Microevolutionary hypothesis of the obesity epidemic.

The obesity epidemic represents potentially the largest phenotypic change in Homo sapiens since the origin of the species. Despite obesity's high heritability, it is generally presumed a change in the gene pool could not have caused the obesity epidemic. Here we advance the hypothesis that a rapid change in the obesogenic gene pool has occurred second to the introduction of modern obstetrics dramatically altering evolutionary pressures on obesity-the microevolutionary hypothesis of the obesity epidemic.

With complements: C3 inhibition in the clinic.

C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell-derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challenges such as very high concentration in blood, increased acute expression, and the elevated risk of infections have historically posed significant challenges in the development of C3-targeted therapeutics.

Inside-Out of Complement in Cancer.

The role of complement in cancer has received increasing attention over the last decade. Recent studies provide compelling evidence that complement accelerates cancer progression. Despite the pivotal role of complement in fighting microbes, complement seems to suppress antitumor immunity regulation of host cell in the tumor microenvironment.

The burden of illness in patients with paroxysmal nocturnal hemoglobinuria receiving treatment with the C5-inhibitors eculizumab or ravulizumab: results from a US patient survey.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening disease with symptoms of hemolysis and thrombosis. Current therapies for this complement-mediated disease rely predominantly on inhibition of the C5 complement protein. However, data on treatment responses and quality of life in C5-inhibitor (C5i)-treated PNH patients are scarce.

Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison.

Objective: In the absence of a head-to-head study, we assessed the comparative effectiveness of pegcetacoplan, a targeted C3 complement inhibitor, vs. ravulizumab, a C5 complement inhibitor, among patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab using matching-adjusted indirect comparison methodology.

Methods: Individual patient data from the PEGASUS study (NCT03500549) comparing pegcetacoplan and eculizumab enabled adjustment for baseline differences compared with published results from the ALXN1210-PNH-302 study (NCT03056040), comparing ravulizumab and eculizumab.

Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus.

The hypothalamic arcuate nucleus (ARH) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS. In lean mice, the adipokine leptin inhibits neuropeptide Y (NPY) and agouti-related peptide (AgRP) neuronal activity, resulting in decreased food intake. Here we show that diet-induced obesity in mice is associated with persistent activation of NPY neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential.

Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons.

Leptin acts via neuronal leptin receptors to control energy balance. Hypothalamic pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP)/Neuropeptide Y (NPY)/GABA neurons produce anorexigenic and orexigenic neuropeptides and neurotransmitters, and express the long signaling form of the leptin receptor (LepRb). Despite progress in the understanding of LepRb signaling and function, the sub-cellular localization of LepRb in target neurons has not been determined, primarily due to lack of sensitive anti-LepRb antibodies.

A herpesvirus encoded deubiquitinase is a novel neuroinvasive determinant.

The neuroinvasive property of several alpha-herpesviruses underlies an uncommon infectious process that includes the establishment of life-long latent infections in sensory neurons of the peripheral nervous system. Several herpesvirus proteins are required for replication and dissemination within the nervous system, indicating that exploiting the nervous system as a niche for productive infection requires a specialized set of functions encoded by the virus. Whether initial entry into the nervous system from peripheral tissues also requires specialized viral functions is not known.

Light-induced fos expression in intrinsically photosensitive retinal ganglion cells in melanopsin knockout (opn4) mice.

Retinal ganglion cells that express the photopigment melanopsin are intrinsically photosensitive (ipRGCs) and exhibit robust synaptically driven ON-responses to light, yet they will continue to depolarize in response to light when all synaptic input from rod and cone photoreceptors is removed. The light-evoked increase in firing of classical ganglion cells is determined by synaptic input from ON-bipolar cells in the proximal sublamina of the inner plexiform layer. OFF-bipolar cells synapse with ganglion cell dendrites in the distal sublamina of the inner plexiform layer.

Two types of melanopsin retinal ganglion cell differentially innervate the hypothalamic suprachiasmatic nucleus and the olivary pretectal nucleus.

Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) innervate the hypothalamic suprachiasmatic nucleus (SCN) and the olivary pretectal nucleus (OPN), providing irradiance information for entrainment of circadian rhythms and for stimulating the pupillary light reflex. In this study, mice were used in which the melanopsin gene was replaced with the tau-lacZ gene. Heterozygous (tau-lacZ+/-) mice express both melanopsin and beta-galactosidase.