Our original review, “Heterogeneity and Diversity of Striatal GABAergic Interneurons,” to which this is an invited update, was published in December, 2010 in Frontiers is Neuroanatomy. In that article, we reviewed several decades’ worth of anatomical and electrophysiological data on striatal parvalbumin (PV)-, neuropeptide Y (NPY)- and calretinin(CR)-expressing GABAergic interneurons from many laboratories including our own. In addition, we reported on a recently discovered novel tyrosine hydroxylase (TH) expressing GABAergic interneuron class first revealed in transgenic TH EGFP reporter mouse line. In this review, we report on further advances in the understanding of the functional properties of previously reported striatal GABAergic interneurons and their synaptic connections. With the application of new transgenic fluorescent reporter and Cre-driver/reporter lines, plus optogenetic, chemogenetic and viral transduction methods, several additional subtypes of novel striatal GABAergic interneurons have been discovered, as well as the synaptic networks in which they are embedded. These findings make it clear that previous hypotheses in which striatal GABAergic interneurons modulate and/or control the firing of spiny neurons principally by simple feedforward and/or feedback inhibition are at best incomplete. A more accurate picture is one in which there are highly selective and specific afferent inputs, synaptic connections between different interneuron subtypes and spiny neurons and among different GABAergic interneurons that result in the formation of functional networks and ensembles of spiny neurons.

Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from crossreactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the bloodbrain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response.autoimmunity | mitochondrial stress | neuropsychiatric lupus | NMDA receptor

The investigational drugs E7820, indisulam and tasisulam (aryl-sulfonamides) promote the degradation of the splicing factor RBM39 in a proteasome-dependent mechanism. While the activity critically depends on the Cullin RING ligase substrate receptor DCAF15, the molecular details remain elusive. Here we present the cryo-EM structure of the DDB1-DCAF15-DDA1 core ligase complex bound to RBM39 and E7820 at 4.4 Å resolution, together with crystal structures of engineered subcomplexes. We show that DCAF15 adopts a novel fold stabilized by DDA1, and that extensive protein-protein contacts between the ligase and substrate mitigate low affinity interactions between aryl-sulfonamides and DCAF15. Our data demonstrates how arylsulfonamides neo-functionalize a shallow, non-conserved pocket on DCAF15 to selectively bind and degrade RBM39 and the closely related splicing factor RBM23 without the requirement for a high affinity ligand, which has broad implications for the de novo discovery of molecular glue degraders.Pharmacologic intervention for many newly discovered disease targets -such as transcription factors, multi-protein complexes or scaffold proteins -is challenging because they lack an enzymatic function to facilitate the design of classical low molecular weight inhibitors. An alternative approach, small molecule-induced protein degradation, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

The covalent Bruton tyrosine kinase (BTK) inhibitor ibrutinib is highly efficacious against multiple B-cell malignancies. However, it is not selective for BTK, and multiple mechanisms of resistance, including the C481S-BTK mutation, can compromise its efficacy. We hypothesized that small-molecule–induced BTK degradation may overcome some of the limitations of traditional enzymatic inhibitors. Here, we demonstrate that BTK degradation results in potent suppression of signaling and proliferation in cancer cells and that BTK degraders efficiently degrade C481S-BTK. Moreover, we discovered DD-03-171, an optimized lead compound that exhibits enhanced antiproliferative effects on mantle cell lymphoma (MCL) cells in vitro by degrading BTK, IKFZ1, and IKFZ3 as well as efficacy against patient-derived xenografts in vivo. Thus, “triple degradation” may be an effective therapeutic approach for treating MCL and overcoming ibrutinib resistance, thereby addressing a major unmet need in the treatment of MCL and other B-cell lymphomas.

SUMMARY Overlapping genes pose an evolutionary dilemma as one DNA sequence evolves under the selection pressures of multiple proteins. Here, we perform systematic statistical and mutational analyses of the overlapping HIV-1 genes tat and rev and engineer exhaustive libraries of non-overlapped viruses to perform deep mutational scanning of each gene independently. We find a “segregated” organization in which overlapped sites encode functional residues of one gene or the other, but never both. Furthermore, this organization eliminates unfit genotypes, providing a fitness advantage to the population. Our comprehensive analysis reveals the extraordinary manner in which HIV minimizes the constraint of overlapping genes and repurposes that constraint to its own advantage. Thus, overlaps are not just consequences of evolutionary constraints, but rather can provide population fitness advantages.

Synchronous optogenetic activation of striatal cholinergic interneurons ex vivo produces a disynaptic inhibition of spiny projection neurons composed of biophysically distinct GABA Afast and GABA Aslow components. This has been shown to be due, at least in part, to activation of nicotinic receptors on GABAergic NPY-neurogliaform interneurons that monosynaptically inhibit striatal spiny projection neurons. Recently, it has been proposed that a significant proportion of this inhibition is actually mediated by activation of presynaptic nicotinic receptors on nigrostriatal terminals that evoke GABA release from the terminals of the dopaminergic nigrostriatal pathway. To disambiguate these the two mechanisms, we crossed mice in which channelrhodopsin is endogenously expressed in cholinergic neurons with Htr3a-Cre mice, in which Cre is selectively targeted to several populations of striatal GABAergic interneurons, including the striatal NPY-neurogliaform interneuron. Htr3a-Cre mice were then virally transduced to express halorhodopsin to allow activation of channelrhodopsin and halorhodopsin, individually or simultaneously. Thus we were able to optogenetically disconnect the interneuron-spiny projection neuron (SPN) cell circuit on a trial-by-trial basis. As expected, optogenetic activation of cholinergic interneurons produced inhibitory currents in SPNs. During simultaneous inhibition of GABAergic interneurons with halorhodopsin, we observed a large, sometimes near complete reduction in both fast and slow components of the cholinergic-evoked inhibition, and a delay in IPSC latency. This demonstrates that the majority of cholinergic-evoked striatal GABAergic inhibition is derived from GABAergic interneurons. These results also reinforce the notion that a semiautonomous circuit of striatal GABAergic interneurons is responsible for transmitting behaviorally relevant cholinergic signals to spiny projection neurons.

It is widely perceived that outcomes are relatively poor following retransplantation (reTX) for recurrent of hepatitis C virus (HCV) infection. Transplant centers debate the utility of offering another liver to these patients. A U.S. study group was formed to retrospectively compare survival after reTX in patients with recurrent HCV (histologically proven) and those transplanted for other indications greater than 90 days after first transplantation, from 1996 to 2004. Patients were divided into 3 groups; group 1: HCV reTX (n ϭ 43), group 2: non-HCV reTX (n ϭ 73), and group 3: recurrent HCV but no reTX (n ϭ 156). They were predominantly male, Caucasian, with mean age of 47.2 yr. The commonest indications for non-HCV reTX were chronic rejection (36%), hepatic artery thrombosis (31%) and recurrent primary sclerosing cholangitis (17%). Duration of hospitalization, number of intensive care unit (ICU) days, and time interval from listing to transplantation or reTX were similar between reTX groups. The 1-yr and 3-yr survival rates after reTX were also similar for HCV reTX and non-HCV reTX groups (1 yr, 69% vs. 73%; 3 yr, 49% vs. 55%). Model for End-Stage Liver Disease (MELD) scores were not predictive of survival from reTX. However, with a MELD score of Ͼ30 in the non HCV group, survival was Ͻ50%. In the recurrent HCV not undergoing reTX group, 30% were reevaluated for reTX but only 15% were listed for reTX and the 3-yr survival was 47%. The most common reasons for not listing for reTX were recurrent HCV within 6 months (22%), fibrosing cholestatic hepatitis (19%), and renal dysfunction (9%). In conclusion, patients retransplanted for recurrent HCV had similar 1-yr and 3-yr survival when compared to patients undergoing reTX for other indications. MELD scores were not predictive of post-reTX survival. Survival was Ͻ50% in the non-HCV reTx group with MELD score of Ͼ30. Many patients with recurrent HCV are not considered for reTX and die from recurrent disease.

The improved life expectancy of patients with cystic fibrosis (CF) has led to a change in the impact of liver disease on the prognosis of this population. Liver transplantation has emerged as the procedure of choice for patients with CF and features of hepatic decompensation and for intractable variceal bleeding as a major manifestation. We retrospectively reviewed the United Network for Organ Sharing database to analyze the outcomes of 55 adults and 148 children with CF who underwent liver transplantation, and we compared them to patients who underwent transplantation for other etiologies. We additionally compared the benefits of liver transplantation among patients who underwent transplantation for cystic fibrosis-related liver disease (CFLD) and those who remained on the waiting list. The 5-year survival rates for children and adults undergoing liver transplantation were 85.8% and 72.7%, respectively (P ¼ 0.016). A multivariate Cox regression analysis comparing pediatric and adult CF patients to patients who underwent transplantation for other etiologies noted lower 5-year survival rates (P < 0.0001). However, compared to those remaining on the waiting list, pediatric transplant recipients with CF (hazard ratio ¼ 0.33, 95% confidence interval ¼ 0.16-0.70, P ¼ 0.004) and adult transplant recipients with CF (hazard ratio ¼ 0.25, 95% confidence interval ¼ 0.11-0.57, P ¼ 0.001) gained a significant survival benefit. In conclusion, long-term outcomes in patients with CFLD are acceptable but are inferior in comparison with the outcomes of those undergoing transplantation for other etiologies. Despite such observations, a survival benefit was noted in transplant patients versus those who remained on the waiting list.