BACKGROUND & AIMS: Gluconeogenesis from amino acids (AAs) maintains glucose homeostasis during fasting. Although glucagon is known to regulate AA catabolism, the contribution of other hormones to it and the scope of transcriptional regulation dictating AA catabolism are unknown. We explored the role of the fasting hormones glucagon and glucocorticoids in transcriptional regulation of AA catabolism genes and AA-dependent gluconeogenesis. METHODS: We tested the RNA expression of AA catabolism genes and glucose production in primary mouse hepatocytes treated with fasting hormones (glucagon, corticosterone) and feeding hormones (insulin, fibroblast growth factor 19). We analyzed genomic data of chromatin accessibility and chromatin immunoprecipitation in mice and primary mouse hepatocytes. We performed chromatin immunoprecipitation in livers of fasted mice to show binding of cAMP responsive element binding protein (CREB) and the glucocorticoid receptor (GR). RESULTS: Fasting induced the expression of 31 genes with various roles in AA catabolism. Of them, 15 were synergistically induced by co-treatment of glucagon and corticosterone. Synergistic gene expression relied on the activity of both CREB and GR and was abolished by treatment with either insulin or fibroblast growth factor 19. Enhancers adjacent to synergistically induced genes became more accessible and were bound by CREB and GR on fasting. Akin to the gene expression pattern, gluconeogenesis from AAs was synergistically induced by glucagon and corticosterone in a CREB- and GR-dependent manner. CONCLUSIONS: Transcriptional regulation of AA catabolism genes during fasting is widespread and is driven by glucagon (via CREB) and corticosterone (via GR). Glucose production in hepatocytes is also synergistically augmented, showing that glucagon alone is insufficient in fully activating gluconeogenesis.
המטרה: לבחון את מקומו של ההקשר המרחבי בחוויות של אבות הומוסקסואלים שהפכו להורים דרך הליכי פונדקאות. הנבדקים: 14 אבות יהודים הומוסקסואלים שהפכו להורים דרך הליכי פונדקאות שנערכו בחו"ל. מחצית מן הנבדקים התגוררו בתל־אביב ומחציתם באזורים כפריים או בעיירות, רחוק מן המרכז. שיטת המחקר: הנבדקים השתתפו במחקר איכותני, שבמסגרתו נערכו ראיונות אישיים. מן הממצאים: ניתוח הראיונות העלה שלוש תמות מרכזיות. תמות אלה ביססו את ההבנה כי חוויותיהם של אבות הומוסקסואליים ניתנות להבנה במונחים הקשורים לתנועה בשני צירים מרחביים סותרים: ציר אחד שמאשרר את ההבחנה בין פריפריה ומרכז; וציר שני שמאתגר הבחנה זו. הבנה זו התחזקה עוד יותר בעקבות העובדה כי כל 14 המרואיינים התייחסו באופן ספונטני מבלי שנשאלו על כך, כי מקומם הגיאוגרפי מהווה גורם שמשפיע על ההתנסויות ההוריות שלהם. התמה הראשונה התייחסה להבדלים שבין המרכז והפריפריה. במסגרת תמה זו, בלטה ההתייחסות של חלק מן המרואיינים לתל־אביב כאל מרחב מקבל ומכיל שמחבק הורות הומוסקסואלית, והדגשת הניכור וההדרה שמאפיינים את האזורים הרחוקים מתל אביב בהקשר זה. התמה השנייה עסקה בתחושות השייכות לפריפריה של חלק מן המרואיינים. תחושות אלו אתגרו את הדימוי החברתי השלילי שדבק בפריפריה כמרחב שמרני ואף הומופובי. במסגרת תמה זו נמצאו מרואיינים שחזרו אל הפריפריה מן המרכז על מנת לגדל את הילדים, תוך שהם נשענים על ההורים המקבלים כמשאבי תמיכה שקיבלו אותם כפי שהם. התמה השלישית והאחרונה התמקדה בתנועת המרואיינים לקראת תחושת ההכללה בסביבות הגאוגרפיות השונות. במסגרת תמה זו נמצאו מרואיינים שהרגישו כי עם הפיכתם להורים, ההבדלים שבין ההטרוסקסואלים וההומוסקסואלים בסביבתם הצטמצם, דבר שאפשר את התפתחותה של תחושת הקבלה וההכללה החברתית. ממצאי המחקר מראים כיצד האבהות ההומוסקסואלית מהווה תופעה בעלת הקשרים מרחביים־גאוגרפיים.
The mounting evidence for the involvement of astrocytes in neuronal circuits function and behavior stands in stark contrast to the lack of detailed anatomical description of these cells and the neurons in their domains. To fill this void, we imaged >30,000 astrocytes in hippocampi made transparent by CLARITY, and determined the elaborate structure, distribution, and neuronal content of astrocytic domains. First, we characterized the spatial distribution of >19,000 astrocytes across CA1 lamina, and analyzed the morphology of thousands of reconstructed domains. We then determined the excitatory somatic content of CA1 astrocytes, and measured the distance between inhibitory neuronal somata to the nearest astrocyte soma. We find that on average, there are almost 14 pyramidal neurons per domain in the CA1, increasing toward the pyramidal layer midline, compared to only five excitatory neurons per domain in the amygdala. Finally, we discovered that somatostatin neurons are found in close proximity to astrocytes, compared to parvalbumin and VIP inhibitory neurons. This work provides a comprehensive large-scale quantitative foundation for studying neuron-astrocyte interactions.
In 2020, racemic-fenfluramine was approved in the U.S. and Europe for the treatment of seizures associated with Dravet syndrome, through a restricted/controlled access program aimed at minimizing safety risks. Fenfluramine had been used extensively in the past as an appetite suppressant, but it was withdrawn from the market in 1997 when it was found to cause cardiac valvulopathy. Available evidence indicates that appetite suppression and cardiac valvulopathy are mediated by different serotonergic mechanisms. In particular, appetite suppression can be ascribed mainly to the enantiomers d-fenfluramine and d-norfenfluramine, the primary metabolite of d-fenfluramine, whereas cardiac valvulopathy can be ascribed mainly to d-norfenfluramine. Because of early observations of markedly improved seizure control in some forms of epilepsy, fenfluramine remained available in Belgium through a Royal Decree after 1997 for use in a clinical trial in patients with Dravet syndrome at average dosages lower than those generally prescribed for appetite suppression. More recently, double-blind placebo-controlled trials established its efficacy in the treatment of convulsive seizures associated with Dravet syndrome and of drop seizures associated with Lennox-Gastaut syndrome, at doses up to 0.7 mg/kg/day (maximum 26 mg/day). Although no cardiovascular toxicity has been associated with the use of fenfluramine in epilepsy, the number of patients exposed to date has been limited and only few patients had duration of exposure longer than 3 years. This article analyzes available evidence on the mechanisms involved in fenfluramine-induced appetite suppression, antiseizure effects and cardiovascular toxicity. Despite evidence that stimulation of 5-HT(2B) receptors (the main mechanism leading to cardiac valvulopathy) is not required for antiseizure activity, there are many critical gaps in understanding fenfluramine's properties which are relevant to its use in epilepsy. Particular emphasis is placed on the remarkable lack of publicly accessible information about the comparative activity of the individual enantiomers of fenfluramine and norfenfluramine in experimental models of seizures and epilepsy, and on receptors systems considered to be involved in antiseizure effects. Preliminary data suggest that l-fenfluramine retains prominent antiseizure effects in a genetic zebrafish model of Dravet syndrome. If these findings are confirmed and extended to other seizure/epilepsy models, there would be an incentive for a chiral switch from racemic-fenfluramine to l-fenfluramine, which could minimize the risk of cardiovascular toxicity and reduce the incidence of adverse effects such as loss of appetite and weight loss.
Past research has demonstrated that many individuals are not well equipped to make financial decisions and hence depend greatly on the flow and quality of financial information. Various governments are implementing reforms aimed at improving the quality of pension financial communication. Certain countries are requiring a move to short-form pension reporting, and some are requiring digital reporting instead of (or in some cases, in addition to) paper reporting. In a series of experiments, we show that the ability to locate information in financial reports is sensitive to the length of the report and to the communication form.
"First Words, Last Words charts an intense "pamphlet war" that took place in sixteenth-century South India. The book explores this controversy as a case study in the dynamics of innovation in early modern India, a time of great intellectual innovation. This debate took place within the traditional discourses of Vedic Hermeneutics, or M\=im\=a\d ms\=a, and its increasingly influential sibling discipline of Ved\=anta, and its proponents among the leading intellectuals and public figures of the period. At the heart of this dispute lies the role of sequence in the cognitive processing of textual information, especially of a scriptural nature. Vy\=asat\=irtha and his grand-pupil Vijay\=indrat\=irtha, writers belonging to the camp of Dualist Ved\=anta, purported to uphold the radical view of their founding father, Madhva, who believed, against a long tradition of M\=im\=a\d ms\=a interpreters, that the closing portion of a scriptural passage should govern the interpretation of its opening. By contrast, the Nondualist Appayya Dikshita ostensibly defended this tradition's preference for the opening. But, as the book shows, the debaters gradually converged on a profoundly novel hermeneutic-cognitive theory in which sequence played little role, if any. In fact, they knowingly broke new ground, and only postured as traditionalists. First Words, Last Words explores the nature of theoretical innovation in this debate and sets it against the background of comparative examples from other major scriptural interpretive traditions. The book briefly surveys the use of sequence in Jewish, Christian, and Islamic hermeneutics and also seeks out parallel cases of covert innovation in these traditions"–
First Words, Last Words charts an intense "pamphlet war" that took place in sixteenth-century South India. Yigal Bronner and Lawrence McCrea explore this controversy as a case study in the dynamics of innovation in early modern India, a time of great intellectual innovation. This debate took place within the traditional discourses of Vedic Hermeneutics, or Mīmāṃsā, and its increasingly influential sibling discipline of Vedānta, and its proponents among the leading intellectuals and public figures of the period.
Bronner and McCrea examine the nature of theoretical innovation in scholastic traditions by focusing on a specific controversy regarding scriptural interpretation and the role of sequence-what comes first and what follows later-in determining our interpretation of a scriptural passage. Vyāsatīrtha and his grand-pupil Vijayīndratīrtha, writers belonging to the camp of Dualist Vedānta, purported to uphold the radical view of their founding father, Madhva, who believed, against a long tradition of Mīmāṃsā interpreters, that the closing portion of a scriptural passage should govern the interpretation of its opening. By contrast, the Nondualist Appayya Dīkṣita ostensibly defended his tradition's preference for the opening. But, as this volume shows, the debaters gradually converged on a profoundly novel hermeneutic-cognitive theory in which sequence played little role, if any.
First Words, Last Words traces both the issue of sequence and the question of innovation through an in-depth study of this debate and through a comparative survey of similar problems in Judaism, Christianity, and Islam, revealing that the disputants in this controversy often pretended to uphold traditional views, when they were in fact radically innovative.
AIM: Most of the intra- and postoperative patient discomfort related to complex mandibular third molar (M3M) extraction is proportional to the invasiveness of the surgery. This can be minimized through the support of dynamic navigation (DN) technology, which can be successfully applied in dental implantology. Material s and methods: Three patients, one female (aged 25 years) and two males (aged 18 and 51 years, respectively) underwent the DN-supported extraction of partially impacted M3Ms with a flapless approach that required minimal bone removal. The patients' discomfort and the speed of recovery were considered to be proof of the quality of the adopted procedure. RESULTS: No postoperative discomfort such as pain or swelling was recorded in the immediate postoperative period, and no complications were reported within a month of the surgery. No medications were prescribed. The procedure lasted no longer than 20 min in all cases. CONCLUSION: Using DN technology, the real-time 3D monitoring of the clinical situation in each surgical phase enabled the surgeon to avoid soft tissue detachment as well as limit bone loss and intraoperative bleeding, thanks to a precise multi–section of the tooth and important nearby anatomical structures, respectively.
The introduction of fluorine atoms into molecules and materials across many fields of academic and industrial research is now commonplace, owing to their unique properties and effects. A particularly interesting feature of fluorine substitution is its impact on the relative orientation of a C?F bond when incorporated with organic molecules. In this Review, we will be shining light on this unique feature by discussing the conformational behaviour of aliphatic carbo- and heterocyclic systems. The conformational preference of each system is associated with various interactions introduced by fluorine substitution such as charge-dipole interactions, dipole-dipole interactions and hyperconjugative interactions. The contribution of each interaction on the stabilization of the fluorinated alicyclic system, which manifests itself in low conformations, will be discussed in details. The novelty of this feature will be demonstrated by presenting the most recent applications.
