Acquired Brain Injury-Induced Hyperphagia and Obesity, Successfully Treated With a GLP-1 Agonist

Background: Several Glucagon-like peptides 1 (GLP-1s) were approved since 2005 for the treatment of DM & obesity. Their usefulness in other conditions is not well studied. We present two cases of hyperphagia after TBI successfully treated with GLP-1 agonists. Clinical cases: Case 1: A 54-year-old female with a history of multiple traumatic brain injuries (multiple falls and a ski accident) complained of years of insatiable hunger leading to hyperphagia and over 20 pounds weight gain. With tremendous will-power, she avoided additional weight gain by adopting a strict meal-plan and increasing her water intake (10–12 liters a day) to relieve her hunger. She sipped so much water, that her sodium remained 123 - 133 mmol/L (ref: 135–146) with dilute urine. Initial tests revealed: IGF-1 315 ng/ml (52–328), FSH 77.5 mIU/ml (23–116.3), LH 24.3 mIU/ml (14.2–52.3), prolactin 17.1 ng.ml (10–54.7), estradiol 17 (<31), TSH 1.09mIU/ml (0.45–4.5), FT4 1.0 ng/dl(0.8–1.8), all within the normal limit for her age. Semaglutide 0.25mg/week was started and increased to 0.5mg/week. Within the first six months of treatment, she experienced 22 pounds of weight loss, hunger relief, less water sipping behavior, and more enjoyment of food. Her sodium rose to 137 mmol/L. Case 2: A 40-year-old female, s/p craniectomy and aneurysm clipping due to intracranial hemorrhage complicated by an ischemic stroke developed sudden, documented, 45-pound weight gain over thirteen months despite aggressive lifestyle modification attempts. Initial labs revealed: TSH 1.33 mIU/ml (0.45–4.5), FT4 1.22 ng/dl (0.8–1.8), midnight salivary cortisol 0.03 mcg/dl (<0.09), ruling out hypothyroidism and Cushing syndrome. Liraglutide 1.8mg/day was started and has resulted to date in 26 pounds (11.8% of maximum weight) by 9 months with an associated decrease in subjective hunger. Conclusion: Hyperphagia can be seen in brain injury, in response to some medications, and some genetic conditions, like Prader-Willi. The exact mechanisms are not clear am may be multifactorial. In the case of brain injury, proposed mechanisms include insatiable hunger due to ventromedial hypothalamic or brain stem dysfunction, or disinhibition and poor impulse control due to frontal lobe injury. GLP-1’s may act on the causal mechanism for increased hunger, or it may result in clinical improvement through a parallel pathway. More studies are warranted to investigate the application of GLP-1’s to hyperphagia.

External Procedural Justice: Do Just Supervisors Shape Officer Trust and Willingness to Take the Initiative With the Public?

Decades of empirical research have shaped our understanding of organizational justice in the workplace and public assessments of police procedures on the street, but only recently has a nascent wave of research sought to better understand the role that officer perceptions of supervisory procedural justice play in shaping their (un)fair interactions with the public. The nascent research testing this relationship has focused on the evidence that officer perceptions of trust in the public is a pathway between internal procedural justice and external procedural justice. This article tests the role of trust and a parallel pathway that incorporates the concepts of work engagement and personal initiative in the procedural justice literature. Relying on a survey of 638 Croatian police officers, this study finds that the effect of supervisory procedural justice on officers’ external procedural justice is positive but indirect through a measure of trust in the public and the proposed engagement/initiative mechanism. The implications of these findings for research and police practice are discussed.

Centromere drive and suppression by parallel pathways for recruiting microtubule destabilizers

SummarySelfish centromere DNA sequences bias their transmission to the egg in female meiosis. Evolutionary theory suggests that centromere proteins evolve to suppress costs of this “centromere drive”. In hybrid mouse models with genetically different maternal and paternal centromeres, selfish centromere DNA exploits a kinetochore pathway to recruit microtubule-destabilizing proteins that act as drive effectors. We show that such functional differences are suppressed by a parallel pathway for effector recruitment by heterochromatin, which is similar between centromeres in this system. Disrupting heterochromatin by CENP-B deletion amplifies functional differences between centromeres, whereas disrupting the kinetochore pathway with a divergent allele of CENP-C reduces the differences. Molecular evolution analyses using newly sequenced Murinae genomes identify adaptive evolution in proteins in both pathways. We propose that centromere proteins have recurrently evolved to minimize the kinetochore pathway, which is exploited by selfish DNA, relative to the heterochromatin pathway that equalizes centromeres, while maintaining essential functions.

Non-canonical autophagy drives alternative ATG8 conjugation to phosphatidylserine

Autophagy is a fundamental catabolic process essential for development, homeostasis and proper immune function 1. During autophagy, a cascade of ATG proteins target intracellular cargoes for lysosomal degradation and recycling 2. This pathway utilises a unique post-translational modification, the conjugation of ATG8 proteins to phosphatidylethanolamine (PE) at autophagosomes, which modulates cargo selection and maturation. ATG8 lipidation also occurs during non-canonical autophagy, a parallel pathway involving Single Membrane ATG8 Conjugation (SMAC) to endolysosomal compartments, which plays a key role in phagocytosis and other processes 3. It has been widely assumed that SMAC involves the same lipidation of ATG8 to PE, but this has yet to be formally tested. Here, we show that ATG8 undergoes alternative lipidation to phosphatidylserine (PS) during non-canonical autophagy/SMAC. Using mass spectrometry, we find that activation of SMAC, by pharmacological agents 4,5, or during non-canonical autophagy processes such as LC3-associated phagocytosis 6,7 and Influenza A virus infection 8, induces the covalent conjugation of ATG8 to PS, as well as PE. This alternative lipidation event is dependent on the ATG16L1 WD40 domain, and occurs at PS enriched endolysosomal membranes. Importantly, we find that the ATG8-PS and ATG8-PE adducts are differentially delipidated by isoforms of the ATG4 family, indicating significant molecular distinctions and mechanisms between these two species.Together, these results provide an important new insight into autophagy signalling, revealing an alternative form of the hallmark ATG8-lipidation event, so widely used to define and assay autophagy. Furthermore, ATG8-PS lipidation provides a specific ‘molecular signature’ for non-canonical autophagy, uncovering a novel means of detecting and monitoring this emerging pathway.

Spatial Regulation of MCAK Promotes Cell Polarization and Focal Adhesion Turnover to Drive Robust Cell Migration

The asymmetric distribution of microtubule (MT) dynamics in migrating cells is important for cell polarization, yet the underlying regulatory mechanisms remain underexplored. Here, we addressed this question by studying the role of the MT depolymerase, MCAK, in the highly persistent migration of RPE-1 cells. MCAK knockdown leads to slowed migration and poor directional movement. Fixed and live cell imaging revealed that MCAK knockdown results in excessive membrane ruffling as well as defects in cell polarization and the maintenance of a major protrusive front. Additionally, loss of MCAK increases the lifetime of focal adhesions by decreasing their disassembly rate. These defects are due in part to the loss of the spatial distribution of MCAK activity, wherein activity is higher in the trailing edge of cells compared to the leading edge. Overexpression of Rac1 has a dominant effect over MCAK activity, placing it downstream or in a parallel pathway to MCAK function in migration. Together, our data support a model that places MCAK at a key nexus of a feedback loop, in which polarized distribution of MCAK activity and subsequent differential regulation of MT dynamics contributes to cell polarity and directional migration.

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

p53 deletion rescues lethal microcephaly in a mouse model with neural stem cell abscission defects

ABSTRACTBuilding a cerebral cortex of the proper size involves balancing rates and timing of neural stem cell (NSC) proliferation, neurogenesis, and cell death. The cellular mechanisms connecting genetic mutations to brain malformation phenotypes are still poorly understood. Microcephaly may result when NSC divisions are too slow, produce neurons too early, or undergo apoptosis, but the relative contributions of these cellular mechanisms to various types of microcephaly are not understood. We previously showed that mouse mutants in Kif20b (formerly called Mphosph1, Mpp1, or KRMP1) have small cortices that show elevated apoptosis, and defects in maturation of NSC midbodies, which mediate cytokinetic abscission. Here we test the contribution of intrinsic NSC apoptosis to brain size reduction in this lethal microcephaly model. By making double mutants with the pro-apoptotic genes Bax and Trp53 (p53), we find that apoptosis of cortical NSCs accounts for most of the microcephaly, but that there is a significant apoptosis-independent contribution as well. Remarkably, heterozygous p53 deletion is sufficient to fully rescue survival of the Kif20b mutant into adulthood. In addition, the NSC midbody maturation defects are not rescued by p53 deletion, showing that they are either upstream of p53 activation, or in a parallel pathway. Thus, this work potentially identifies a novel midbody-mediated pathway for p53 activation, and elucidates both NSC apoptosis and abscission mechanisms that could underlie human microcephaly or other brain malformations.

A GAP that Divides

Cytokinesis in metazoan cells is mediated by an actomyosin-based contractile ring that assembles in response to activation of the small GTPase RhoA. The guanine nucleotide exchange factor that activates RhoA during cytokinesis, ECT-2, is highly regulated. In most metazoan cells, with the notable exception of the early Caenorhabditis elegans embryo, RhoA activation and furrow ingression require the centralspindlin complex. This exception is due to the existence of a parallel pathway for RhoA activation in C. elegans. Centralspindlin contains CYK-4 which contains a predicted Rho family GTPase-activating protein (GAP) domain. The function of this domain has been the subject of considerable debate. Some publications suggest that the GAP domain promotes RhoA activation (for example, Zhang and Glotzer, 2015; Loria, Longhini and Glotzer, 2012), whereas others suggest that it functions to inactivate the GTPase Rac1 (for example, Zhuravlev et al., 2017). Here, we review the mechanisms underlying RhoA activation during cytokinesis, primarily focusing on data in C. elegans. We highlight the importance of considering the parallel pathway for RhoA activation and detailed analyses of cyk-4 mutant phenotypes when evaluating the role of the GAP domain of CYK-4.