therefore propose that, at variance with the traditional serial flow of information model, long-term fearful memories recruit two parallel circuits in the amygdala, one relying on the LA-to-CeA pathway and the other relying solely on BA, which operate independently and mediate distinct defensive responses.
MeSH term(s)	Acoustic Stimulation ; Animals ; Avoidance Learning/physiology ; Basolateral Nuclear Complex/metabolism ; Basolateral Nuclear Complex/pathology ; Behavior, Animal ; Central Amygdaloid Nucleus/metabolism ; Central Amygdaloid Nucleus/pathology ; Fear/physiology ; Halorhodopsins/genetics ; Halorhodopsins/metabolism ; Male ; Memory/physiology ; Microscopy, Confocal ; Rats ; Rats, Wistar
Chemical Substances	Halorhodopsins
Language	English
Publishing date	2018-01-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-19074-3
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Article ; Online: Endoplasmic reticulum stress and oxidative stress drive endothelial dysfunction induced by high selenium.

Zachariah, Matshediso / Maamoun, Hatem / Milano, Larissa / Rayman, Margaret P / Meira, Lisiane B / Agouni, Abdelali

Journal of cellular physiology

2020 Volume 236, Issue 6, Page(s) 4348–4359

Abstract: Selenium is an essential trace element important for human health. A balanced intake is, however, crucial to maximize the health benefits of selenium. At physiological concentrations, selenium mediates antioxidant, anti-inflammatory, and pro-survival ... ...

Abstract	Selenium is an essential trace element important for human health. A balanced intake is, however, crucial to maximize the health benefits of selenium. At physiological concentrations, selenium mediates antioxidant, anti-inflammatory, and pro-survival actions. However, supra-nutritional selenium intake was associated with increased diabetes risk leading potentially to endothelial dysfunction, the initiating step in atherosclerosis. High selenium causes apoptosis in cancer cells via endoplasmic reticulum (ER) stress, a mechanism also implicated in endothelial dysfunction. Nonetheless, whether ER stress drives selenium-induced endothelial dysfunction, remains unknown. Here, we investigated the effects of increasing concentrations of selenium on endothelial cells. High selenite reduced nitric oxide bioavailability and impaired angiogenesis. High selenite also induced ER stress, increased reactive oxygen species (ROS) production, and apoptosis. Pretreatment with the chemical chaperone, 4-phenylbutyrate, prevented the toxic effects of selenium. Our findings support a model where high selenite leads to endothelial dysfunction through activation of ER stress and increased ROS production. These results highlight the importance of tailoring selenium supplementation to achieve maximal health benefits and suggest that prophylactic use of selenium supplements as antioxidants may entail risk.
MeSH term(s)	Cell Line ; Dose-Response Relationship, Drug ; Endoplasmic Reticulum Stress/drug effects ; Gene Expression Regulation ; Human Umbilical Vein Endothelial Cells/drug effects ; Human Umbilical Vein Endothelial Cells/metabolism ; Human Umbilical Vein Endothelial Cells/pathology ; Humans ; Neovascularization, Physiologic/drug effects ; Nitric Oxide/metabolism ; Oxidative Stress/drug effects ; Reactive Oxygen Species/metabolism ; Sodium Selenite/toxicity
Chemical Substances	Reactive Oxygen Species ; Nitric Oxide (31C4KY9ESH) ; Sodium Selenite (HIW548RQ3W)
Language	English
Publishing date	2020-11-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3116-1
ISSN	1097-4652 ; 0021-9541
ISSN (online)	1097-4652
ISSN	0021-9541
DOI	10.1002/jcp.30175
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Uc I Zs.212: Show issues

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Article: Reversible Inactivation of the Higher Order Auditory Cortex during Fear Memory Consolidation Prevents Memory-Related Activity in the Basolateral Amygdala during Remote Memory Retrieval.

Cambiaghi, Marco / Renna, Annamaria / Milano, Luisella / Sacchetti, Benedetto

Frontiers in behavioral neuroscience

2017 Volume 11, Page(s) 138

Abstract: Recent findings have shown that the auditory cortex, and specifically the higher order Te2 area, is necessary for the consolidation of long-term fearful memories and that it interacts with the amygdala during the retrieval of long-term fearful memories. ... ...

Abstract	Recent findings have shown that the auditory cortex, and specifically the higher order Te2 area, is necessary for the consolidation of long-term fearful memories and that it interacts with the amygdala during the retrieval of long-term fearful memories. Here, we tested whether the reversible blockade of Te2 during memory consolidation may affect the activity changes occurring in the amygdala during the retrieval of fearful memories. To address this issue, we blocked Te2 in a reversible manner during memory consolidation processes. After 4 weeks, we assessed the activity of Te2 and individual nuclei of the amygdala during the retrieval of long-term memories. Rats in which Te2 was inactivated upon memory encoding showed a decreased freezing and failed to show Te2-to-basolateral amygdala (BLA) synchrony during memory retrieval. In addition, the expression of the immediate early gene zif268 in the lateral, basal and central amygdala nuclei did not show memory-related enhancement. As all sites were intact upon memory retrieval, we propose that the auditory cortex represents a key node in the consolidation of fear memories and it is essential for amygdala nuclei to support memory retrieval process.
Language	English
Publishing date	2017-07-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452960-6
ISSN	1662-5153
ISSN	1662-5153
DOI	10.3389/fnbeh.2017.00138
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Article ; Online: A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene.

Gao, Yuandi / Guitton-Sert, Laure / Dessapt, Julien / Coulombe, Yan / Rodrigue, Amélie / Milano, Larissa / Blondeau, Andréanne / Larsen, Nicolai Balle / Duxin, Julien P / Hussein, Samer / Fradet-Turcotte, Amélie / Masson, Jean-Yves

Nature communications

2023 Volume 14, Issue 1, Page(s) 381

Abstract: Fanconi Anemia (FA) is a rare, genome instability-associated disease characterized by a deficiency in repairing DNA crosslinks, which are known to perturb several cellular processes, including DNA transcription, replication, and repair. Formaldehyde, a ... ...

Abstract	Fanconi Anemia (FA) is a rare, genome instability-associated disease characterized by a deficiency in repairing DNA crosslinks, which are known to perturb several cellular processes, including DNA transcription, replication, and repair. Formaldehyde, a by-product of metabolism, is thought to drive FA by generating DNA interstrand crosslinks (ICLs) and DNA-protein crosslinks (DPCs). However, the impact of formaldehyde on global cellular pathways has not been investigated thoroughly. Herein, using a pangenomic CRISPR-Cas9 screen, we identify EXO1 as a critical regulator of formaldehyde-induced DNA lesions. We show that EXO1 knockout cell lines exhibit formaldehyde sensitivity leading to the accumulation of replicative stress, DNA double-strand breaks, and quadriradial chromosomes, a typical feature of FA. After formaldehyde exposure, EXO1 is recruited to chromatin, protects DNA replication forks from degradation, and functions in parallel with the FA pathway to promote cell survival. In vitro, EXO1-mediated exonuclease activity is proficient in removing DPCs. Collectively, we show that EXO1 limits replication stress and DNA damage to counteract formaldehyde-induced genome instability.
MeSH term(s)	Humans ; CRISPR-Cas Systems ; DNA ; DNA Damage/drug effects ; DNA Damage/genetics ; DNA Repair/drug effects ; DNA Repair/genetics ; DNA Repair Enzymes/genetics ; DNA Repair Enzymes/metabolism ; DNA Replication/drug effects ; DNA Replication/genetics ; Exodeoxyribonucleases/genetics ; Exodeoxyribonucleases/metabolism ; Fanconi Anemia/chemically induced ; Fanconi Anemia/genetics ; Formaldehyde/toxicity ; Genomic Instability/drug effects ; Genomic Instability/genetics ; Drug Tolerance/genetics
Chemical Substances	DNA (9007-49-2) ; DNA Repair Enzymes (EC 6.5.1.-) ; EXO1 protein, human (EC 3.1.-) ; Exodeoxyribonucleases (EC 3.1.-) ; Formaldehyde (1HG84L3525)
Language	English
Publishing date	2023-01-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-35802-y
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