A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart.

Cardiomyocytes are subjected to the intense mechanical stress and metabolic demands of the beating heart. It is unclear whether these cells, which are long-lived and rarely renew, manage to preserve homeostasis on their own. While analyzing macrophages lodged within the healthy myocardium, we discovered that they actively took up material, including mitochondria, derived from cardiomyocytes. Cardiomyocytes ejected dysfunctional mitochondria and other cargo in dedicated membranous particles reminiscent of neural exophers, through a process driven by the cardiomyocyte's autophagy machinery that was enhanced during cardiac stress. Depletion of cardiac macrophages or deficiency in the phagocytic receptor Mertk resulted in defective elimination of mitochondria from the myocardial tissue, activation of the inflammasome, impaired autophagy, accumulation of anomalous mitochondria in cardiomyocytes, metabolic alterations, and ventricular dysfunction. Thus, we identify an immune-parenchymal pair in the murine heart that enables transfer of unfit material to preserve metabolic stability and organ function. VIDEO ABSTRACT.

ER and Nutrient Stress Promote Assembly of Respiratory Chain Supercomplexes through the PERK-eIF2α Axis.

Endoplasmic reticulum (ER) stress and unfolded protein response are energetically challenging under nutrient stress conditions. However, the regulatory mechanisms that control the energetic demand under nutrient and ER stress are largely unknown. Here we show that ER stress and glucose deprivation stimulate mitochondrial bioenergetics and formation of respiratory supercomplexes (SCs) through protein kinase R-like ER kinase (PERK). Genetic ablation or pharmacological inhibition of PERK suppresses nutrient and ER stress-mediated increases in SC levels and reduces oxidative phosphorylation-dependent ATP production. Conversely, PERK activation augments respiratory SCs. The PERK-eIF2α-ATF4 axis increases supercomplex assembly factor 1 (SCAF1 or COX7A2L), promoting SCs and enhanced mitochondrial respiration. PERK activation is sufficient to rescue bioenergetic defects caused by complex I missense mutations derived from mitochondrial disease patients. These studies have identified an energetic communication between ER and mitochondria, with implications in cell survival and diseases associated with mitochondrial failures.

Inverse regulation of SOS1 and HKT1 protein localization and stability by SOS3/CBL4 in Arabidopsis thaliana.

To control net sodium (Na+) uptake, Arabidopsis plants utilize the plasma membrane (PM) Na+/H+ antiporter SOS1 to achieve Na+ efflux at the root and Na+ loading into the xylem, and the channel-like HKT1;1 protein that mediates the reverse flux of Na+ unloading off the xylem. Together, these opposing transport systems govern the partition of Na+ within the plant yet they must be finely co-regulated to prevent a futile cycle of xylem loading and unloading. Here, we show that the Arabidopsis SOS3 protein acts as the molecular switch governing these Na+ fluxes by favoring the recruitment of SOS1 to the PM and its subsequent activation by the SOS2/SOS3 kinase complex under salt stress, while commanding HKT1;1 protein degradation upon acute sodic stress. SOS3 achieves this role by direct and SOS2-independent binding to previously unrecognized functional domains of SOS1 and HKT1;1. These results indicate that roots first retain moderate amounts of salts to facilitate osmoregulation, yet when sodicity exceeds a set point, SOS3-dependent HKT1;1 degradation switches the balance toward Na+ export out of the root. Thus, SOS3 functionally links and co-regulates the two major Na+ transport systems operating in vascular plants controlling plant tolerance to salinity.

S-acylated and nucleus-localized SALT OVERLY SENSITIVE3/CALCINEURIN B-LIKE4 stabilizes GIGANTEA to regulate Arabidopsis flowering time under salt stress.

The precise timing of flowering in adverse environments is critical for plants to secure reproductive success. We report a mechanism in Arabidopsis (Arabidopsis thaliana) controlling the time of flowering by which the S-acylation-dependent nuclear import of the protein SALT OVERLY SENSITIVE3/CALCINEURIN B-LIKE4 (SOS3/CBL4), a Ca2+-signaling intermediary in the plant response to salinity, results in the selective stabilization of the flowering time regulator GIGANTEA inside the nucleus under salt stress, while degradation of GIGANTEA in the cytosol releases the protein kinase SOS2 to achieve salt tolerance. S-acylation of SOS3 was critical for its nuclear localization and the promotion of flowering, but partly dispensable for salt tolerance. SOS3 interacted with the photoperiodic flowering components GIGANTEA and FLAVIN-BINDING, KELCH REPEAT, F-BOX1 and participated in the transcriptional complex that regulates CONSTANS to sustain the transcription of CO and FLOWERING LOCUS T under salinity. Thus, the SOS3 protein acts as a Ca2+- and S-acylation-dependent versatile regulator that fine-tunes flowering time in a saline environment through the shared spatial separation and selective stabilization of GIGANTEA, thereby connecting two signaling networks to co-regulate the stress response and the time of flowering.

Gut microbiota signatures of vulnerability to food addiction in mice and humans.

OBJECTIVE: Food addiction is a multifactorial disorder characterised by a loss of control over food intake that may promote obesity and alter gut microbiota composition. We have investigated the potential involvement of the gut microbiota in the mechanisms underlying food addiction. DESIGN: We used the Yale Food Addiction Scale (YFAS) 2.0 criteria to classify extreme food addiction in mouse and human subpopulations to identify gut microbiota signatures associated with vulnerability to this disorder. RESULTS: Both animal and human cohorts showed important similarities in the gut microbiota signatures linked to food addiction. The signatures suggested possible non-beneficial effects of bacteria belonging to the Proteobacteria phylum and potential protective effects of Actinobacteria against the development of food addiction in both cohorts of humans and mice. A decreased relative abundance of the species Blautia wexlerae was observed in addicted humans and of Blautia genus in addicted mice. Administration of the non-digestible carbohydrates, lactulose and rhamnose, known to favour Blautia growth, led to increased relative abundance of Blautia in mice faeces in parallel with dramatic improvements in food addiction. A similar improvement was revealed after oral administration of Blautia wexlerae as a beneficial microbe. CONCLUSION: By understanding the crosstalk between this behavioural alteration and gut microbiota, these findings constitute a step forward to future treatments for food addiction and related eating disorders.

Endothelial dysfunction and persistent inflammation in severe post-COVID-19 patients: implications for gas exchange.

BACKGROUND: Understanding the enduring respiratory consequences of severe COVID-19 is crucial for comprehensive patient care. This study aims to evaluate the impact of post-COVID conditions on respiratory sequelae of severe acute respiratory distress syndrome (ARDS). METHODS: We examined 88 survivors of COVID-19-associated severe ARDS six months post-intensive care unit (ICU) discharge. Assessments included clinical and functional evaluation as well as plasma biomarkers of endothelial dysfunction, inflammation, and viral response. Additionally, an in vitro model using human umbilical vein endothelial cells (HUVECs) explored the direct impact of post-COVID plasma on endothelial function. RESULTS: Post-COVID patients with impaired gas exchange demonstrated persistent endothelial inflammation marked by elevated ICAM-1, IL-8, CCL-2, and ET-1 plasma levels. Concurrently, systemic inflammation, evidenced by NLRP3 overexpression and elevated levels of IL-6, sCD40-L, and C-reactive protein, was associated with endothelial dysfunction biomarkers and increased in post-COVID patients with impaired gas exchange. T-cell activation, reflected in CD69 expression, and persistently elevated levels of interferon-ß (IFN-ß) further contributed to sustained inflammation. The in vitro model confirmed that patient plasma, with altered levels of sCD40-L and IFN-ß proteins, has the capacity to alter endothelial function. CONCLUSIONS: Six months post-ICU discharge, survivors of COVID-19-associated ARDS exhibited sustained elevation in endothelial dysfunction biomarkers, correlating with the severity of impaired gas exchange. NLRP3 inflammasome activity and persistent T-cell activation indicate on going inflammation contributing to persistent endothelial dysfunction, potentially intensified by sustained viral immune response.

Quantification of Solid Embryonic Cerebellar Graft Volume in a Degenerative Ataxia Model.

Substitution of lost neurons by neurotransplantation would be a possible management of advanced degenerative cerebellar ataxias in which insufficient cerebellar reserve remains. In this study, we examined the volume and structure of solid embryonic cerebellar grafts in adult Lurcher mice, a model of olivocerebellar degeneration, and their healthy littermates. Grafts taken from enhanced green fluorescent protein (EGFP)-positive embryos were injected into the cerebellum of host mice. Two or six months later, the brains were examined histologically. The grafts were identified according to the EGFP fluorescence in frozen sections and their volumes were estimated using the Cavalieri principle. For gross histological evaluation, graft-containing slices were processed using Nissl and hematoxylin-eosin staining. Adjustment of the volume estimation approach suggested that it is reasonable to use all sections without sampling, but that calculation of values for up to 20% of lost section using linear interpolation does not constitute substantial error. Mean graft volume was smaller in Lurchers than in healthy mice when examined 6 months after the transplantation. We observed almost no signs of graft destruction. In some cases, compact grafts disorganized the structure of the host's cerebellar cortex. In Lurchers, the grafts had a limited contact with the host's cerebellum. Also, graft size was of greater variability in Lurchers than in healthy mice. The results are in compliance with our previous findings that Lurcher phenotype-associated factors have a negative effect on graft development. These factors can hypothetically include cerebellar morphology, local tissue milieu, or systemic factors such as immune system abnormalities.

SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells.

BACKGROUND: Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells. METHODS: In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence. RESULTS: S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1ß formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1ß. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC. CONCLUSION: S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element. Video Abstract.

Oocyte collection and outcome following oncologic treatment: a retrospective multicentre study.

PURPOSE: This study assesses fertility treatment outcomes in female patients who had undergone successful oocyte retrieval following cancer therapy. METHODS: Between January 2020 and December 2022, we collected fertility treatment data from six participating centres in Spain and Germany. All patients associated with this data had undergone successful oocyte retrieval following cancer treatment. RESULTS: Women had most frequently been diagnosed with a haematological (41.9%), breast (22.6%) or gynaecological malignancy (12.9%); two thirds (67.7%) had previously received a chemotherapy, half a radiotherapy (53.3%) and 45.2% had undergone surgery. On average, 7 years (range 0-28) had passed between cancer treatment and first ovarian stimulation cycle. Forty-nine ovarian stimulation cycles had been conducted on these 31 women between 2004 and 2021 (mean age at first oocyte collection following treatment: 34.8 ± 5.7 years). On average, 7 oocytes were collected per cycle (range 0-26) and 11 were collected per patient (range 0-51). Out of the 190 oocytes collected for immediate use of artificial reproductive technique, 139 were fertilised at a rate of 73%. Live birth rate per fresh transfer was 45% (9/20); no births were reported following cryotransfer (0/10). Mean values of anti-Mullerian hormone (AMH) before stimulation declined with time since treatment; however, oocytes were successfully collected from four women with an AMH of <0.5 ng/ml, although no pregnancies were reported. Ten pregnancies were documented; 3 ended in miscarriage. Two twin and 5 single pregnancies resulted in nine live births. On average, children were carried to term. CONCLUSION: In this small cohort, oocytes were successfully collected after chemotherapy and radiotherapy, despite-in individual cases-low AMH values. Further studies are needed to enrich the database and ultimately provide appropriate counselling to female cancer patients regarding expectations and ART outcome following cancer therapy.

Exploring the link between hedonic overeating and prefrontal cortex dysfunction in the Ts65Dn trisomic mouse model.

Individuals with Down syndrome (DS) have a higher prevalence of obesity compared to the general population. Conventionally, this has been attributed to endocrine issues and lack of exercise. However, deficits in neural reward responses and dopaminergic disturbances in DS may be contributing factors. To investigate this, we focused on a mouse model (Ts65Dn) bearing some triplicated genes homologous to trisomy 21. Through detailed meal pattern analysis in male Ts65Dn mice, we observed an increased preference for energy-dense food, pointing towards a potential "hedonic" overeating behavior. Moreover, trisomic mice exhibited higher scores in compulsivity and inflexibility tests when limited access to energy-dense food and quinine hydrochloride adulteration were introduced, compared to euploid controls. Interestingly, when we activated prelimbic-to-nucleus accumbens projections in Ts65Dn male mice using a chemogenetic approach, impulsive and compulsive behaviors significantly decreased, shedding light on a promising intervention avenue. Our findings uncover a novel mechanism behind the vulnerability to overeating and offer potential new pathways for tackling obesity through innovative interventions.

Lateral-type posterior fossa ependymomas in pediatric patients: a national collaborative study.

PURPOSE: To review a multicentric series of lateral-type posterior fossa ependymomas operated in the last ten years and to analyze the factors related to clinical evolution and tumor survival. METHODS: Descriptive, retrospective study. Active members of the Spanish Society of Pediatric Neurosurgery were invited to participate in this multicentric study. Clinical and radiological data were incorporated to an open database. The role of histologic grade, grade of resection, postoperative morbidities, and clinical follow-up was evaluated through bivariate associations (chi-square), Kaplan-Meier's curves (log-rank test), and multivariate analysis (binary logistic regression). RESULTS: Fourteen centers entered the study, and 25 cases with a minimum follow-up of 6 months were included. There were 13 boys and 12 girls with a mean age close to 3 years. Mean tumor volume at diagnosis was over 60 cc. A complete resection was achieved in 8 patients and a near-total resection in 5 cases. Fifteen tumors were diagnosed as ependymoma grade 2 and ten as ependymoma grade 3. Major morbidity occurred postoperatively in 14 patients but was resolved in twelve within 6 months. There were six cases of death and 11 cases of tumor progression along the observation period. Mean follow-up was 44.8 months. Major morbidity was significantly associated with histologic grade but not with the degree of resection. Overall and progression-free survival were significantly associated with complete surgical resection. At the last follow-up, 16 patients carried a normal life, and three displayed a mild restriction according to Lansky's scale. CONCLUSIONS: Lateral-type posterior fossa ependymomas constitute a specific pathologic and clinical tumor subtype with bad prognosis. Gross total resection is the goal of surgical treatment, for it significantly improves prognosis with no additional morbidity. Neurological deficits associated to lower cranial nerve dysfunction are common, but most are transient. Deeper genetic characterization of these tumors may identify risk factors that guide new treatments and stratification of adjuvant therapies.

Antenna Booster Element for Multiband Operation.

The escalating demand for versatile wireless devices has fostered the need to reduce the antenna footprint to support the integration of multiple new functionalities. This poses a significant challenge for the Internet of things (IoT) antenna designers tasked with creating antennas capable of supporting multiband operation within physical constraints. This work aims to address this challenge by focusing on the optimization of an antenna booster element to achieve multiband performance, accomplished through the design of a band-reject filter. This proposal entails a printed circuit board (PCB) measuring 142 mm × 60 mm, with a clearance area of 12 mm × 40 mm, incorporating an antenna booster element of 30 mm × 3 mm × 1 mm (0.07 λ). This configuration covers frequencies in the LFR (low-frequency range) from 698 MHz to 960 MHz and the HFR (high-frequency range) from 1710 MHz to 2690 MHz. A theoretical analysis is conducted to optimize bandwidth in both frequency regions. Finally, a prototype validates the analytic results.

Cilastatin as a Potential Anti-Inflammatory and Neuroprotective Treatment in the Management of Glaucoma.

Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.

[Emergency medicine: what's new in 2023]. / Médecine d'urgence: ce qui a changé en 2023.

Research in prehospital and in-hospital emergency medicine is essential to the development of this discipline. By calling certain practices into question (thrombolysis for minor strokes, use of coagulation factors for patients with severe polytrauma), providing access to new technologies (video-laryngoscopy, POCT troponins in pre-hospital care) or questioning new practices (double defibrillation, pulmonary US in pneumonia), research enables emergency physicians to adapt their day-to-day practice.

La recherche en médecine d'urgence, tant sur le plan préhospitalier qu'hospitalier, est nécessaire et même indispensable à la fois au développement de cette discipline, mais également à la reconnaissance de ses spécificités. Par la remise en question de certaines pratiques (thrombolyse pour les AVC mineurs, utilisation de facteurs de la coagulation pour le polytraumatisé sévère), l'accès à de nouvelles technologies (vidéo-laryngoscopie, troponines POCT en préhospitalier) ou le questionnement sur de nouvelles pratiques (double défibrillation, US pulmonaire dans la pneumonie), la recherche permet aux urgentistes d'adapter leur pratique quotidienne à l'état de l'art.

Macrophages direct cancer cells through a LOXL2-mediated metastatic cascade in pancreatic ductal adenocarcinoma.

OBJECTIVE: The lysyl oxidase-like protein 2 (LOXL2) contributes to tumour progression and metastasis in different tumour entities, but its role in pancreatic ductal adenocarcinoma (PDAC) has not been evaluated in immunocompetent in vivo PDAC models. DESIGN: Towards this end, we used PDAC patient data sets, patient-derived xenograft in vivo and in vitro models, and four conditional genetically-engineered mouse models (GEMMS) to dissect the role of LOXL2 in PDAC. For GEMM-based studies, K-Ras +/LSL-G12D;Trp53 LSL-R172H;Pdx1-Cre mice (KPC) and the K-Ras +/LSL-G12D;Pdx1-Cre mice (KC) were crossed with Loxl2 allele floxed mice (Loxl2Exon2 fl/fl) or conditional Loxl2 overexpressing mice (R26Loxl2 KI/KI) to generate KPCL2KO or KCL2KO and KPCL2KI or KCL2KI mice, which were used to study overall survival; tumour incidence, burden and differentiation; metastases; epithelial to mesenchymal transition (EMT); stemness and extracellular collagen matrix (ECM) organisation. RESULTS: Using these PDAC mouse models, we show that while Loxl2 ablation had little effect on primary tumour development and growth, its loss significantly decreased metastasis and increased overall survival. We attribute this effect to non-cell autonomous factors, primarily ECM remodelling. Loxl2 overexpression, on the other hand, promoted primary and metastatic tumour growth and decreased overall survival, which could be linked to increased EMT and stemness. We also identified tumour-associated macrophage-secreted oncostatin M (OSM) as an inducer of LOXL2 expression, and show that targeting macrophages in vivo affects Osm and Loxl2 expression and collagen fibre alignment. CONCLUSION: Taken together, our findings establish novel pathophysiological roles and functions for LOXL2 in PDAC, which could be potentially exploited to treat metastatic disease.

Inflammasome activation mediated by oxidised low-density lipoprotein in patients with sleep apnoea and early subclinical atherosclerosis.

BACKGROUND: Atherosclerosis is a common comorbidity of obstructive sleep apnoea (OSA) patients, caused by the interaction of dyslipidaemia and systemic inflammation. The OSA pro-inflammatory response is mediated by NLRP3 inflammasome activation, which requires a priming signal mediated by intermittent hypoxia (IH) and an activation signal provided by soluble stimulus present in plasma. Our objectives were to study oxidised low-density lipoprotein (oxLDL) expression in OSA patients with or without early subclinical atherosclerosis (eSA) as well as its contribution to NLRP3 activation and tissue factor (TF) release. METHODS: We analysed oxLDL, key components of the NLRP3 inflammasome cascade and TF in plasma and monocytes from OSA patients and non-apnoeic subjects, with or without eSA as determined by increased carotid intima-media thickness without the appearance of atherosclerotic plaques. The oxLDL contribution to NLRP3 inflammasome activation was assessed using in vitro models. RESULTS: High levels of oxLDL were identified in plasma from OSA patients, particularly in those with eSA, as well as an overexpression of NLRP3 cascade components and TF. Furthermore, in vitro models showed that both oxLDL and plasma from OSA patients with eSA act synergistically with IH as a priming and activation signal of NLRP3 that enhances the inflammatory response, pyroptosis and TF release. CONCLUSIONS: OSA patients with eSA exhibit NLRP3 activation by IH and the presence of oxLDL capable of releasing TF, constituting a pathway for the interaction between dyslipidaemia and systemic inflammation in the development of atherosclerotic lesions.

Obstructive sleep apnoea is related to melanoma aggressiveness through paraspeckle protein-1 upregulation.

BACKGROUND: In patients with obstructive sleep apnoea (OSA), intermittent hypoxia induces overexpression of paraspeckle component (PSPC)1, a master modulator of transforming growth factor (TGF)-ß signalling, which promotes cell cancer progression through epithelial-mesenchymal transition (EMT) and acquisition of cancer stem cell (CSC)-like features. However, the persistence of intermittent hypoxia-induced effects on PSPC1, and their consequences in cancer patients are not known. To this effect, circulating PSPC1 levels were compared in patients with cutaneous melanoma with or without OSA, and their relationship with tumour aggressiveness along with the in vitro effects of soluble PSPC1 and intermittent hypoxia on melanoma cell aggressiveness mechanisms were assessed. METHODS: In 292 cutaneous melanoma patients, sleep studies and serum levels of PSPC1 and TGF-ß were evaluated. The effect of PSPC1 on expression of EMT and CSC transcription factors was assessed using melanoma cell lines with patient sera under both normoxia and intermittent hypoxia conditions. RESULTS: PSPC1 levels were higher in patients with moderate-severe OSA compared with mild OSA or non-OSA patients. Serum levels of PSPC1 were associated with several cutaneous melanoma clinical aggressiveness indicators. Both intermittent hypoxia exposures and serum from OSA patients upregulated TGF-ß expression and amplified the expression of transcription factors associated with EMT activation and acquisition of CSC characteristics. CONCLUSION: In cutaneous melanoma patients, OSA severity is associated with higher PSPC1 serum levels, which jointly with intermittent hypoxia would enhance the self-reprogramming capabilities of EMT and CSC feature acquisition of melanoma cells, promoting their intrinsic aggressiveness.

Cell-type- and region-specific modulation of cocaine seeking by micro-RNA-1 in striatal projection neurons.

The persistent and experience-dependent nature of drug addiction may result in part from epigenetic alterations, including non-coding micro-RNAs (miRNAs), which are both critical for neuronal function and modulated by cocaine in the striatum. Two major striatal cell populations, the striato-nigral and striato-pallidal projection neurons, express, respectively, the D1 (D1-SPNs) and D2 (D2-SPNs) dopamine receptor, and display distinct but complementary functions in drug-evoked responses. However, a cell-type-specific role for miRNAs action has yet to be clarified. Here, we evaluated the expression of a subset of miRNAs proposed to modulate cocaine effects in the nucleus accumbens (NAc) and dorsal striatum (DS) upon sustained cocaine exposure in mice and showed that these selected miRNAs were preferentially upregulated in the NAc. We focused on miR-1 considering the important role of some of its predicted mRNA targets, Fosb and Npas4, in the effects of cocaine. We validated these targets in vitro and in vivo. We explored the potential of miR-1 to regulate cocaine-induced behavior by overexpressing it in specific striatal cell populations. In DS D1-SPNs miR-1 overexpression downregulated Fosb and Npas4 and reduced cocaine-induced CPP reinstatement, but increased cue-induced cocaine seeking. In DS D2-SPNs miR-1 overexpression reduced the motivation to self-administer cocaine. Our results indicate a role of miR1 and its target genes, Fosb and Npas4, in these behaviors and highlight a precise cell-type- and region-specific modulatory role of miR-1, illustrating the importance of cell-specific investigations.

Autothreshold algorithm feasibility and safety in left bundle branch pacing.

AIMS: Autothreshold algorithms enable remote monitoring of patients with conventional pacing, but there is limited information on their performance in left bundle branch pacing (LBBP). Our objective was to analyse the behaviour of the autothreshold algorithm in LBBP and compare it with conventional pacing and manual thresholds during initial device programming (acute phase), after 1-7 days (subacute), and 1-3 months later (chronic). METHODS AND RESULTS: A prospective, non-randomized, single-centre comparative study was conducted. Consecutive patients with indication for cardiac pacing were enrolled. Implants were performed in the left bundle branch area or the right ventricle endocardium at the discretion of the operator. Left bundle branch pacing was determined according to published criteria. Autothreshold algorithm was activated in both groups whenever allowed by the device. Seventy-five patients were included, with 50 undergoing LBBP and 25 receiving conventional pacing. Activation of the autothreshold algorithm was more feasible in later phases, showing a favourable trend towards bipolar pacing. Failures in algorithm activation were primarily due to insufficient safety margins (82.8% in LBBP and 90% in conventional pacing). The remainder was attributed to atrial tachyarrhythmias (10.3% and 10%, respectively) and electrical noise (the remaining 6.9% in the LBBP group). In the LBBP group, there were not statistically significant differences between manual and automatic thresholds, and both remained stable during follow-up (mean increase of 0.50 V). CONCLUSION: The autothreshold algorithm is feasible in LBBP, with a favourable trend towards bipolar pacing. Automatic thresholds are similar to manual in patients with LBBP, and they remain stable during follow-up.

Lymphoepithelial cyst of the pancreas: can common imaging features help to avoid resection?

BACKGROUND: Differentiation of cystic pancreatic neoplasms remains a challenging task for radiologists regarding the main aim of identifying malignant and premalignant lesions. PURPOSE: The study aimed to compare the radiological features of lymphoepithelial cysts (LEC) with other cystic pancreatic lesions, which could help to differentiate them in order to avoid unnecessary resection. MATERIAL AND METHODS: We retrospectively reviewed 10 cases of resected and histopathologically confirmed LECs during a 12-year period with available imaging studies; 20 patients with mucinous cystic neoplasms (MCN), 20 patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMN), and 20 patients with serous cystic neoplasms (SCN) were selected to serve as control groups. Imaging findings as well as clinical data were analyzed. RESULTS: The following imaging morphology of LEC was identified: simple cystic appearance (20%) and mixed cystic-solid appearance (80%) with either a diffuse subsolid component (30%) or mural nodule(s) (50%). All lesions revealed exophytic location with a strong male predominance (9:1). MCNs occurred exclusively in middle-aged women, IPMN in both sexes showed slight male predominance (13:7), and SCN showed female predominance (5:15). Median patient age in LEC (48.5, IQR 47-54.5) was significantly younger compared to IPMN (p < 0.001) and SCN (p = 0.02). Unenhanced CT attenuation of LEC was higher than MCNs (p = 0.025) and IPMNs (p = 0.021), showing no significant difference to SCN (p = 0.343). CONCLUSION: The present study provides key radiological features of LEC for the differentiation from other cystic pancreatic lesions such as increased CT attenuation in the unenhanced phase, absence of a connection to the main pancreatic duct (MPD), and exophytic location. In addition to these imaging features, clinical data, such as male predominance in LEC, must be considered for the differentiation of cystic pancreatic lesions.