SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.

SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron-specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1-null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1-expressing neurons in the paraventricular hypothalamus (PVHSH2B1) and a PVHSH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVHSH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVHSH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVHSH2B1 neurons causes obesity. In male and female mice, either embryonic-onset or adult-onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN-projecting PVHSH2B1 subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN-projecting PVHSH2B1 neurons protects against diet-induced obesity. SH2B1 binds to TrkB and enhances brain-derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVHSH2B1 neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVHSH2B1→DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF/TrkB signaling.

Preventing Preterm Birth: Exploring Innovative Solutions.

This review examines the complexities of preterm birth (PTB), emphasizes the pivotal role of inflammation in the pathogenesis of preterm labor, and assesses current available interventions. Antibiotics, progesterone analogs, mechanical approaches, nonsteroidal anti-inflammatory drugs, and nutritional supplementation demonstrate a limited efficacy. Tocolytic agents, targeting uterine activity and contractility, inadequately prevent PTB by neglecting to act on uteroplacental inflammation. Emerging therapies targeting toll-like receptors, chemokines, and interleukin receptors exhibit promise in mitigating inflammation and preventing PTB.

Rapid, biochemical tagging of cellular activity history in vivo.

Intracellular calcium (Ca2+) is ubiquitous to cell signaling across all biology. While existing fluorescent sensors and reporters can detect activated cells with elevated Ca2+ levels, these approaches require implants to deliver light to deep tissue, precluding their noninvasive use in freely-behaving animals. Here we engineered an enzyme-catalyzed approach that rapidly and biochemically tags cells with elevated Ca2+ in vivo. Ca2+-activated Split-TurboID (CaST) labels activated cells within 10 minutes with an exogenously-delivered biotin molecule. The enzymatic signal increases with Ca2+ concentration and biotin labeling time, demonstrating that CaST is a time-gated integrator of total Ca2+ activity. Furthermore, the CaST read-out can be performed immediately after activity labeling, in contrast to transcriptional reporters that require hours to produce signal. These capabilities allowed us to apply CaST to tag prefrontal cortex neurons activated by psilocybin, and to correlate the CaST signal with psilocybin-induced head-twitch responses in untethered mice.

Psychoplastogenic DYRK1A Inhibitors with Therapeutic Effects Relevant to Alzheimer's Disease.

Tauopathy, neuronal atrophy, and psychological impairments are hallmarks of neurodegenerative diseases, such as Alzheimer's disease, that currently lack efficacious clinical treatments capable of rectifying these issues. To address these unmet needs, we used rational drug design to combine the pharmacophores of DYRK1A inhibitors and isoDMTs to develop psychoplastogenic DYRK1A inhibitors. Using this approach, we discovered a nonhallucinogenic compound capable of promoting cortical neuron growth and suppressing tau hyperphosphorylation while also having the potential to mitigate the biological and psychological symptoms of dementia. Together, our results suggest that hybridization of the DYRK1A and psychoplastogen pharmacophores represents a promising strategy for identifying compounds that might address the cognitive as well as the behavioral and psychological symptoms of dementia.

Ants (Hymenoptera: Formicidae) and termites (Blattodea: Termitoidae) in the diet of wild white-bellied pangolin (Phataginus tricuspis) in forest-savanna habitats of Cameroon.

The white-bellied pangolin Phataginus tricuspis (Rafinesque 1821) is a semiarboreal species occurring in tropical sub-Saharan Africa. It is the world's most trafficked African pangolin species based on volumes recorded in seizures. Reintroduction of confiscated live pangolins and ex-situ rearing are being explored worldwide as a conservation action. However, the husbandry of seized animals is challenging as the diet of the white-bellied pangolin is poorly known and little studied. We analyzed the stomach contents of dead white-bellied pangolins from two forest-savanna protected areas. Stomach content samples from 13 white-bellied pangolin specimens contained ~165,000 Arthropoda, mostly Hymenoptera (60.34%) and Blattodea (39.66%). Overall, we identified 39 termite and 105 ant species consumed as prey by pangolins. Individual pangolins examined had fed on a maximum of 31 ant species and 13 termite species. The termite and ant species richness varied significantly across the pangolins' last consumed meal. We recorded 24 ant genera dominated by Crematogaster (relative importance [RI] = 17.28). Out of 18 termite genera recorded, the genus Pseudacanthotermes (RI = 17.21) was the most important prey. Ten ant species were preferentially eaten by white-bellied pangolin, with Crematogaster acis being the most common prey species. Four species of termite were most frequently eaten with Pseudacanthotermes militaris being the most abundant. The mean abundance of ants and termites varied among pangolin individuals. The season did not influence the mean abundance of termites eaten by pangolin individuals. However, ant abundance in stomach contents was significantly higher in the dry season. An improved understanding of pangolin feeding behavior and prey selection may help inform conservation husbandry efforts. For example, nutritional analysis of the food eaten by wild pangolins can guide the development of nutritional diets for captive pangolins.

Hepatic danger signaling triggers TREM2+ macrophage induction and drives steatohepatitis via MS4A7-dependent inflammasome activation.

Metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH), is an advanced stage of metabolic fatty liver disease. The pathogenic mechanisms of MASH center on hepatocyte injury and the ensuing immune response within the liver microenvironment. Recent work has implicated TREM2+ macrophages in various disease conditions, and substantial induction of TREM2+ NASH-associated macrophages (NAMs) serves as a hallmark of metabolic liver disease. Despite this, the mechanisms through which NAMs contribute to MASH pathogenesis remain poorly understood. Here, we identify membrane-spanning 4-domains a7 (MS4A7) as a NAM-specific pathogenic factor that exacerbates MASH progression in mice. Hepatic MS4A7 expression was strongly induced in mouse and human MASH and associated with the severity of liver injury. Whole-body and myeloid-specific ablation of Ms4a7 alleviated diet-induced MASH pathologies in male mice. We demonstrate that exposure to lipid droplets (LDs), released upon injury of steatotic hepatocytes, triggered NAM induction and exacerbated MASH-associated liver injury in an MS4A7-dependent manner. Mechanistically, MS4A7 drove NLRP3 inflammasome activation via direct physical interaction and shaped disease-associated cell states within the liver microenvironment. This work reveals the LD-MS4A7-NLRP3 inflammasome axis as a pathogenic driver of MASH progression and provides insights into the role of TREM2+ macrophages in disease pathogenesis.

The Effects of Psychedelics on Neuronal Physiology.

Psychedelics are quite unique among drugs that impact the central nervous system, as a single administration of a psychedelic can both rapidly alter subjective experience in profound ways and produce sustained effects on circuits relevant to mood, fear, reward, and cognitive flexibility. These remarkable properties are a direct result of psychedelics interacting with several key neuroreceptors distributed across the brain. Stimulation of these receptors activates a variety of signaling cascades that ultimately culminate in changes in neuronal structure and function. Here, we describe the effects of psychedelics on neuronal physiology, highlighting their acute effects on serotonergic and glutamatergic neurotransmission as well as their long-lasting effects on structural and functional neuroplasticity in the cortex. We propose that the neurobiological changes leading to the acute and sustained effects of psychedelics might be distinct, which could provide opportunities for engineering compounds with optimized safety and efficacy profiles.

Therapeutic mechanisms of psychedelics and entactogens.

Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.

Predicting resistance management skill from psychotherapy experience, intellectual humility and emotion regulation.

OBJECTIVE: Resistance management in psychotherapy remains a foundational skill that is associated with positive client outcomes (Westra, H. A., & Norouzian, N. (2018). Using motivational interviewing to manage process markers of ambivalence and resistance in cognitive behavioral therapy. Cognitive Therapy and Research, 42(2), 193-203). However, little is known about which therapist characteristics contribute to successful management of resistance. Research has suggested that psychotherapy performance does not improve with experience (Goldberg, S. B., Rousmaniere, T., Miller, S. D., Whipple, J., Nielsen, S. L., Hoyt, W. T., & Wampold, B. E. (2016). Do psychotherapists improve with time and experience? A longitudinal analysis of outcomes in a clinical setting. Journal of Counseling Psychology, 63(1), 1-11), that psychotherapists lack humility (Macdonald, J., & Mellor-Clark, J. (2015). Correcting psychotherapists' blindsidedness: Formal feedback as a means of overcoming the natural limitations of therapists. Clinical Psychology & Psychotherapy, 22(3), 249-257), and that difficult therapeutic moments may dysregulate therapist emotions (Muran, J. C., & Eubanks, C. F. (2020). Therapist performance under pressure: Negotiating emotion, difference, and rupture. American Psychological Association). This study aimed to 1) identify whether psychotherapy experience (i.e., training versus no training and number of years of psychotherapy experience) was associated with resistance management skill, and 2) identify whether humility and difficulties regulating emotions among trained individuals were each associated with resistance management. METHOD: A sample of 76 trained and 98 untrained participants were recruited for the present study. All participants completed the Comprehensive Intellectual Humility Scale (CIHS, Krumrei-Mancuso, E. J., & Rouse, S. V. (2016). The development and validation of the comprehensive intellectual humility scale. Journal of Personality Assessment, 98(2), 209-221), the Difficulties in Emotion Regulation Scale (DERS; Gratz, K. L., & Roemer, L. (2004). Multidimensional assessment of emotion regulation and dysregulation: Development, factor structure, and initial validation of the difficulties in emotion regulation scale. Journal of Psychopathology and Behavioral Assessment, 26(1), 41-54), and the Resistance Vignette Task (RVT; Westra, H. A., Nourazian, N., Poulin, L., Hara, K., Coyne, A., Constantino, M. J., Olson, D., & Antony, M. M. (2021). Testing a deliberate practice workshop for developing appropriate responsivity to resistance markers: A randomized clinical trial. Psychotherapy, 58, 175-185 ) which was used to assess resistance management skill. RESULTS: Trained individuals performed significantly better on resistance management than untrained individuals; however, years of experience within the trained sample were not associated with resistance management. Conversely, lower humility and greater difficulties regulating emotions were each associated with significantly poorer resistance management in trained individuals. CONCLUSION: These findings suggest the possibility of improving training to focus on key skills, like resistance management, through supporting humility and emotion regulation in training, as opposed to simply acquiring more experience.

Ascribing understanding to ourselves and others.

We commonly attribute an understanding of language to others including very young infants, and, more controversially, to other animals and computers. Although we adults attribute or "ascribe" understanding to very young children, only in the late preschool years do the children themselves begin to ascribe understanding to themselves and others a competence that comes with learning the meaning of the word "understand." It is argued that ascription of understanding to others allows the creation of shared belief while self-ascription allows one to introspect on one's understanding: to know that one understands, to understand expressions that young children would simply reject as false, and to understand hypotheticals and counterfactuals. This competence applies to both understanding spoken expressions and reading comprehension. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

A novel approach to risk exposure and epigenetics-the use of multidimensional context to gain insights into the early origins of cardiometabolic and neurocognitive health.

BACKGROUND: Each mother-child dyad represents a unique combination of genetic and environmental factors. This constellation of variables impacts the expression of countless genes. Numerous studies have uncovered changes in DNA methylation (DNAm), a form of epigenetic regulation, in offspring related to maternal risk factors. How these changes work together to link maternal-child risks to childhood cardiometabolic and neurocognitive traits remains unknown. This question is a key research priority as such traits predispose to future non-communicable diseases (NCDs). We propose viewing risk and the genome through a multidimensional lens to identify common DNAm patterns shared among diverse risk profiles. METHODS: We identified multifactorial Maternal Risk Profiles (MRPs) generated from population-based data (n = 15,454, Avon Longitudinal Study of Parents and Children (ALSPAC)). Using cord blood HumanMethylation450 BeadChip data, we identified genome-wide patterns of DNAm that co-vary with these MRPs. We tested the prospective relation of these DNAm patterns (n = 914) to future outcomes using decision tree analysis. We then tested the reproducibility of these patterns in (1) DNAm data at age 7 and 17 years within the same cohort (n = 973 and 974, respectively) and (2) cord DNAm in an independent cohort, the Generation R Study (n = 686). RESULTS: We identified twenty MRP-related DNAm patterns at birth in ALSPAC. Four were prospectively related to cardiometabolic and/or neurocognitive childhood outcomes. These patterns were replicated in DNAm data from blood collected at later ages. Three of these patterns were externally validated in cord DNAm data in Generation R. Compared to previous literature, DNAm patterns exhibited novel spatial distribution across the genome that intersects with chromatin functional and tissue-specific signatures. CONCLUSIONS: To our knowledge, we are the first to leverage multifactorial population-wide data to detect patterns of variability in DNAm. This context-based approach decreases biases stemming from overreliance on specific samples or variables. We discovered molecular patterns demonstrating prospective and replicable relations to complex traits. Moreover, results suggest that patterns harbour a genome-wide organisation specific to chromatin regulation and target tissues. These preliminary findings warrant further investigation to better reflect the reality of human context in molecular studies of NCDs.

A systematic review of immune-based interventions for perinatal neuroprotection: closing the gap between animal studies and human trials.

BACKGROUND: Perinatal infection/inflammation is associated with a high risk for neurological injury and neurodevelopmental impairment after birth. Despite a growing preclinical evidence base, anti-inflammatory interventions have not been established in clinical practice, partly because of the range of potential targets. We therefore systematically reviewed preclinical studies of immunomodulation to improve neurological outcomes in the perinatal brain and assessed their therapeutic potential. METHODS: We reviewed relevant studies published from January 2012 to July 2023 using PubMed, Medline (OvidSP) and EMBASE databases. Studies were assessed for risk of bias using the SYRCLE risk of bias assessment tool (PROSPERO; registration number CRD42023395690). RESULTS: Forty preclinical publications using 12 models of perinatal neuroinflammation were identified and divided into 59 individual studies. Twenty-seven anti-inflammatory agents in 19 categories were investigated. Forty-five (76%) of 59 studies reported neuroprotection, from all 19 categories of therapeutics. Notably, 10/10 (100%) studies investigating anti-interleukin (IL)-1 therapies reported improved outcome, whereas half of the studies using corticosteroids (5/10; 50%) reported no improvement or worse outcomes with treatment. Most studies (49/59, 83%) did not control core body temperature (a known potential confounder), and 25 of 59 studies (42%) did not report the sex of subjects. Many studies did not clearly state whether they controlled for potential study bias. CONCLUSION: Anti-inflammatory therapies are promising candidates for treatment or even prevention of perinatal brain injury. Our analysis highlights key knowledge gaps and opportunities to improve preclinical study design that must be addressed to support clinical translation.

Rapid Synthesis of Psychoplastogenic Tropane Alkaloids.

Tropane alkaloids are an important class of biologically active small molecules characterized by their 8-azabicyclo[3.2.1]octane core. Because of their numerous medicinal applications, microbial biosynthesis and a variety of chemical syntheses have been designed for individual family members. However, current approaches are not amenable to late-stage structural diversification at N8, C3, C6, or C7, positions that are critical for modulating the biological properties of these molecules. Here, we describe a general approach to the synthesis of tropane alkaloids and their analogues that relies on the construction of the 8-azabicyclo[3.2.1]octane core through aziridination of a cycloheptadiene intermediate, followed by vinyl aziridine rearrangement. Using this strategy, we synthesized six tropane alkaloids and several analogues in only 5-7 steps. Given that the tropane alkaloid scopolamine has been reported to promote structural neuroplasticity and produce antidepressant effects, we tested five tropane-containing compounds for their ability to promote dendritic spine growth in cultured cortical neurons. We found that the orientation of the C3 substituent may play a role in the psychoplastogenic effects of tropane alkaloids. Our work provides a robust platform for producing tropane analogs for future structure-activity relationship studies.

Neuroplasticity: The Continuum of Change.

Neuroplasticity is a term that is increasingly permeating mainstream discourse and being used by the popular press to simplify descriptions of how the brain changes in response to stimuli such as exercise, sleep, food, drugs of abuse, and medicines, among others. However, it is a complex, multifaceted concept representing a continuum connecting molecular, cellular, and circuit-level changes and their effects on human behavior. In this Viewpoint, we examine neuroplasticity from several perspectives to construct a holistic view of this ambiguous term. By engaging experts across various scientific disciplines, we attempt to provide an easy entry point to the concept of neuroplasticity for readers of ACS Chemical Neuroscience. By highlighting how neuroplasticity changes in both health and disease, we demonstrate that the concept is applicable to both adaptive and maladaptive responses to stimuli, underscoring its significance in chemical neuroscience.

Synthetic Strategies toward Lysergic Acid Diethylamide: Ergoline Synthesis via α-Arylation, Borrowing Hydrogen Alkylation, and C-H Insertion.

Lysergic acid diethylamide (LSD), a semisynthetic ergoline alkaloid analogue and hallucinogen, is a potent psychoplastogen with promising therapeutic potential. While a variety of synthetic strategies for accessing ergoline alkaloids have emerged, the complexity of the tetracyclic ring system results in distinct challenges in preparing analogues with novel substitution patterns. Methods of modulating the hallucinogenic activity of LSD by functionalization at previously inaccessible positions are of continued interest, and efficient syntheses of the ergoline scaffold are integral toward this purpose. Here, we report novel C-C bond forming strategies for preparing the ergoline tetracyclic core, focusing on the relatively unexplored strategy of bridging the B- and D-ring systems last. Following cross-coupling to first join the A- and D-rings, we explored a variety of methods for establishing the C-ring, including intramolecular α-arylation, borrowing hydrogen alkylation, and rhodium-catalyzed C-H insertion. Our results led to a seven-step formal synthesis of LSD and the first methods for readily introducing substitution on the C-ring. These strategies are efficient for forming ergoline-like tetracyclic compounds and analogues, though they each face unique challenges associated with elaboration to ergoline natural products. Taken together, these studies provide important insights that will guide future synthetic strategies toward ergolines.

Comparison of the Quality of Recovery-15 score in patients undergoing oncoplastic breast-conserving surgery under monitored anesthesia care versus general anesthesia: a prospective quality improvement study.

PURPOSE: Whether changing the institutional practice from general anesthesia (GA) to monitored anesthesia care (MAC) affects postoperative quality of recovery for oncoplastic breast-conserving surgery (BCS) is currently unknown. We designed this quasi-experimental study to evaluate a quality improvement (QI) initiative instituted in Edmonton, AB, Canada. METHODS: We chose a prospective controlled cohort study design for this QI study, where patients underwent oncoplastic BCS under MAC in one hospital and BCS under GA at another hospital (control). A total of 125 patients undergoing surgery between May 2021 and February 2022 were enrolled. Exclusion criteria were male sex, total mastectomy, or age under 18. All other patients were included. The primary outcome was the change in Quality of Recovery-15 score at 24 hr compared with a preoperative baseline. Secondary outcomes included intra- and postoperative time profiles, perioperative analgesic and antiemetic use and length of hospital stay. Statistical analysis included a propensity score analysis to account for confounding variables. RESULTS: Sixty-four patients received GA and 61 MAC. No enrolled patients were lost to follow up but two were excluded secondarily. No patients receiving MAC needed conversion to GA or unplanned airway management. Monitored anesthesia care was associated with superior outcomes for the primary outcome (ß/SE[ß], 3.31; 99.5% confidence interval, 0.45 to 6.17; P = 0.001) and most secondary outcomes, when accounting for confounding factors. CONCLUSIONS: A care transformation initiative for patients undergoing oncoplastic BCS under MAC was associated with a higher quality recovery profile and shorter length of stay without any increase in perioperative or postoperative adverse events.

RéSUMé: OBJECTIF: On ignore actuellement si le fait de modifier la pratique institutionnelle de l'anesthésie générale (AG) à la sédation procédurale (monitored anesthesia care) affecte la qualité de la récupération postopératoire en cas de chirurgie mammaire conservatrice oncoplastique. Nous avons conçu cette étude quasi expérimentale pour évaluer une initiative d'amélioration de la qualité mise en place à Edmonton, Alberta, Canada. MéTHODE: Nous avons choisi une méthodologie d'étude de cohorte prospective contrôlée pour cette étude d'amélioration de la qualité, dans laquelle des patientes ont bénéficié d'une chirurgie mammaire conservatrice oncoplastique sous sédation procédurale dans un hôpital et de la même chirurgie sous anesthésie générale dans un autre hôpital (groupe témoin). Au total, 125 patientes bénéficiant d'une intervention chirurgicale entre mai 2021 et février 2022 ont été recrutées. Les critères d'exclusion étaient le sexe masculin, la mastectomie totale ou un âge de moins de 18 ans. Toutes les autres personnes ont été incluses. Le critère d'évaluation principal était la variation du score de Qualité de la récupération 15 à 24 heures par rapport aux valeurs initiales préopératoires. Les critères d'évaluation secondaires comprenaient les profils temporels per- et postopératoires, l'utilisation périopératoire d'analgésiques et d'antiémétiques et la durée du séjour à l'hôpital. L'analyse statistique comprenait une analyse par score de propension pour tenir compte des variables de confusion. RéSULTATS: Soixante-quatre patientes ont reçu une anesthésie générale et 61 une sédation procédurale. Aucune patiente recrutée n'a été perdue au suivi, mais deux ont été exclues secondairement. Aucune patiente recevant une sédation procédurale n'a eu besoin d'une conversion en anesthésie générale ou d'une prise en charge non planifiée des voies aériennes. La sédation procédurale était associée à des issues supérieures pour le critère d'évaluation principal (ß/ET[ß], 3,31; intervalle de confiance à 99,5 %, 0,45 à 6,17; P = 0,001) et la plupart des critères d'évaluation secondaires, en tenant compte des facteurs de confusion. CONCLUSION: Une initiative de transformation des soins pour les patientes bénéficiant d'une chirurgie mammaire conservatrice oncoplastique sous sédation procédurale a été associée à un profil de récupération de meilleure qualité et à une durée de séjour plus courte sans augmentation des événements indésirables périopératoires ou postopératoires.

Pharmacological blockade of the interleukin-1 receptor suppressed Escherichia coli lipopolysaccharide-induced neuroinflammation in preterm fetal sheep.

BACKGROUND: Intraamniotic inflammation is associated with preterm birth, especially in cases occurring before 32 weeks' gestation, and is causally linked with an increased risk for neonatal mortality and morbidity. Targeted anti-inflammatory interventions may assist in improving the outcomes for pregnancies impacted by intrauterine inflammation. Interleukin-1 is a central upstream mediator of inflammation. Accordingly, interleukin-1 is a promising candidate target for intervention therapies and has been targeted previously using the interleukin-1 receptor antagonist, anakinra. Recent studies have shown that the novel, noncompetitive, allosteric interleukin-1 receptor inhibitor, rytvela, partially resolved inflammation associated with preterm birth and fetal injury. In this study, we used a preterm sheep model of chorioamnionitis to investigate the anti-inflammatory efficacy of rytvela and anakinra, administered in the amniotic fluid in the setting of intraamniotic Escherichia coli lipopolysaccharide exposure. OBJECTIVE: We hypothesized that both rytvela and anakinra would reduce lipopolysaccharide-induced intrauterine inflammation and protect the fetal brain. STUDY DESIGN: Ewes with a singleton fetus at 105 days of gestation (term is ∼150 days) were randomized to one of the following groups: (1) intraamniotic injections of 2 mL saline at time=0 and time=24 hours as a negative control group (saline group, n=12); (2) intraamniotic injection of 10 mg Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2 mL saline at time=0 hours and time=24 hours as an inflammation positive control group (lipopolysaccharide group, n=11); (3) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 2.5 mg rytvela at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of rytvela (lipopolysaccharide + rytvela group, n=10); or (4) intraamniotic injection of Escherichia coli lipopolysaccharide in 2 mL saline and intraamniotic injections of 100 mg anakinra at time=0 hours and time=24 hours to test the anti-inflammatory efficacy of anakinra (lipopolysaccharide + anakinra group, n=12). Amniotic fluid was sampled at time 0, 24, and 48 hours (ie, at each intervention and at delivery). Fetal umbilical cord blood was collected at delivery for differential blood counts and chemical studies. Inflammation was characterized by the analysis of fetal tissue cytokine and chemokine levels using quantitative polymerase chain reaction, enzyme-linked inmmunosorbent assay, and histology. The primary study outcome of interest was the assessment of anakinra and rytvela brain-protective effects in the setting of Escherichia coli lipopolysaccharide-induced intrauterine inflammation. Secondary outcomes of interest were to assess protection from fetal and intrauterine (ie, amniotic fluid, chorioamnion) inflammation. RESULTS: Intraamniotic administration of lipopolysaccharide caused inflammation of the fetal lung, brain, and chorioamnionitis in preterm fetal sheep. Relative to treatment with saline only in the setting of lipopolysaccharide exposure, intraamniotic administration of both rytvela and anakinra both significantly prevented periventricular white matter injury, microglial activation, and histologic chorioamnionitis. Anakinra showed additional efficacy in inhibiting fetal lung myeloperoxidase activity, but its use was associated with metabolic acidaemia and reduced fetal plasma insulin-like growth factor-1 levels at delivery. CONCLUSION: Intraamniotic administration of rytvela or anakinra significantly inhibited fetal brain inflammation and chorioamnionitis in preterm fetal sheep exposed to intraamniotic lipopolysaccharide. In addition, anakinra treatment was associated with potential negative impacts on the developing fetus.

Suppression of food intake by Glp1r/Lepr-coexpressing neurons prevents obesity in mouse models.

The adipose-derived hormone leptin acts via its receptor (LepRb) in the brain to control energy balance. A potentially unidentified population of GABAergic hypothalamic LepRb neurons plays key roles in the restraint of food intake and body weight by leptin. To identify markers for candidate populations of LepRb neurons in an unbiased manner, we performed single-nucleus RNA-Seq of enriched mouse hypothalamic LepRb cells, identifying several previously unrecognized populations of hypothalamic LepRb neurons. Many of these populations displayed strong conservation across species, including GABAergic Glp1r-expressing LepRb (LepRbGlp1r) neurons, which expressed more Lepr than other LepRb cell populations. Ablating Lepr from LepRbGlp1r cells provoked hyperphagic obesity without impairing energy expenditure. Similarly, improvements in energy balance caused by Lepr reactivation in GABA neurons of otherwise Lepr-null mice required Lepr expression in GABAergic Glp1r-expressing neurons. Furthermore, restoration of Glp1r expression in LepRbGlp1r neurons in otherwise Glp1r-null mice enabled food intake suppression by the GLP1R agonist, liraglutide. Thus, the conserved GABAergic LepRbGlp1r neuron population plays crucial roles in the suppression of food intake by leptin and GLP1R agonists.

Spare the Nipple: A Systematic Review of Tumor Nipple-Distance and Oncologic Outcomes in Nipple-Sparing Mastectomy.

BACKGROUND: Preserving the nipple-areolar complex (NAC) in breast cancer surgery improves patient satisfaction and quality of life. The oncologic safety of NSM in tumors < 2 cm from the nipple remains in question. We conducted a systematic review to determine whether TND < 2 cm was associated with increased risk of LRR in patients undergoing NSM. METHODS: We included studies of invasive or in situ breast cancer < 2 cm from NAC undergoing NSM which reported LRR rates. LRR rates were stratified by TND and culminated across studies. Cohort study quality was assessed using Newcastle-Ottawa Criteria. Meta-analysis was not possible due to heterogeneity in reporting survival outcomes. RESULTS: We identified seven retrospective cohort studies with 2295 patients and 18 case series with 3507 patients. Direct tumor involvement of NAC was considered an absolute contraindication to NSM in all studies. In cohort studies, median follow-up was 31-112 (range 14-204) months. Cohorts with TND < 2 cm did not have a significantly higher rate of LRR. Amongst case series, 275 patients had TND < 2 cm. Combined LRR in case series was 2.6%, with median follow-up 10.4-71 (range 0-158) months. CONCLUSIONS: Our systematic review did not identify TND < 2 cm as a significant risk factor for LRR. NSM appears oncologically safe in select patients with TND < 2 cm. Given the improved quality of life associated with NSM compared to skin-sparing mastectomy, we suggest NSM as the procedure of choice in appropriately selected patients.