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Optically levitated multiple nanoparticles have emerged as a platform for studying complex fundamental physics such as non-equilibrium phenomena, quantum entanglement, and light–matter interaction, which could be applied for sensing weak forces and torques with high sensitivity and accuracy. An optical trapping landscape of increased complexity is needed to engineer the interaction between levitated particles beyond the single harmonic trap. However, existing platforms based on spatial light modulators for studying interactions between levitated particles suffered from low efficiency, instability at focal points, the complexity of optical systems, and the scalability for sensing applications. Here, we experimentally demonstrated that a metasurface which forms two diffraction-limited focal points with a high numerical aperture (∼0.9) and high efficiency (31 %) can generate tunable optical potential wells without any intensity fluctuations. A bistable potential and double potential wells were observed in the experiment by varying the focal points’ distance, and two nanoparticles were levitated in double potential wells for hours, which could be used for investigating the levitated particles’ nonlinear dynamics, thermal dynamics and optical binding. This would pave the way for scaling the number of levitated optomechanical devices or realizing paralleled levitated sensors.

Mixed adenoneuroendocrine carcinoma (MANEC) is an exceptionally rare type of cancer associated to the gastrointestinal tract, without a clearly established and optimal therapeutic management. These tumors present with non-specific symptoms or histopathological findings to distinguish them from pure adenocarcinomas. We report the case of a 64-year-old male diagnosed with a high grade mixed adeneuroendocrine carcinoma of the gastric antrum, stage T2N3Mx. The patient underwent radical gastrectomy and the histopathological examination of the surgically resected specimen revealed a tumor mass containing both adenocarcinoma and poorly differentiated neuroendocrine components. Immunostaining for Chromogranin A and Synaptophysin was positive in the neuroendocrine component and negative in the adenocarcinoma component, which was positive for CK7 and CK20. Ki67 proliferation index was 95%. Using this report as reference, we also discuss the imunohistopathological features, clinical behavior and therapeutic management of mixed adenoneuroendocrine carcinomas, presenting a brief review of literature regarding this rare, yet highly aggressive tumor. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the immunomodulatory effect of the staphylococcal vaccine inoculated subcutaneous in 15 patients with chronic periodontitis. Bacteriological investigation of samples collected from the periodontal pocket for aerobic and anaerobic microorganisms was performed by classic bacteriological procedures before and after vaccination. The microbiological investigations revealed high frequency of Staphylococcus spp isolation and the presence of the most common anaerobe agents incriminated in human periodontitis like Fusobacterium, Porphyromonas, Peptostreptococcus, Veillonenella spp and the reduction of this flora in the periodontal pocket after therapy. The data presented in our study suggest an immunomodulatory effect of staphylococcal vaccine therapy in periodontitis and high frequency of Staphylococcus spp recovering from the periodontal pocket of investigated subjects. [ABSTRACT FROM AUTHOR]

The ideal screening test for cervical cancer is the one that has the ability to correctly and effectively identify all patients with premalignant changes, while at the same time exclude those without changes. Unfortunately, no test is perfect. Cervicovaginal cytology is the traditional screening method, independently described by Aurel Babeș and George Papanicolaou in 1927 and 1928, respectively. Data from the scientific literature report a relatively low sensitivity for conventional cytology, ranging from 20% to 50%, and a specificity in the identification of HSIL lesions that can reach up to 90%, based on the experience of the examiner. Given the mechanism of cervical carcinogenesis, the detection of human papillomavirus (HPV) infection is currently one of the main screening alternatives, especially in the context of the dramatic cost reductions which occurred in the recent years. HPV testing may have a sensitivity of up to 17% higher compared to classical cytology, but the latter is known for a slightly increased specificity compared to HPV testing. Although HPV testing is more effective in identifying high­grade lesions, it generates more indications for colposcopy. However, a negative HPV result is more encouraging than a negative cytological result, because the cytological examination is more likely to be false negative, which would lead to delays in the application of appropriate treatment. Regardless of age group stratification, cytological and HPV co­testing have a much higher sensitivity (>92%) in the identification of premalignant lesions compared to isolated testing. [ABSTRACT FROM AUTHOR]

By examining jaw structure in humans and cattle, the authors observed that hypothesis regarding the way occlusal forces (OF) are „absorbed“ in periodontium, started from a false premises, as following: A. It has been considered that depth and endurance of cribriform compact of socket are much broader than in reality. Thus, periodontal function has been overestimated both qualitatively and quantitatively. OF "absorption" characteristic has been assigned to it, while periodontium „take up“ OF and than propagate them to the jaws, where OF are „distributed and balanced“. Periodontium has quantitatively oversized and OF have been assumed as reaching high values. The nervous system (NS) actually controls the OF. B. Socket is assumed to be supported (surrounded) by spongious bone, while OF would be balanced by their dissipation within a „cell-type“ proofing structure. In fact, external compact of jaw and interdental septum are attached on the edge socket as far as half of its height, which is ruggedized forming a proofing ring so that a proof structure is achieved balancing OF through a „bridge-type“ construction. Morphologically, periodontium (around the teeth) comprises the gum (of ectodermic and mesodermic origin) and ligament, cement, cribriform compact (of mesodermic origin from follicular bag). From functional and systemic view point, periodontium is actually much broader, integrated within the body, with three levels of adjustment and control: a. Adjustment and control of system inputs - OF are commended by the NS, developed by masticator muscles and exercised by the opposite teeth. b. OF attenuation with shock and OF deliver to the jaw. Pull forces (pF) and pressure (P) arise in periodontium on internal area of socket and lateral area (functional periodontium). Cribriform compact form is similar to teeth, as resulting from the balance between pF of dental socket ligaments (to the inner socket) and P from inside (through the arrow effect of teeth that decreases the volume of dental socket space). Tension will induce bone apposition and pressure will determine bone resorption so that compact socket is in neutral balance zone between P and pF. In apex surrounded by spongious bone of low endurance, only vertical pressure forces arise, elongating the „filament“ so that apex will be modeled according to OF resultant in apex area as a vector. Distribution of ligament intra-socket fibers from functional periodontium and apex confirms the proposed model. c. Distribution and balancing of OF in jaw within a proof structure „bridge with „bankseat“ type - external bone compacts and interdental septum and beam (the teeth), while sectional area of socket appears as a „filament“ (arch) inserted at end pieces (on socket edge) in bankseats. Filament elongation depends on the OF which charge it. Discharging OF is made on maxillary basis (jaw basal arm and proofing structure of the skull). OF horizontal components are cross balanced (oral-vestibular) through endurance of external compacts of jaws and longitudinal along with dental arches, in cascade through the contact point: mesial to the opposite arch and distal to the proofing shoulder - piriform tubercle and maxillary tuberosity. In absence of the next teeth, spongious bone with lower endurance is opposed to the horizontal force. d. The model proposed for OF balance confirms the fact that periodontium is integrating part of organism and its disorder may also have a systemic cause, so that the periodontal exam should be complemented by a general medical assessment of the whole body. [ABSTRACT FROM AUTHOR]

Background: The changes DSM-5 brought to the diagnostic criteria for posttraumatic stress disorder (PTSD) resulted in revising the most widely used instrument in assessing PTSD, namely the Posttraumatic Checklist for DSM-5 (PCL-5). Objective: This study examined the psychometric properties of the Romanian version of the PCL-5, tested its diagnostic utility against the Structured Clinical Interview for DSM-5 (SCID-5), and investigated the latent structure of PTSD symptoms through correlated symptom models and bifactor modelling. Method: A total sample of 727 participants was used to test the psychometric properties and underlying structure of the PCL-5 and 101 individuals underwent clinical interviews using SCID-5. Receiver operating characteristic curve (ROC) analyses were performed to test the diagnostic utility of the PCL-5 and identify optimal cut-off scores based on Youden's J index. Confirmatory Factor Analyses (CFAs) and bifactor modelling were performed to investigate the latent structure of PTSD symptoms. Results: Estimates revealed that the PCL-5 is a valuable tool with acceptable diagnostic accuracy compared to SCID-5 diagnoses, indicating a cut-off score of >47. The CFAs provide empirical support for Anhedonia, Hybrid, and bifactor models. The findings are limited by using retrospective, self-report data and the high percentage of female participants. Conclusions: The PCL-5 is a psychometrically sound instrument that can be useful in making provisional diagnoses within community samples and improving trauma-informed practices.

The endeavour to comprehend why certain individuals develop posttraumatic stress disorder (PTSD) symptoms subsequent to experiencing traumatic events, while others do not, underscores the paramount importance of pretraumatic risk factors. This meta-analysis summarises the extant results of studies assessing risk factors prior exposure and PTSD symptoms following an index event on the same participants. It includes 43 studies (N = 19,239) yielding 174 effect sizes of pretraumatic risk factors categories such as demographic factors, cognitive factors, personality traits, coping styles, psychopathology, psychophysiological and environmental factors, which were examined using a three-level meta-analysis. Additionally, univariate random-effects meta-analyses were performed to separately investigate individual risk factors reported in more than one study. The findings revealed significant, small and medium associations for all categories, except for demographic factors and coping styles, also highlighting that certain individual risk factor domains (i.e. previous mental disorders, negative emotionality, sleep complaints and PTSD symptoms) represent the strongest predictors for PTSD symptoms after subsequent exposure. Several moderators were also investigated for individual risk factors. Future research could benefit from considering the interplay of pretraumatic risk factors to draw a more complex picture of the aetiology and underlying mechanisms of PTSD symptoms., (© 2023 John Wiley & Sons Ltd.)

Crohn's disease and ulcerative colitis remain debilitating disorders, characterized by progressive bowel damage and possible lethal complications. The growing number of applications for artificial intelligence in gastrointestinal endoscopy has already shown great potential, especially in the field of neoplastic and pre-neoplastic lesion detection and characterization, and is currently under evaluation in the field of inflammatory bowel disease management. The application of artificial intelligence in inflammatory bowel diseases can range from genomic dataset analysis and risk prediction model construction to the disease grading severity and assessment of the response to treatment using machine learning. We aimed to assess the current and future role of artificial intelligence in assessing the key outcomes in inflammatory bowel disease patients: endoscopic activity, mucosal healing, response to treatment, and neoplasia surveillance.

The influence of storage conditions on the mechanical recycling of pre-consumer waste (PRE-CW) from the manufacture of multilayer packaging films starting from starch compounds using a renewable-based polymer with PCL and PBAT, which are biodegradable conventional-based polyesters, was studied. It was found that, unlike materials based on conventional-origin polymers that accumulate in the environment for hundreds of years, the studied compounds degraded, even in the solid state, duringstorage in unventilated spaces and during the rainy hot summers with alternatingheat and rain. The degradation of the mechanically recycled compounds obtained from PRE-CW stored in such conditions was highlighted by the comparative analysis with the primary compounds, which proved the following: specific FTIR spectra changes; 2-3-times higher melt fluidity than for primary compounds; melting in successive processes over the entire positive temperatures range, up to 115 °C, such as in cases of compositional de-mixing of incompatible blends, faced to a single melting endotherm with a maximum at around 120 °C for the primar thermal degradation with the movement of the main destruction stages towards higher temperatures; a high quantity residue at 750 °C in air; dispersed mechanical resistance properties y compounds; crystallization at temperatures 10 °C-15 °C higher. The elimination of storage before the mechanical recycling of the pre-consumer waste from this type of polymeric compound fabrication is a way to increase the mechanical recycling efficiency while obtaining new materials with functional properties required by the applications.

Background: Nations marked by a Marxist-Leninist ideology have suffered greatly due to a culture of abuse emphasized by the absolute absence of psychology, thus contributing to a diminished ability in recognizing the consequences of traumatic experiences., Objective: To improve the assessment of the presence and severity of posttraumatic stress disorder (PTSD) in such a cultural context, our paper aimed at developing an alternative self-report measure for PTSD - the Post Traumatic Symptom Scale (PTSs) , developed by clinicians with wide relevant expertise, based on the natural language people use to describe its subjective experience. This research used multiple samples consistent with the corresponding objectives. Mokken Scale Analysis and the Classical Test Theory were both employed. The proposed scale was tested against five competing PTSD models, whilst also investigating the symptoms' clusters in two different samples by using, to our knowledge, a network analysis approach for the first time., Method: The results indicated excellent psychometric properties regarding internal consistency and temporal reliability, as well as convergent and discriminant validity. The results of MSA showed that the scale fully conforms to the assumptions of the monotone homogeneity model, interpreted as positive evidence for its use in clinical purposes. The factor analyses pointed that the newer models outperformed the standard DSM-5 model, with bifactor models displaying better fit indexes than second-order models. Finally, a distinct pattern of symptom activation in the high-risk group (i.e. first-responders) was found, bringing support for symptoms overlapping between PTSD and affective disorders, thus reinforcing the idea of bridge symptoms which has significant clinical implications., Results: This study presents an alternative sound instrument for measuring PTSD symptomatology focused on how people naturally describe their subjective experiences. Theoretical and practical implications are discussed alongside limitations., Highlights: The construction of PTSs encompasses cultural trauma and one's subjective experience.PTSs was tested against the five major competing models of PTSD.Network analyses suggest different patterns in a student sample vs. a first-responders one, with the accent on the negative alterations in cognitions and mood (NACM) model., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Fibular hemimelia is defined as a partial or complete absence of the fibula. Alongside fibular deformities, there is a wide spectrum of anomalies, foot deformities, and absent rays. A literature review showed only a handful of cases of prenatal diagnosis of fibular hemimelia. It is a rare disorder that might be isolated or associated with visceral anomalies., (©2022 JOURNAL of MEDICINE and LIFE.)

Aggressive behavior is rarely observed in virgin female mice but is specifically triggered in lactation where it facilitates protection of offspring. Recent studies demonstrated that the hypothalamic ventromedial nucleus (VMN) plays an important role in facilitating aggressive behavior in both sexes. Here, we demonstrate a role for the pituitary hormone, prolactin, acting through the prolactin receptor in the VMN to control the intensity of aggressive behavior exclusively during lactation. Prolactin receptor deletion from glutamatergic neurons or specifically from the VMN resulted in hyperaggressive lactating females, with a marked shift from intruder-directed investigative behavior to very high levels of aggressive behavior. Prolactin-sensitive neurons in the VMN project to a wide range of other hypothalamic and extrahypothalamic regions, including the medial preoptic area, paraventricular nucleus, and bed nucleus of the stria terminalis, all regions known to be part of a complex neuronal network controlling maternal behavior. Within this network, prolactin acts in the VMN to specifically restrain male-directed aggressive behavior in lactating females. This action in the VMN may complement the role of prolactin in other brain regions, by shifting the balance of maternal behaviors from defense-related activities to more pup-directed behaviors necessary for nurturing offspring., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Transition into motherhood involves profound physiological and behavioral adaptations that ensure the healthy development of offspring while maintaining maternal health. Dynamic fluctuations in key hormones during pregnancy and lactation induce these maternal adaptations by acting on neural circuits in the brain. Amongst these hormonal changes, lactogenic hormones (e.g., prolactin and its pregnancy-specific homolog, placental lactogen) are important regulators of these processes, and their receptors are located in key brain regions controlling emotional behaviors and maternal responses. With pregnancy and lactation also being associated with a marked elevation in the risk of developing mood disorders, it is important to understand how hormones are normally regulating mood and behavior during this time. It seems likely that pathological changes in mood could result from aberrant expression of these hormone-induced behavioral responses. Maternal mental health problems during pregnancy and the postpartum period represent a major barrier in developing healthy mother-infant interactions which are crucial for the child's development. In this review, we will examine the role lactogenic hormones play in driving a range of specific maternal behaviors, including motivation, protectiveness, and mother-pup interactions. Understanding how these hormones collectively act in a mother's brain to promote nurturing behaviors toward offspring will ultimately assist in treatment development and contribute to safeguarding a successful pregnancy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Georgescu, Swart, Grattan and Brown.)

Obesity and type 2 diabetes are key healthcare challenges of the 21st century. Subsequent to its discovery in 1948, serotonin (5-hydroxytryptamine; 5-HT) has emerged as a principal modulator of energy homeostasis and body weight, prompting it to be a target of weight loss medications (eg, fenfluramine, D-fenfluramine, fenfluramine-phentermine and sibutramine). The potential risk of off-target effects led to these medications being withdrawn from clinical use and spurred drug discovery into 5-HT receptor selective ligands. The serotonin 2C receptor (5-HT 2C R) is the primary receptor through which 5-HT impacts feeding and body weight and 5-HT 2C R agonist lorcaserin was released for obesity treatment in 2012. Obese patients with type 2 diabetes prescribed medications that produce weight loss commonly observe improvements in type 2 diabetes. However, recent research has provided compelling evidence that 5-HT 2C R agonists produce effects on blood glucose and insulin sensitivity independent of weight loss. As such, neuroactive 5-HT 2C R agonists are a potential new category of type 2 diabetes medications. 5-HT is also expressed within pancreatic β cells, is co-released with insulin and may have a role in modulating insulin secretion. This review highlights the latest advances in the function of 5-HT in body weight, insulin release and glycaemic control., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

In addition to its critical role in lactation, the anterior pituitary hormone prolactin also influences a broad range of other physiological processes. In particular, widespread expression of prolactin receptor (Prlr) in the brain has highlighted pleiotropic roles for prolactin in regulating neuronal function, including maternal behaviour, reproduction and energy balance. Research into the central actions of prolactin has predominately focused on effects on gene transcription via the canonical JAK2/STAT5; however, it is evident that prolactin can exert rapid actions to stimulate activity in specific populations of neurones. We aimed to investigate how widespread these rapid actions of prolactin are in regions of the brain with large populations of prolactin-sensitive neurones, and whether physiological state alters these responses. Using transgenic mice where the Cre-dependent calcium indicator, GCaMP6f, was conditionally expressed in cells expressing the long form of the Prlr, we monitored changes in levels of intracellular calcium ([Ca 2+ ] i ) in ex vivo brain slice preparations as a surrogate marker of cellular activity. Here, we surveyed hypothalamic regions implicated in the diverse physiological functions of prolactin such as the arcuate (ARC) and paraventricular nuclei of the hypothalamus (PVN), as well as the medial preoptic area (MPOA). We observed that, in the ARC of males and in both virgin and lactating females, prolactin can exert rapid actions to stimulate neuronal activity in the majority of Prlr-expressing neurones. In the PVN and MPOA, we found a smaller subset of cells that rapidly respond to prolactin. In these brain regions, the effects we detected ranged from rapid or sustained increases in [Ca 2+ ] i to inhibitory effects, indicating a heterogeneous nature of these Prlr-expressing populations. These results enhance our understanding of mechanisms by which prolactin acts on hypothalamic neurones and provide insights into how prolactin might influence neuronal circuits in the mouse brain., (© 2020 British Society for Neuroendocrinology.)

Genetic research has revealed pro-opiomelanocortin (POMC) to be a fundamental regulator of energy balance and body weight in mammals. Within the brain, POMC is primarily expressed in the arcuate nucleus of the hypothalamus (ARC), while a smaller population exists in the brainstem nucleus of the solitary tract (POMCNTS). We performed a neurochemical characterization of this understudied population of POMC cells using transgenic mice expressing green fluorescent protein (eGFP) under the control of a POMC promoter/enhancer (PomceGFP). Expression of endogenous Pomc mRNA in the nucleus of the solitary tract (NTS) PomceGFP cells was confirmed using fluorescence-activating cell sorting (FACS) followed by quantitative PCR. In situ hybridization histochemistry of endogenous Pomc mRNA and immunohistochemical analysis of eGFP revealed that POMC is primarily localized within the caudal NTS. Neurochemical analysis indicated that POMCNTS is not co-expressed with tyrosine hydroxylase (TH), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), brain-derived neurotrophic factor (BDNF), nesfatin, nitric oxide synthase 1 (nNOS), seipin, or choline acetyltransferase (ChAT) cells, whereas 100% of POMCNTS is co-expressed with transcription factor paired-like homeobox2b (Phox2b). We observed that 20% of POMCNTS cells express receptors for adipocyte hormone leptin (LepRbs) using a PomceGFP:LepRbCre:tdTOM double-reporter line. Elevations in endogenous or exogenous leptin levels increased the in vivo activity (c-FOS) of a small subset of POMCNTS cells. Using ex vivo slice electrophysiology, we observed that this effect of leptin on POMCNTS cell activity is postsynaptic. These findings reveal that a subset of POMCNTS cells are responsive to both changes in energy status and the adipocyte hormone leptin, findings of relevance to the neurobiology of obesity., (© Endocrine Society 2020.)

Cardiac channelopathies, mainly Long QT and Brugada syndromes, are genetic disorders for which genotype/phenotypes relationships remains to be improved. To provide new insights into the Brugada syndrome pathophysiology, a mutational study was performed on a 64-year-old man presented with isolated exertional dyspnea (NYHA class: II-III), hypertension, chronic kidney disease, coronary disease, an electrocardiogram suggesting a Brugada type 1-like pattern with ST-segment elevation in leads V1-V2. Molecular diagnosis study was performed using molecular strategy based on the sequencing of a panel of 19 Brugada-associated genes. The proband was carrier of 2 TRPM4 null alleles [IVS9+1G > A and p. Trp525X] resulting in the absence of functional hTRPM4 proteins. Due to this unexpected genotype, meta-analysis of previously reported TRPM4 variations associated with cardiac pathologies was performed using ACMG guidelines. All were detected in a heterozygous status. This additional meta-analysis indicated that most of them could not be considered definitely as pathogen. In conclusion, our study reports, for the first time, identification of compound heterozygous TRPM4 null mutations in a proband with, at an arrhythmogenic level, only a Brugada type 1-like electrocardiogram. By combining the genotype/phenotype relationship of this case and analysis of previously reported TRPM4 variations, we suggest that loss-of-function TRPM4 variations, in a heterozygous status, could not be considered as pathogenic or likely pathogenic mutations in cardiac channelopathies such as Long QT syndrome or Brugada syndrome., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

To meet the challenge to human health posed by obesity, a better understanding of the regulation of feeding is essential. Medications targeting 5-hydroxytryptamine (5-HT; serotonin) 2C receptors (htr2c; 5-HT 2C R) improve obesity. Here we probed the functional significance of 5-HT 2C Rs specifically within the brainstem nucleus of the solitary tract (5-HT 2C R NTS ) in feeding behavior. Selective activation of 5-HT 2C R NTS decreased feeding and was sufficient to mediate acute food intake reductions elicited by the 5-HT 2C R agonist obesity medication lorcaserin. Similar to pro-opiomelanocortin neurons expressed within the hypothalamic arcuate nucleus (POMC ARC ), a subset of POMC NTS neurons co-expressed 5-HT 2C Rs and were activated by 5-HT 2C R agonists. Knockdown of POMC NTS prevented the acute appetite-suppressive effect of lorcaserin, whereas POMC ARC knockdown prevented the full anorectic effect. These data identify 5-HT 2C R NTS as a sufficient subpopulation of 5-HT 2C Rs in reducing food intake when activated and reveal that 5-HT 2C R agonist obesity medications require POMC within the NTS and ARC to reduce food intake., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The increasing prevalence of type 2 diabetes (T2D) and associated morbidity and mortality emphasizes the need for a more complete understanding of the mechanisms mediating glucose homeostasis to accelerate the identification of new medications. Recent reports indicate that the obesity medication lorcaserin, a 5-hydroxytryptamine (5-HT, serotonin) 2C receptor (5-HT 2C R) agonist, improves glycemic control in association with weight loss in obese patients with T2D. Here we evaluate whether lorcaserin has an effect on glycemia without body weight loss and how this effect is achieved., Methods: Murine models of common and genetic T2D were utilized to probe the direct effect of lorcaserin on glycemic control., Results: Lorcaserin dose-dependently improves glycemic control in mouse models of T2D in the absence of reductions in food intake or body weight. Examining the mechanism of this effect, we reveal a necessary and sufficient neurochemical mediator of lorcaserin's glucoregulatory effects, brain pro-opiomelanocortin (POMC) peptides. To clarify further lorcaserin's therapeutic brain circuit, we examined the receptor target of POMC peptides. We demonstrate that lorcaserin requires functional melanocortin4 receptors on cholinergic preganglionic neurons (MC4R ChAT ) to exert its effects on glucose homeostasis. In contrast, MC4R ChAT signaling did not impact lorcaserin's effects on feeding, indicating a divergence in the neurocircuitry underpinning lorcaserin's therapeutic glycemic and anorectic effects. Hyperinsulinemic-euglycemic clamp studies reveal that lorcaserin reduces hepatic glucose production, increases glucose disposal and improves insulin sensitivity., Conclusions: These data suggest that lorcaserin's action within the brain represents a mechanistically novel treatment for T2D: findings of significance to a prevalent global disease., (Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Obesity is primarily due to food intake in excess of the body's energetic requirements, intake that is not only associated with hunger but also the incentive value of food. The 5-hydroxytryptamine 2C receptor (5-HT 2C R) is a target for the treatment of human obesity. Mechanistically, 5-HT 2C Rs are positioned to influence both homeostatic feeding circuits within the hypothalamus and reward circuits within the ventral tegmental area (VTA). Here we investigated the role of 5-HT 2C Rs in incentive motivation using a mathematical model of progressive ratio (PR) responding in mice. We found that the 5-HT 2C R agonist lorcaserin significantly reduced both ad libitum chow intake and PR responding for chocolate pellets and increased c-fos expression in VTA 5-HT 2C R expressing γ-aminobutyric acid (GABA) neurons, but not 5-HT 2C R expressing dopamine (DA) neurons. We next adopted a chemogenetic approach using a 5-HT 2C R CRE line to clarify the function of subset of 5-HT 2C receptor expressing VTA neurons in the modulation of appetite and food-motivated behavior. Activation of VTA 5-HT 2C receptor expressing neurons significantly reduced ad libitum chow intake, operant responding for chocolate pellets, and the incentive value of food. In contrast, chemogenetic inhibition of VTA 5-HT 2C receptor expressing neurons had no effect on the feeding behavior. These results indicate that activation of the subpopulation of 5-HT 2C R neurons within the VTA is sufficient to significantly reduce homeostatic feeding and effort-based intake of palatable food, and that this subset has an inhibitory role in motivational processes. These findings are relevant to the treatment of obesity.

Objective: Obesity is one of the primary healthcare challenges of the 21st century. Signals relaying information regarding energy needs are integrated within the brain to influence body weight. Central among these integration nodes are the brain pro-opiomelanocortin (POMC) peptides, perturbations of which disrupt energy balance and promote severe obesity. However, POMC neurons are neurochemically diverse and the crucial source of POMC peptides that regulate energy homeostasis and body weight remains to be fully clarified., Methods: Given that a 5-hydroxytryptamine 2c receptor (5-HT2CR) agonist is a current obesity medication and 5-HT2CR agonist's effects on appetite are primarily mediated via POMC neurons, we hypothesized that a critical source of POMC regulating food intake and body weight is specifically synthesized in cells containing 5-HT2CRs. To exclusively manipulate Pomc synthesis only within 5-HT2CR containing cells, we generated a novel 5-HT 2C R (CRE) mouse line and intercrossed it with Cre recombinase-dependent and hypothalamic specific reactivatable Pomc (NEO) mice to restrict Pomc synthesis to the subset of hypothalamic cells containing 5-HT2CRs. This provided a means to clarify the specific contribution of a defined subgroup of POMC peptides in energy balance and body weight., Results: Here we transform genetically programed obese and hyperinsulinemic male mice lacking hypothalamic Pomc with increased appetite, reduced physical activity and compromised brown adipose tissue (BAT) into lean, healthy mice via targeted restoration of Pomc function only within 5-HT2CR expressing cells. Remarkably, the same metabolic transformation does not occur in females, who despite corrected feeding behavior and normalized insulin levels remain physically inactive, have lower energy expenditure, compromised BAT and develop obesity., Conclusions: These data provide support for the functional heterogeneity of hypothalamic POMC neurons, revealing that Pomc expression within 5-HT2CR expressing neurons is sufficient to regulate energy intake and insulin sensitivity in male and female mice. However, an unexpected sex difference in the function of this subset of POMC neurons was identified with regard to energy expenditure. We reveal that a large sex difference in physical activity, energy expenditure and the development of obesity is driven by this subpopulation, which constitutes approximately 40% of all POMC neurons in the hypothalamic arcuate nucleus. This may have broad implications for strategies utilized to combat obesity, which at present largely ignore the sex of the obese individual.

NHERF1/EBP50, an adaptor protein required for epithelial morphogenesis, has been implicated in the progression of various human malignancies. NHERF1-deficient mice have intestinal brush border structural defects and we report here that they also have disorganized ependymal cilia with development of non-obstructive hydrocephalus. Examination of mouse and human brain tissues revealed highest NHERF1 expression at the apical plasma membrane of ependymal cells. In ependymal tumors, NHERF1 expression was retained in polarized membrane structures, such as microlumens, rosettes and canals, where it co-localized with some of its ligands, such as moesin and PTEN. Analysis of a comprehensive panel of 113 tumors showed robust NHERF1 labeling of microlumens in 100% of ependymomas, subependymomas, and pediatric anaplastic ependymomas, and in 67% of adult anaplastic ependymomas. NHERF1 staining was present in 35% of ependymoma cases that lacked reactivity for EMA, the routine immunohistochemical marker used for ependymoma diagnosis. NHERF1 labeling of microlumens was either absent or rarely seen in other types of brain tumors analyzed, denoting NHERF1 as a reliable diagnostic marker of ependymal tumors. Anaplastic foci and a subset of adult anaplastic ependymomas showed complete absence of NHERF1-labeled polarity structures, consistent with a loss of differentiation in these aggressive tumors. These data highlight a role for NHERF1 in ependymal morphogenesis with direct application to the diagnosis of ependymal tumors.

Target of rapamycin complex 1 (TORC1), which controls growth in response to nutrients, promotes ageing in multiple organisms. The fission yeast Schizosaccharomyces pombe emerges as a valuable genetic model system to study TORC1 function and cellular ageing. Here we exploited the combinatorial action of rapamycin and caffeine, which inhibit fission yeast growth in a TORC1-dependent manner. We screened a deletion library, comprising ∼84% of all non-essential fission yeast genes, for drug-resistant mutants. This screen identified 33 genes encoding functions such as transcription, kinases, mitochondrial respiration, biosynthesis, intra-cellular trafficking, and stress response. Among the corresponding mutants, 5 showed shortened and 21 showed increased maximal chronological lifespans; 15 of the latter mutants showed no further lifespan increase with rapamycin and might thus represent key targets downstream of TORC1. We pursued the long-lived sck2 mutant with additional functional analyses, revealing that the Sck2p kinase functions within the TORC1 network and is required for normal cell growth, global protein translation, and ribosomal S6 protein phosphorylation in a nutrient-dependent manner. Notably, slow cell growth was associated with all long-lived mutants while oxidative-stress resistance was not.

Unlabelled: Surgery of the hypertrophic cardiomyopathy remains controversial. The safest procedure and the simples procedure is the mitral valve replacement. Septal myomectomy is difficult because of the poor surgical exposure and complications: incomplete resection, complete heart block, ventricular septal defect., Case Presentation: A 56 years old man with hypertrophic cardiomyopathy, double coronary stenosis and grade II mitral regurgitation by systolic anterior motion was long time stable under treatment with b-blockers. He developed angina and the circumflex and the left anterior descending arteries were stented. Re-stenosis developed in the left anterior descending stent and the patient was referred to surgery. The intraventricular gradient was 80 mmHg and the maximal septal thickness 28 mm. He was successfully treated by septal myomectomy and bypass on the left anterior descending artery with the left internal thoracic artery. Perioperative transesophageal echography was used to establish the limits of the surgical resection and to control the remnant gradient. The patient is asymptomatic 6 months after the procedure, he has a 30 mmHg remnant gradient and a grade I mitral regurgitation., Conclusion: Septal myomectomy is a safe alternative to mitral valve replacement for hypertrophic cardiomyopathy. This procedure must be guided by perioperative transesophageal echography to avoid incomplete resection.

Unlabelled: trophic cardiomyopathy remains controversial. The safest procedure and the simplest procedure is the mitral valve replacement. Septal myomectomy is difficult because of the poor surgical exposure and complications: incomplete resection, complete heart block, ventricular septal defect., Case Presentation: A 56-years old man with hypertrophic cardiomyopathy, double coronary stenosis and grade II mitral regurgitation by systolic anterior motion was long time stable under treatment with b-blockers. He developed angina and the circumflex and the left anterior descending arteries were stented. Re-stenosis developed in the left anterior descending stent and the patient was referred to surgery. The intraventricular gradient was 80 mmHg and the maximal septal thickness 28 mm. He was successfully treated by septal myomectomy and bypass on the left anterior descending artery with the left internal thoracic artery. Perioperative transesophageal echography was used to establish the limits of the surgical resection and to control the remnant gradient. The patient is asymptomatic 6 months after the procedure, he has a 30 mmHg remnant gradient and a grade I mitral regurgitation., Conclusion: Septal myomectomy is a safe alternative to mitral valve replacement for hypertrophic cardiomyopathy. This procedure must be guided by perioperative transesophageal echography to avoid incomplete resection.

The case of a 75 years old woman with hereditary hemorrhagic telangiectasia (HHT) is presented. This condition is an autosomal dominant mucocutaneous and visceral fibrovascular dysplasia in which telangiectasia, arteriovenous malformations and aneurysms may be widely distributed throughout the cardiovascular system. It is usually recognized as a "triad" of telangiectasia, recurrent epistaxis and a family history of the disorder.