Search

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor (TF) that regulates a variety of biological processes, including a key role in mediating mitochondrial metabolism. It has been shown that STAT3 performs this function by translocating in minute amounts into mitochondria and interacting with mitochondrial proteins and genome. However, whether STAT3 localizes in mitochondria is still up for debate. To decipher the role of mitochondrial STAT3 requires a detailed understanding of its cellular localization. Using Percoll density gradient centrifugation, we surprisingly found that STAT3 is not located in the mitochondrial fraction, but instead, in the mitochondria-associated endoplasmic reticulum membrane (MAM) fraction. This was confirmed by sub-diffraction image analysis of labeled mitochondria in embryonic astrocytes. Also, we find that other TFs that have been previously found to localize in mitochondria are also found instead in the MAM fraction. Our results suggest that STAT3 and other transcriptional factors are, contrary to prior studies, consolidated specifically at MAMs, and further efforts to understand mitochondrial STAT3 function must take into consideration this localization, as the associated functional consequences offer a different interpretation to the questions of STAT3 trafficking and signaling in the mitochondria.

Abstract Idiopathic normal pressure hydrocephalus (iNPH) is a neuropathology with unknown cause characterised by gait impairment, cognitive decline and ventriculomegaly. These patients often present comorbidity with Alzheimer’s disease (AD), including AD pathological hallmarks such as amyloid plaques mainly consisting of amyloid β-peptide and neurofibrillary tangles consisting of hyperphosphorylated tau protein. Even though some of the molecular mechanisms behind AD are well described, little is known about iNPH. Several studies have reported that mitochondria-endoplasmic reticulum contact sites (MERCS) regulate amyloid β-peptide metabolism and conversely that amyloid β-peptide can influence the number of MERCS. MERCS have also been shown to be dysregulated in several neurological pathologies including AD. In this study we have used transmission electron microscopy and show, for the first time, several mitochondria contact sites including MERCS in human brain biopsies. These unique human brain samples were obtained during neurosurgery from 14 patients that suffer from iNPH. Three of these 14 patients presented comorbidities with other dementias: one patient with AD, one with AD and vascular dementia and one patient with Lewy body dementia. Furthermore, we report that the numbers of MERCS are increased in biopsies obtained from patients diagnosed with dementia. Moreover, the presence of both amyloid plaques and neurofibrillary tangles correlates with decreased contact length between endoplasmic reticulum and mitochondria, while amyloid plaques alone do not seem to affect endoplasmic reticulum-mitochondria apposition. Interestingly, we report a significant positive correlation between the number of MERCS and ventricular cerebrospinal fluid amyloid β-peptide levels, as well as with increasing age of iNPH patients.

We use the comparative method of language acquisition research in this article to investigate children’s expression of directional clitics in two Eastern Mayan languages – K’iche’ and Mam (Pye and Pfeiler, 2014; Pye, 2017). The comparative method in historical linguistics reconstructs the grammatical antecedents of modern languages and traces the evolution of each linguistic feature (Paul, 1889; Campbell, 1998). This history informs research on language acquisition by demonstrating how phonological and morphological features interact in the evolution of new uses for common inherited traits. Children acquiring modern languages must learn the arbitrary constraints imposed on their language by its history.

Pioneering work in the 1990s started to address an interesting question. How is the main cellular energy source, adenosine triphosphate (ATP), imported into the mammalian endoplasmic reticulum (ER)? Despite its high-energy demand, large volume, and structural as well as functional complexity, the ER harbors no intricate system for ATP synthesis or regeneration. Although the original biochemical reconstitution approaches established hallmarks of the ATP transport into the ER including nucleotide selectivity, affinity, and antiport mode, the more recent live-cell imaging methods employing sensitive, localized molecular probes identified the elusive ATP/adenosine diphosphate (ADP) exchanger. According to its selectivity and localization, the identified SLC35B1 protein was rebranded AXER. Here, we discuss the identification and regulation of AXER plus the cytosolic partners (AMP-activated protein kinase, AMPK) and subcellular structures (mitochondrial–ER contact sites, MERCs) acting in concert with it to orchestrate energy homeostasis of the mammalian ER. Furthermore, we combine the two seemingly controversial regulatory mechanisms (lowER and CaATiER) in a unifying hypothesis. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) are the most malignant brain tumors in humans and have a very poor prognosis. Temozolomide (TMZ), the only chemotherapeutic drug for GBM treatment, induced apoptosis but frequently developed resistance. Non-apoptotic cell death offers an alternative strategy to fight cancers. Our previous studies showed that 2-methoxy-6-acetyl-7-methyljuglone (MAM), a natural product, induced necroptosis in lung and colon cancer cells. The current study is designed to investigate its therapeutic potentials for GBM with in vitro and in vivo models. The protein expression of NAD(P)H: quinone oxidoreductase 1 (NQO1) in human GBM specimens were detected by immunohistochemistry. Effect of MAM on NQO1 was measured by recombinant protein and cellular thermal shift assay. The roles of NQO1 activation, superoxide (O 2−) generation, calcium (Ca2+) accumulation, and c-Jun N-terminal kinase (JNK1/2) activation in MAM-induced cell death in U87 and U251 glioma cells were investigated. The effect of MAM on tumor growth was tested with a U251 tumor xenograft zebrafish model. Results showed that the NQO1 expression is positively correlated with the degree of malignancy in GBM tissues. MAM could directly bind and activate NQO1. Furthermore, MAM treatment induced rapid O 2− generation, cytosolic Ca2+ accumulation, and sustained JNK1/2 activation. In addition, MAM significantly suppressed tumor growth in the zebrafish model. In conclusion, MAM induced GBM cell death by triggering an O 2− /Ca2+/JNK1/2 dependent programmed necrosis. NQO1 might be the potential target for MAM and mediated its anticancer effect. This non-apoptotic necrosis might have therapeutic potentials for GBM treatment. Image 1 • MAM induced non-apoptotic programmed necrosis in human GBM cells by targeting NQO1. • MAM-induced NQO1-dependent necrosis is mediated by superoxide generation, calcium accumulation, and JNK1/2 activation. • MAM shows anticancer effect in xenograft zebrafish model possibly mediated by induction of programmed necrosis. [ABSTRACT FROM AUTHOR]

Background: Reprogramming human induced pluripotent stem cells (iPSCs) from somatic cells and generating three-dimensional brain organoids from these iPSCs provide access to live human neuronal tissue with disease-specific genetic backgrounds. Methods: Cerebral organoids were generated from iPSCs of eight bipolar disorder (BPI) patients and eight healthy control individuals. RNA-seq experiments were undertaken using RNA isolated from the cerebral organoids. Functional activity in the cerebral organoids was studied using microelectrode arrays. Results: RNA-seq data comparing gene expression profiles in the cerebral organoids showed downregulation of pathways involved in cell adhesion, neurodevelopment, and synaptic biology in bipolar disorder along with upregulation of genes involved in immune signaling. The central hub in the network analysis was neurocan (NCAN), which is located in a locus with evidence for genome-wide significant association in BPI. Gene ontology analyses suggested deficits related to endoplasmic reticulum biology in BPI, which was supported by cellular characterization of ER–mitochondria interactions. Functional studies with microelectrode arrays revealed specific deficits in response to stimulation and depolarization in BPI cerebral organoids. Conclusions: Our studies in cerebral organoids from bipolar disorder showed dysregulation in genes involved in cell adhesion, immune signaling, and endoplasmic reticulum biology; implicated a central role for the GWAS hit NCAN in the biology of BPI; and showed evidence of deficits in neurotransmission. [ABSTRACT FROM AUTHOR]

The pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α -synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD pathogenesis. Besides the long-known loss of the organelles’ bioenergetics function resulting in diminished ATP synthesis, more recent studies in the field have increasingly focused on compromised mitochondrial quality control as well as impaired biochemical processes specifically localized to ER–mitochondria interfaces (such as lipid biosynthesis and calcium homeostasis). In this review, we will discuss how dysregulated mitochondrial crosstalk with other organelles contributes to PD pathogenesis. [ABSTRACT FROM AUTHOR]

We use the comparative method of language acquisition research in this article to investigate children's expression of directional clitics in two Eastern Mayan languages – K'iche' and Mam (Pye and Pfeiler, 2014; Pye, 2017). The comparative method in historical linguistics reconstructs the grammatical antecedents of modern languages and traces the evolution of each linguistic feature (Paul, 1889; Campbell, 1998). This history informs research on language acquisition by demonstrating how phonological and morphological features interact in the evolution of new uses for common inherited traits. Children acquiring modern languages must learn the arbitrary constraints imposed on their language by its history. [ABSTRACT FROM AUTHOR]

Presenilin 2 (PS2), one of the three proteins in which mutations are linked to familial Alzheimer’s disease (FAD), exerts different functions within the cell independently of being part of the γ-secretase complex, thus unrelated to toxic amyloid peptide formation. In particular, its enrichment in endoplasmic reticulum (ER) membrane domains close to mitochondria (i.e., mitochondria-associated membranes, MAM) enables PS2 to modulate multiple processes taking place on these signaling hubs, such as Ca2+ handling and lipid synthesis. Importantly, upregulated MAM function appears to be critical in AD pathogenesis. We previously showed that FAD-PS2 mutants reinforce ER–mitochondria tethering, by interfering with the activity of mitofusin 2, favoring their Ca2+ crosstalk. Here, we deepened the molecular mechanism underlying PS2 activity on ER–mitochondria tethering, identifying its protein loop as an essential domain to mediate the reinforced ER–mitochondria connection in FAD-PS2 models. Moreover, we introduced a novel tool, the PS2 loop domain targeted to the outer mitochondrial membrane, Mit-PS2-LOOP, that is able to counteract the activity of FAD-PS2 on organelle tethering, which possibly helps in recovering the FAD-PS2-associated cellular alterations linked to an increased organelle coupling.

Mitochondria associated membranes (MAM), which are the contact sites between endoplasmic reticulum (ER) and mitochondria, have emerged as an important hub for signaling molecules to integrate the cellular and organelle homeostasis, thus facilitating the adaptation of energy metabolism to nutrient status. This review explores the dynamic structural and functional features of the MAM and summarizes the various abnormalities leading to the impaired insulin sensitivity and metabolic diseases.

Abstract Background Maternal obesity alters oocytes and subsequent fetal metabolism. An increasing number of studies have shown that the endoplasmic reticulums (ER) or mitochondria have important effects on oocyte quality, but there has been no study of the effect of mitochondria-associated ER membranes (MAMs) on oocyte quality. The present study was designed to assess whether the level of MAM and MAM-related proteins were different in oocytes from obese and control mice. Results First, oocytes from mice with high-fat-diet (HFD)-induced obesity had higher levels (either greater numbers or a higher proportion for the same numbers) of MAM than oocytes from control mice. The abundance of MAM-related proteins in oocytes from obese mice was significantly greater at both the messenger RNA and protein levels, including inositol 1,4,5-trisphosphate receptor, type 1 (IP3R1), inositol 1,4,5-trisphosphate receptor, type 2 (IP3R2) and phosphofurin acidic cluster sorting protein 2 (PACS-2). Further, there was an increase in mitochondrial Ca2+ ([Ca2+]m) which was associated with increased apoptosis and compromised cytoplasmic maturation in oocytes from obese mice. Down-regulation of MAM-related protein IP3R1 in oocytes from obese mice decreased [Ca2+]m and apoptosis and improved cytoplasmic maturation but did not reduce the overall MAM level. However, down-regulating MAM-related protein PACS-2 in oocytes from obese mice did reduce the level of MAM and [Ca2+]m, which decreased the rate of apoptosis and improved cytoplasmic maturation of oocytes from obese mice. Conclusions It is possible that enriched MAM could increase [Ca2+]m, and this increase has been found to be associated with increased apoptosis and compromised cytoplasmic maturation in oocytes from obese mice. This finding suggests a novel therapeutic target for obesity-induced oocyte defects.

Regulation of cell life and death by members of the BCL-2 family of proteins occurs at the mitochondria. Large portions of the mitochondria's outer membrane are found in tight approximation with the endoplasmic reticulum (ER), known as mitochondria-associated membranes (MAMs) or mitochondria-ER contact sites (MERCs). We recently reported that BOK is present within MAMs where it regulates Ca2+ transfer from the ER to the mitochondria, appropriate MAM components and MERC structure, and apoptosis. [ABSTRACT FROM AUTHOR]

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Metabolic dysfunction is a hallmark of multiple amyotrophic lateral sclerosis (ALS) models with a majority of ALS patients exhibiting hypermetabolism. The central sites of metabolism in the cell are mitochondria, capable of utilising a multitude of cellular substrates in an array of ATP-generating reactions. With reactive oxygen species (ROS) production occurring during some of these reactions, mitochondria can contribute considerably to oxidative stress. Mitochondria are also very dynamic organelles, interacting with other organelles, undergoing fusion/fission in response to changing metabolic states and being turned over by the cell regularly. Disruptions to many of these mitochondrial functions and processes have been reported in ALS models, largely indicating compromised mitochondrial function, increased ROS production by mitochondria, disrupted interactions with the endoplasmic reticulum and reduced turnover. This chapter summarises methods routinely used to assess mitochondria in ALS models and the alterations that have been reported in these models., (Copyright © 2024. Published by Elsevier Inc.)

Peptide mapping with mass spectrometry (MS) is an important tool for protein characterization in the biopharmaceutical industry. Historically, peptide mapping monitors post-translational modifications (PTMs) of protein products and process intermediates during development. Multi-attribute monitoring (MAM) methods have been used previously in commercial release and stability testing panels to ensure control of selected critical quality attributes (CQAs). Our goal is to use MAM methods as part of an overall analytical testing strategy specifically focused on CQAs, while removing or replacing historical separation methods that do not effectively distinguish CQAs from non-CQAs due to co-elution. For example, in this study, we developed a strategy to replace a profile-based ion-exchange chromatography (IEC) method using a MAM method in combination with traditional purity methods to ensure control of charge variant CQAs for a commercial antibody (mAb) drug product (DP). To support this change in commercial testing strategy, the charge variant CQAs were identified and characterized during development by high-resolution LC-MS and LC-MS/MS. The charge variant CQAs included PTMs, high molecular weight species, and low molecular weight species. Thus, removal of the IEC method from the DP specification was achieved using a validated LC-MS MAM method on a QDa system to directly measure the charge variant PTM CQAs in combination with size exclusion chromatography (SE-HPLC) and capillary electrophoresis (CE-SDS) to measure the non-PTM charge variant CQAs. Bridging data between the MAM, IEC, and SE-HPLC methods were included in the commercial marketing application to justify removing IEC from the DP specification. We have also used this MAM method as a test for identity to reduce the number of QC assays. This strategy has received approvals from several health authorities.

This work is part of a research project aimed at developing a bio-based binder, composed mainly of polylactic acid (PLA), to produce Ti6Al4V feedstock suitable for use in MAM (Metal Additive Manufacturing) via mFFF (metal Fused Filament Fabrication), in order to manufacture a titanium alloy specimen. While in Bragaglia et al. the mechanical characteristics of this sample were analyzed, the aim used of this study is to compare the mentioned mFFF process with one of the most used MAM processes in aerospace applications, known as Selective Laser Sintering (SLS), based on the Life Cycle Assessment (LCA) method. Despite the excellent properties of the products manufactured via SLS, this 3D printing technology involves high upfront capital costs while mFFF is a cheaper process. Moreover, the mFFF process has the advantage of potentially being exported for production in microgravity or weightless environments for in-space use. Nevertheless, most scientific literature shows comparisons of the Fused Filament Fabrication (FFF) printing stage with other AM technologies, and there are no comparative LCA "Candle to Gate" studies with mFFF processes to manufacture the same metal sample. Therefore, both MAM processes are analyzed with the LCA "Candle to Gate" method, from the extraction of raw materials to the production of the finished titanium alloy sample. The main results demonstrate a higher impact (+50%) process for mFFF and higher electrical energy consumption (7.31 kWh) compared to SLS (0.32 kWh). After power consumption, the use of titanium becomes the main contributor of Global Warming Potential (GWP) and Abiotic Depletion Potential (ADP) for both processes. Finally, an alternative scenario is evaluated in which the electrical energy is exclusively generated through photovoltaics. In this case, the results show how the mFFF process develops a more sustainable outcome than SLS.

Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human induced pluripotent stem (iPS) cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM., Competing Interests: YI, MY, TY, KH, TN, TS No competing interests declared, (© 2023, Ito, Yamagata et al.)

Acute lung injury (ALI) caused by endotoxin represents one of the common clinical emergencies. Mitochondria-associated endoplasmic reticulum membranes (MAM) serve as a critical link between mitochondria and endoplasmic reticulum (ER), which has an essential effect on maintaining intracellular homeostasis. As an important component of MAM, type-1 inositol-1,4,5-trisphosphate receptor (IP3R-1) mediates the ER-to-mitochondrial transport of Ca 2+ . This study explored the role of IP3R-1 and MAM in ALI. Besides the levels of inflammasome-associated components interleukin (IL)-6, tumor necrosis factor (TNF)-α, and malonyldialdehyde (MDA) were increased in both bronchoalveolar lavage fluid (BALF) and serum, increased cross-sectional area of mitochondria, elevated MAM formation, and decreased respiratory control ratio (RCR) were observed within lung tissues collected in lipopolysaccharide (LPS)-treated mice, accompanied by upregulation of IP3R-1 in total lung lysates and MAM. Ca 2+ uptake level in the mitochondria, production of reactive oxygen species (ROS) in the mitochondria, and the formation of MAM were elevated within LPS-treated MLE-12 cells, and all those changes in response to LPS were partly inhibited by knocking down of IP3R-1 expression in MLE-12 cells. Collectively, IP3R-1 has a critical effect on MAM formation and mitochondrial dysfunction, which could be innovative therapeutic targets for ALI caused by endotoxin., Competing Interests: Declaration Of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The multi-attribute method (MAM) has emerged significantly in recent years to support biotherapeutic protein characterization from process development to the QC environment. MAM is a liquid chromatography mass spectrometry (LC-MS) based peptide mapping approach, which combines the benefits from liquid chromatography coupled to high resolution accurate mass mass spectrometry (LC-HRAM MS), enabling direct assessment of protein sequence and product quality attributes with site specificity. These product quality attributes may impact efficacy, safety, stability, and process robustness. MAM is intended to replace conventional analytical approaches as it offers a more streamlined strategy for parallel monitoring of multiple attributes in a single analysis with high sensitivity and confidence, and ultimately supports more robust Quality by Design (QbD) approaches and faster decision cycles for biotherapeutic development. MAM consists of three main stages. The first stage is sample digestion, which typically entails proteolytic digestion of the protein. The second stage is reversed-phase chromatographic separation of the generated peptides and detection by HRAM MS in two phases. During MAM Phase I (discovery phase), data-dependent acquisition (DDA) MS/MS is performed to enable confident identification of peaks and development of a peptide workbook. During MAM Phase II (monitoring phase), full MS acquisition is only carried out for the monitoring of predefined product quality attributes (PQAs). The third stage is data processing, which entails analysis and reporting for each of the two phases including evaluation of sequence coverage, assessment of PQAs and peptide workbook creation during phase I, and targeted monitoring of predefined product attributes and new peak detection (NPD) during phase II. The latter is a comparative analysis that uses a base peak alignment algorithm to determine any non-monitored differences between the LC-MS chromatograms of a test sample and a reference standard. © 2023 The Authors. Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: In-solution sample digestion Alternate Protocol: Automated sample digestion Basic Protocol 2: Reversed-phase chromatographic separation and detection by HRAM-MS (RPLC-HRAM MS) Basic Protocol 3: Data processing and reporting., (© 2023 The Authors. Current Protocols published by Wiley Periodicals LLC.)

Aims: Most chemotherapeutic agents exploit apoptotic signaling to trigger cancer cell death, which frequently results in drug resistance. Necroptosis, a nonapoptotic form of regulated cell death, offers an alternative strategy to eradicate apoptosis-resistant cancer cells. We previously reported a natural necroptosis inducer 2-methoxy-6-acetyl-7-methyljuglone (MAM) in A549 lung cancer cells. The current study is designed to investigate the detailed necroptotic signaling and its cytotoxicity on drug-resistant cancer cells. Furthermore, in vivo anticancer effects were also evaluated in nude mice model. Results: MAM directly targets receptor-interacting protein 1 (RIP1) kinase in A549 and H1299 cells, which is responsible for reactive oxygen species (ROS, mainly hydrogen peroxide) generation. A positive feedback loop between calcium (Ca2+) and c-Jun N-terminal kinase (JNK) occurred following ROS generation, leading to lysosomal membrane permeabilization and mitochondrial dysfunction. MAM showed similar cytotoxic potency toward cisplatin-resistant A549 (A549/Cis) cells by inducing necroptosis as confirmed by the protective effect of 7-Cl-O-Nec-1 (Nec-1s) and by the morphological characteristics obtained via transmission electron microscopy. Interestingly, tumor necrosis factor alpha (TNFα) was not involved in this process. Intraperitoneal injection of MAM significantly suppressed tumor growth in A549 tumor xenograft without significant body weight loss and multiorgan toxicities. Innovation and Conclusion: Our findings demonstrate that MAM induces necroptosis in A549 and H1299 lung cancer cells by targeting RIP1 kinase and ROS in a TNFα-independent manner. MAM kills A549/Cis cells with similar potency through induction of necroptosis. MAM shows anticancer effect in animal model. The present study raises the therapeutic possibility and strategy to combat cancer by the induction of necroptosis. [ABSTRACT FROM AUTHOR]

Abstract The versatility of mitochondrial metabolism and its fine adjustments to specific physiological or pathological conditions regulate fundamental cell pathways, ranging from proliferation to apoptosis. In particular, Ca2+ signalling has emerged as a key player exploited by mitochondria to tune their activity according with cell demand. The functional interaction between mitochondria and endoplasmic reticulum (ER) deeply impacts on the correct mitochondrial Ca2+ signal, thus modulating cell bioenergetics and functionality. Indeed, Ca2+ released by the ER is taken up by mitochondria where, both in the intermembrane space and in the matrix, it regulates the activity of transporters, enzymes and proteins involved in organelles' metabolism. In this review, we will briefly summarize Ca2+-dependent mechanisms involved in the regulation of mitochondrial activity. Moreover, we will discuss some recent reports, in which alterations in mitochondrial Ca2+ signalling have been associated with specific pathological conditions, such as neurodegeneration and cancer. Highlights • ER-mitochondria Ca2+ transfer stimulates cell bioenergetics. • Ca2+-regulated mitochondrial activity is essential for highly energy demanding excitable cells. • Defective mitochondrial Ca2+ uptake is associated with several pathologies. [ABSTRACT FROM AUTHOR]

Emerging evidence indicates that Ca2+ is a vital factor in modulating the pathogenesis of Alzheimer's disease (AD). In healthy neurons, Ca2+ concentration is balanced to maintain a lower level in the cytosol than in the extracellular space or certain intracellular compartments such as endoplasmic reticulum (ER) and the lysosome, whereas this homeostasis is broken in AD. On the plasma membrane, the AD hallmarks amyloid-β (Aβ) and tau interact with ligand-gated or voltage-gated Ca2+-influx channels and inhibit the Ca2+-efflux ATPase or exchangers, leading to an elevated intracellular Ca2+ level and disrupted Ca2+ signal. In the ER, the disabled presenilin "Ca2+ leak" function and the direct implications of Aβ and presenilin mutants contribute to Ca2+-signal disorder. The enhanced ryanodine receptor (RyR)-mediated and inositol 1,4,5-trisphosphate receptor (IP3R)-mediated Ca2+ release from the ER aggravates cytosolic Ca2+ disorder and triggers apoptosis; the down-regulated ER Ca2+ sensor, stromal interaction molecule (STIM), alleviates store-operated Ca2+ entry in plasma membrane, leading to spine loss. The increased transfer of Ca2+ from ER to mitochondria through mitochondria-associated ER membrane (MAM) causes Ca2+ overload in the mitochondrial matrix and consequently opens the cellular damage-related channel, mitochondrial permeability transition pore (mPTP). In this review, we discuss the effects of Aβ, tau and presenilin on neuronal Ca2+ signal, focusing on the receptors and regulators in plasma membrane and ER; we briefly introduce the involvement of MAM-mediated Ca2+ transfer and mPTP opening in AD pathogenesis. [ABSTRACT FROM AUTHOR]

Highlights • Female rats exposed to MAM on embryonic day 17 show behavioral correlates of positive and negative schizophrenia symptoms. • The behavioral deficits observed in female MAM rats vary across the estrous cycle. • Female MAM rats also display deficits in GABAergic interneurons in the ventral hippocampus. Abstract Although there are clear sex differences in individuals with schizophrenia, preclinical research has historically favored the use of male rats for behavioral studies. The methylazoxymethanol acetate (MAM) model is a gestational disruption model of schizophrenia and has been reported to produce robust behavioral, neurophysiological and anatomical alterations in male rats; however, whether similar effects are observed in female rats is less well known. In this study, we characterize the behavioral, electrophysiological and molecular alterations induced by prenatal MAM administration in female rats while also examining the potential effects of the estrous cycle on schizophrenia-like behaviors. Specifically, MAM-treated female offspring demonstrated deficits in sensorimotor gating, latent inhibition, and social interaction, consistent with those observed in male animals. Interestingly, amphetamine-induced locomotor activity, latent inhibition, and social interaction were also affected by the estrous cycle. To examine the potential cellular mechanisms associated with these behavioral alterations, we analyzed hippocampal parvalbumin (PV) interneurons. Deficits in PV interneuron number and high-frequency gamma oscillations were disrupted in female MAM-treated rats regardless of the stage of the estrous cycle; however, alterations in PV protein expression were more prominent during metestrus/diestrus. Taken together, these data suggest that prenatal MAM exposure in female rats produces robust behavioral, molecular, and physiological deficits consistent with those observed in the male MAM model of schizophrenia. Moreover, our results also suggest that specific schizophrenia-like symptoms can also be influenced by the estrous cycle, and further emphasize the importance of sex as a biological variable when using preclinical models. [ABSTRACT FROM AUTHOR]

Abstract ER-mitochondria contact sites represent hubs for signaling that control mitochondrial biology related to several aspects of cellular survival, metabolism, cell death sensitivity and metastasis, which all contribute to tumorigenesis. Altered ER-mitochondria contacts can deregulate Ca2+ homeostasis, phospholipid metabolism, mitochondrial morphology and dynamics. MAM represent both a hot spot in cancer onset and progression and an Achilles' heel of cancer cells that can be exploited for therapeutic perspectives. Over the past years, an increasing number of cancer-related proteins, including oncogenes and tumor suppressors, have been localized in MAM and exert their pro- or antiapoptotic functions through the regulation of Ca2+ transfer and signaling between the two organelles. In this review, we highlight the central role of ER-mitochondria contact sites in tumorigenesis and focus on chemotherapeutic drugs or potential targets that act on MAM properties for new therapeutic approaches in cancer. Highlights • Mitochondria-associated membranes (MAM) are ER regions in contact with mitochondria. • MAM represent hubs for signaling and mechanisms that control cellular homeostasis. • MAM alterations have an important role in cancer and can be harnessed for therapy. [ABSTRACT FROM AUTHOR]

Pridopidine is a small molecule in clinical development for the treatment of Huntington's disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor. [ABSTRACT FROM AUTHOR]

Aim: Metacommunity ecology is a vibrant area of research that has received increased attention in recent years, since it provides a framework to assess the underlying dispersal‐ and niche‐based processes that create non‐random and ecologically meaningful patterns in species assemblages across the landscape. Here we set out to test for the role of dispersal limitation, species sorting and shared effects in the assembly of pond macrophyte metacommunities across an extensive area within the Iberian Plateau, and to identify which traits, environmental variables and spatial scales are driving local community structure. Location: North‐western Spain (Iberian Plateau). Taxon: Pond macrophytes. Methods: We established a novel combination of robust methods capable of identifying the processes and most important landscape scales involved in the assembly of communities. We used metacommunity assembly modelling and multivariate multi‐scale codependence analysis (mMCA) to first estimate the relative importance of spatial and environmental effects on community structure, and then to identify significant trait–environment relationships and spatial scales. Results: Analyses showed that the greatest effects were seen for the spatial and mixed spatial and niche‐based scenarios, particularly among wind‐dispersed species. Thus, dispersal limitation interfered with species sorting in determining assemblage structure by hindering species' tracking of local environmental conditions. After accounting for this, the metacommunity assembly model revealed that species' traits were involved in determining abundance structure. mMCA identified the main trait–environment relationships (and spatial scales) as fruit size‐nutrient status (~300 km) and growth form‐mean pond depth (~250 km). Main conclusions: Our study suggests that dispersal limitation acted in concert with species sorting to influence the community assembly processes underlying selection for particular traits in functional niche space. Accordingly, we emphasize the need to go beyond the traditional taxonomic‐based analyses of community composition and the predominant thinking of considering spatial and environmental processes as two alternative and mutually exclusive scenarios of community assembly. [ABSTRACT FROM AUTHOR]

The recent development of scientific imaging techniques have lead to the identification of various novel organellar functions. Most of these functions are perfomred in limited areas within organelles. These local functional organelle regions are referred to as 'zones'. In mitochondria, there are various types of zones exist, including the apoptosis zone, necrosis zone, mitophagy zone, mitochondrial‐derived vesicle budding zone, innate immunity zone, etc. The membrane contact site between mitochondria and the endoplasmic reticulum, which is referred to as MAM, is also considered a zone. This contact site is crucial for various biological events, such as lipid transfer, sterol exchange, Ca2+ transfer, autophagy and the suppression of neurological disorders. Therefore, the elucidation of organelle zones is essential towards a deeper understanding of cell biology. [ABSTRACT FROM AUTHOR]

Since the 1950s, electron microscopic observations have suggested the existence of special regions where the distinct organelle membranes are closely apposed to each other, yet their molecular basis and functions have not been examined for a long time. Recent studies using yeast as a model organism identified multiple organelle-membrane tethering sites/factors, such as ERMES (ER – m itochondria e ncounter s tructure), NVJ (N uclear– v acuole j unction), vCLAMP (V a c uo l e a nd m itochondria p atch) and MICOS (Mi tochondrial co ntact s ite). Among them, ERMES is the best-characterized contact-site protein complex, which was found to function as not only an organelle-tethering factor but also a phospholipid transfer protein complex. In this review, we will discuss recent advances in the characterization of ERMES and other organelle contact zones, vCLAMP, NVJ and MICOS in yeast. [ABSTRACT FROM AUTHOR]

Abstract Low-density nanocellular polymers are required to take advantage of the full potential of these materials as high efficient thermal insulators. However, their production is still a challenging task. One promising approach is the use of nanostructured polymer blends of poly(methyl methacrylate) (PMMA) and a block copolymer poly(methyl methacrylate)-poly(butyl acrylate)-poly(methyl methacrylate) (MAM), which are useful for promoting nucleation but seem to present a severe drawback, as apparently avoid low relative densities. In this work, new strategies to overcome this limitation and produce low-density nanocellular materials based on these blends are investigated. First, the effect of very low amounts of the MAM copolymer is analysed. It is detected that nanostructuration can be prevented using low copolymer contents, but nucleation is still enhanced as a result of the copolymer molecules with high CO 2 affinity dispersed in the matrix, so nanocellular polymers are obtained using very low percentages of the copolymer. Second, the influence of the foaming temperature is studied. Results show that for systems in which there is not a clear nanostructuration, cells can grow more freely and smaller relative densities can be achieved. For these studies, blends of PMMA with MAM with copolymer contents from 10 wt% and as low as 0.1 wt% are used. For the first time, the production strategies proposed in this work have allowed obtaining low density (relative density 0.23) nanocellular polymers based on PMMA/MAM blends. Graphical abstract Image 1 Highlights • Low-density nanocellular polymers based on PMMA/MAM blends are produced. • Low MAM copolymer contents, as low as 0.1 wt%, are used to produce such materials. • The physical mechanisms that allow this reduction of the density are discussed. [ABSTRACT FROM AUTHOR]

Aberrant hippocampal activity is observed in individuals with schizophrenia and is thought to underlie the augmented dopamine system function associated with psychosis. The pathway by which the ventral hippocampus (vHipp) regulates dopamine neuron activity has been demonstrated previously and involves a glutamatergic projection to the nucleus accumbens (NAc). Recent postmortem studies have confirmed glutamatergic abnormalities in the NAc of individuals with schizophrenia. Specifically, an increase in vesicular glutamate transporter 2 (vGlut2) expression was reported. Although projections from the hippocampus do express vGlut2, inputs from the thalamus are more likely to account for this alteration; however, the role of thalamic inputs to the NAc in the regulation of dopamine neuron activity has not been elucidated. Here, using male Sprague Dawley rats, we demonstrate that a subset of NAc medium spiny neurons receive convergent inputs from the vHipp and paraventricular nucleus of the thalamus (PVT), with both regions working synergistically to regulate dopamine neuron activity. Activation of either the vHipp or PVT increases the number of spontaneously active dopamine neurons in the ventral tegmental area. Moreover, this regulation requires simultaneous activity in both regions because PVT inactivation can reverse vHipp-induced increases in dopamine neuron population activity and vHipp inactivation can reverse PVT-induced increases. This is relevant to schizophrenia because inactivation of either the vHipp or PVT is sufficient to reverse aberrant dopamine system function in two distinct rodent models. These data suggest that thalamic abnormalities may contribute to the aberrant dopamine system function observed in schizophrenia and that the PVT represents a novel site of intervention for psychosis. [ABSTRACT FROM AUTHOR]

Patients with neuropsychiatric and neurological disorders often express limbic circuit abnormalities and deficits in information processing. While these disorders appear to have diverse etiologies, their common features suggest neurodevelopmental origins. Neurodevelopment is a prolonged process of diverse events including neurogenesis/apoptosis, axon pathfinding, synaptogenesis, and pruning, to name a few. The precise timing of the neurodevelopmental insult to these processes likely determines the resulting functional outcome. We used the epilepsy and schizophrenia-related gestational day 17 methylazoxymethanol acetate model to examine the impact of this timed neurodevelopmental insult on principal cell morphology and synaptic network function of the dorsal hippocampus (dHPC) circuit. Our observed structural and functional alterations in dHPC are compartment specific, indicating that adverse global exposure during gestation can produce specific alterations and distort information processing in neural circuits that underlie cognitive abilities. [ABSTRACT FROM AUTHOR]

Organic polymers can be made porous via continuous or discontinuous expansion processes in scCO2. The resulting foams properties are controlled by the interplay of three groups of parameters: (i) Chemical, (ii) physico-chemical, and (iii) technological/process that are explained in this paper. The advantages and drawbacks of continuous (extrusion, injection foaming) or discontinuous (batch foaming) foaming processes in scCO2, will be discussed in this article; especially for micro or nano cellular polymers. Indeed, a challenge is to reduce both specific mass (e.g., ρ < 100 kg·m−3) and cell size (e.g., average pore diameter ϕaveragepores < 100 nm). Then a particular system where small “objects” (coreshells CS, block copolymer MAM) are perfectly dispersed at a micrometric to nanometric scale in poly(methyl methacrylate) (PMMA) will be presented. Such “additives”, considered as foaming aids, are aimed at “regulating” the foaming and lowering the pore size and/or density of PMMA based foams. Differences between these additives will be shown. Finally, in a PMMA/20 wt% MAM blend, via a quasi one-step batch foaming, a “porous to nonporous” transition is observed in thick samples. A lower limit of pore size (around 50 nm) seems to arise.

Adalimumab drug product (Humira ®), the first fully human monoclonal antibody (mAb) approved by FDA in 2002, led the top ten list of best-selling mAbs in 2018 and has been the most profitable drug in the world. With the expiration of patent protection in Europe in 2018 and in United States by 2023, the landscape is changing as up to 10 adalimumab biosimilars are expected to enter the market in the US. Biosimilars offer the potential to lower costs on health care systems and increase patient accessibility. The analytical similarity of seven different adalimumab biosimilars was accomplished in the present study using the multi-attribute method (MAM), a LC-MS based peptide mapping technique that allows for primary sequence assessment and evaluation of multiple quality attributes including deamidation, oxidation, succinimide formation, N- and C- terminal composition and detailed N-glycosylation analysis. In the first step, characterization of the most relevant post-translational modifications of a reference product was attained during the discovery phase of MAM. During the second step, as part of the MAM targeted monitoring phase, adalimumab batch-to batch variability was evaluated to define statistical intervals for the establishment of similarity ranges. The third step describes biosimilarity evaluation of predefined quality attributes and new peak detection for the assessment of any new or modified peak compared to the reference product. This study highlights a new perspective of the MAM approach and its underlying power for biotherapeutic comparability exercises in addition to analytical characterization. MAM offers a streamlined comparability assessment workflow based on high-confidence quality attribute analysis using high-resolution accurate mass mass spectrometry (HRAM MS) and the capability to detect any new or modified peak compared to the reference product. [Display omitted] • Adalimumab reference product patent expiration forces the need for a streamlined method to assess analytical comparability. • Multi-attribute method allows for the comparison of seven adalimumab biosimilars with high sensitivity and specificity. • Detailed N-glycosylation and 15 quality attributes are reported for adalimumab reference product in a single analysis. • The evaluation of batch-to-batch variability is the basis to establish the acceptance criteria for analytical comparability. [ABSTRACT FROM AUTHOR]

Drug resistance is a major challenge in cancer treatment. The substrates of NAD(P)H:quinone oxidoreductase 1 (NQO1) show a promising anticancer effect in clinical trials. We previously identified a natural NQO1 substrate 2-methoxy-6-acetyl-7-methyljuglone (MAM) with a potent anticancer effect. The present study was designed to explore the efficacy of MAM in fighting against drug-resistant non-small cell lung cancer (NSCLC). The anticancer effect of MAM was evaluated in cisplatin-resistant A549 and AZD9291-resistant H1975 cells. The interaction of MAM with NQO1 was measured by cellular thermal shift assay and drug affinity responsive target stability assay. The NQO1 activity and expression were measured using NQO1 recombinant protein, Western blotting, and immunofluorescence staining assay. The roles of NQO1 were examined by NQO1 inhibitor, small interfering RNA (siRNA), and short hairpin RNA (shRNA). The roles of reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation were determined. MAM induced significant cell death in drug-resistant cells with similar potency to that of parental cells, which were completely abolished by NQO1 inhibitor, NQO1 siRNA, and iron chelators. MAM activates and binds to NQO1, which triggers ROS generation, LIP increase, and lipid peroxidation. MAM significantly suppressed tumor growth in the tumor xenograft zebrafish model. These results showed that MAM induced ferroptosis by targeting NQO1 in drug-resistant NSCLC cells. Our findings provided a novel therapeutic strategy for fighting against drug resistance by induction of NQO1-mediated ferroptosis. [Display omitted] • MAM showed significant anticancer effect in cisplatin and AZD9291 resistant NSCLC. • NQO1 mediated MAM's anticancer effect both in vitro and in vivo. • MAM triggers NQO1 mediated ferroptosis in lung cancer cells. [ABSTRACT FROM AUTHOR]

This paper presents a new design of a perforated plate-type acoustic metamaterial (PAM) to evade the influence of membrane pre-tension on the acoustic performance of metamaterials and to enable air ventilation while achieving the designated sound insulation. The study embarks on the analysis of sound insulation mechanism of a typical perforated membrane-type acoustic metamaterial (MAM) from the acoustic context, and discloses that sound transmission loss (STL) peaks of a perforated MAM are due to the strong wave interference between sound sources transmitted through the orifice(s) and the membrane(s). The sound insulation mechanism is explored further in the study by an acoustic impedance analysis of a perforated metamaterial using an electro-acoustic analogy in the latter part of the paper, and the result confirms that the STL peaks of a perforated PAM (or MAM) are indeed the outcome of a strong sound interference. The study also compares an experiment test and a finite element simulation on the sound transmission of a perforated PAM based on the new design. The result confirms that the new perforated PAM can yield a good broadband STL at relatively low frequencies. A practical application using the perforated PAM design is applied to reduce the noise propagation from the compressor compartment of a commercial refrigerator. The test result verifies the effectiveness of the design in terms of both sound reduction and air ventilation. [ABSTRACT FROM AUTHOR]

The pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder, is complex and involves the impairment of crucial intracellular physiological processes. Importantly, in addition to abnormal α-synuclein aggregation, the dysfunction of various mitochondria-dependent processes has been prominently implicated in PD pathogenesis. Besides the long-known loss of the organelles’ bioenergetics function resulting in diminished ATP synthesis, more recent studies in the field have increasingly focused on compromised mitochondrial quality control as well as impaired biochemical processes specifically localized to ER−mitochondria interfaces (such as lipid biosynthesis and calcium homeostasis). In this review, we will discuss how dysregulated mitochondrial crosstalk with other organelles contributes to PD pathogenesis.

Las organizaciones contemporáneas se han visto abocadas a la gestión creciente de activos digitales de naturaleza audiovisual y multimedia, muchos de ellos de interés patrimonial. El presente artículo realiza la revisión y análisis de cinco gestores de activos multimedia de plena significación en la actualidad. Tras sistematizar las características generales y módulos que deben satisfacer este tipo de sistemas, hemos procedido a la evaluación de los sistemas de gestión documental seleccionados, alcanzando como resultado la discusión de las ventajas que nos proporciona cada uno de ellos, sus características distintivas, así como la evaluación de su adecuación profesional.

Sigma-1 receptor ligands have been long expected to serve as drugs for treatment of human diseases such as neurodegenerative disorders, depression, idiopathic pain, drug abuse, and cancer. Recent research exploring the molecular function of the sigma-1 receptor started unveiling underlying mechanisms of the therapeutic activity of those ligands. Via the molecular chaperone activity, the sigma-1 receptor regulates protein folding/degradation, ER/oxidative stress, and cell survival. The chaperone activity is activated or inhibited by synthetic sigma-1 receptor ligands in an agonist-antagonist manner. Sigma-1 receptors are localized at the endoplasmic reticulum (ER) membranes that are physically associated with the mitochondria (MAM: mitochondria-associated ER membrane). In specific types of neurons (e.g., those at the spinal cord), sigma-1 receptors are also clustered at ER membranes that juxtapose postsynaptic plasma membranes. Recent studies indicate that sigma-1 receptors, partly in sake of its unique subcellular localization, regulate the mitochondria function that involves bioenergetics and free radical generation. The sigma-1 receptor may thus provide an intracellular drug target that enables controlling ER stress and free radical generation under pathological conditions.

Stress-induced release of glucocorticoid is an important amyloidogenic factor that upregulates amyloid precursor protein (APP) and β secretase 1 (BACE1) levels. Glucocorticoid also contributes to the pathogenesis of Alzheimer's disease (AD) by increasing ER-mitochondria connectivity, in which amyloid β (Aβ) processing occurs rigorously because of its lipid raft-rich characteristics. However, the mechanism by which glucocorticoid enhances γ-secretase activity in the mitochondrial-associated membrane of ER (MAM) and subsequent accumulation of mitochondrial Aβ is unclear. In this study, we determined how glucocorticoid enhances Aβ production in MAM using SH-SY5Y cells and ICR mice. First, we observed that cortisol-induced Aβ accumulation in mitochondria preceded its extracellular apposition by enhancing γ-secretase activity, which was the result of increased presenilin 1 (PSEN1) localization in MAM. Screening data revealed that cortisol selectively downregulated the ER retrieval protein Rer1, which triggered its maturation and subsequent entry into the endocytic secretory pathway of PSEN1. Accordingly, overexpression of RER1 reversed the deleterious effects of mitochondrial Aβ on mitochondrial respiratory function and neuronal cell viability. Notably, we found that cortisol guided the glucocorticoid receptor (GR) to bind directly to the RER1 promoter, thus trans-repressing its expression. Inhibiting GR function reduced Aβ accumulation at mitochondria and improved the outcome of a spatial memory task in mice exposed to corticosterone. Taken together, glucocorticoid enhances PSEN1-mediated Aβ generation at MAM by downregulating Rer1, which is a potential target at early stages of AD pathogenesis., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Gestational and perinatal disruption of neural development increases the risk of developing schizophrenia (SCZ) later in life. Embryonic day 17 (E17) methylazoxymethanol (MAM) treatment leads to histological, physiological and behavioural abnormalities in post-puberty rats that model the neuropathological and cognitive deficits reported in SCZ patients. However, the validity of E17 MAM-exposed mice to model SCZ has not been explored. Here we treated E17 C57BL/6 mouse dams with various dosages of MAM. We found that this mouse strain was more vulnerable to MAM treatment than rats and there were gender differences in behavioural abnormalities, histological changes and prefrontal cortical gene expression profiles in MAM (7.5 mg/kg)-exposed mice. Both male and female MAM-exposed mice had deficits in prepulse inhibition. Female MAM-exposed mice exhibited mildly increased spontaneous locomotion activity and social recognition deficits, while male mice were normal. Consistently, only female MAM-exposed mice exhibited reduced brain weight, decreased size of prefrontal cortex (PFC) and enlarged lateral ventricles. Transcriptome analysis of the PFC revealed that there were more differentially expressed genes in female MAM-exposed mice than those in male mice. Moreover, expression of Pvalb , Arc and genes in their association networks were downregulated in the PFC of female MAM-exposed mice. These results indicate that E17 MAM-exposure in C57BL/6 mice leads to behavioural changes that model certain deficits reported in SCZ patients. MAM-exposed female mice may be used to study gene expression changes, inhibitory neural circuit dysfunction and glutamatergic synaptic plasticity deficits with a possible relation to those in the brains of SCZ patients. [ABSTRACT FROM AUTHOR]