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Dopamine synapses play a crucial role in volitional movement and reward-related behaviors, while dysfunction of dopamine synapses causes various psychiatric and neurological disorders. Despite this significance, the true biological nature of dopamine synapses remains poorly understood. Here, we show that dopamine transmission is strongly correlated with GABA co-transmission across the brain and dopamine synapses are structured and function like GABAergic synapses with marked regional heterogeneity. In addition, GABAergic-like dopamine synapses are clustered on the dendrites, and GABA transmission at dopamine synapses has distinct physiological properties. Interestingly, the knockdown of neuroligin-2, a key postsynaptic protein at GABAergic synapses, unexpectedly does not weaken GABA co-transmission but instead facilitates it at dopamine synapses in the striatal neurons. More importantly, the attenuation of GABA co-transmission precedes deficits in dopaminergic transmission in animal models of Parkinson's disease. Our findings reveal the spatial and functional nature of GABAergic-like dopamine synapses in health and disease. [Display omitted] • GABAergic-like DA synapses exist in the brain with regional heterogeneity • GABA co-transmission is physiologically distinct from typical GABA transmission • GABA co-transmission can be critical for the maintenance of DA synapses • GABA co-transmission attenuates faster than DA transmission in animal models of PD Kim et al. discover that GABAergic-like dopamine synapses exist in the brain. GABA co-transmission at these synapses can be critical for the survival and maintenance of dopamine synapses in health and brain diseases. [ABSTRACT FROM AUTHOR]

We present a novel, real-time algorithm for computing the continuous penetration depth (CPD) between two interpenetrating rigid models bounded by triangle meshes. Our algorithm guarantees gradient continuity for the penetration depth (PD) results, unlike conventional penetration depth (PD) algorithms that may have directional discontinuity due to the Euclidean projection operator involved with PD computation. Moreover, unlike prior CPD algorithms, our algorithm is able to handle an orientation change in the underlying model and deal with a topologically-complicated model with holes. Given two intersecting models, we interpolate tangent planes continuously on the boundary of the Minkowski sums between the models and find the closest point on the boundary using Phong projection. Given the high complexity of computing the Minkowski sums for polygonal models in 3D, our algorithm estimates a solution subspace for CPD and dynamically constructs and updates the Minkowski sums only locally in the subspace. We implemented our algorithm on a standard PC platform and tested its performance in terms of speed and continuity using various benchmarks of complicated rigid models, and demonstrated that our algorithm can compute CPD for general polygonal models consisting of tens of thousands of triangles with a hole in a few milli-seconds while guaranteeing the continuity of PD gradient. Moreover, our algorithm can compute more optimal PD values than a state-of-the-art PD algorithm due to the dynamic Minkowski sum computation. [ABSTRACT FROM AUTHOR]

The main causes of early hearing deficit in circling mice have been reported to be early degeneration of the organ of Corti and deterioration of spiral ganglion neurons. As an exact cochlear pathology is essential to explain our previous results regarding the auditory brainstem circuits of developing circling mice, we reinvestigated the cochlear pathology in developing circling mice (14, 22, and 38 days old). It has been reported that the organ of Corti in circling mice completely degenerates as early as postnatal day (P) 21 and that circling mice are deaf by P18. Although we confirmed that circling mice were deaf at P15 and that hair bundles of outer hair cells were defective at P18, complete degeneration of the organ of Corti was not observed by P38 in circling mice. At P22, the type I cell-like spiral ganglion cell density in circling mice was reduced to 78% of that of control mice (ICR mice), but it was not significantly different from that of other control mice (heterozygous ( +/cir ) mice, littermates of circling mice) that could hear at P22. Our data suggest that other factors, such as absence of neurotransmitter release from inner hair cells, should be considered to explain the early hearing deficit observed at P15 in circling mice. [ABSTRACT FROM AUTHOR]

Objective Although the endovascular aneurysm repair trial 2 (EVAR-2) demonstrated no benefit of EVAR in high-risk (HR) patients, EVAR is still performed widely in this patient cohort. This study compares the midterm outcomes after EVAR in HR patients with those in normal-risk (NR) patients. In turn, these data are compared with the EVAR-2 data. Methods A retrospective review from January 2006 to December 2013 identified 247 patients (75 HR [30.4%], 172 NR [69.6%]) who underwent elective EVAR for infrarenal aortic aneurysm in an academic tertiary institution and its affiliated Veterans Administration hospital. The same HR criteria used in the EVAR-2 trial were employed. Overall survival, graft-related complications, and reintervention rates were estimated by the Kaplan-Meier method. HR group outcomes were compared with the EVAR-2 data. Results HR patients had a larger abdominal aortic aneurysm size and had a higher prevalence of cardiac disease ( P < .01), chronic obstructive pulmonary disease ( P = .02), renal insufficiency ( P < .01), and cancer ( P < .01). Use of aspirin (63% HR vs 66% NR; P = .6), statin (83% HR vs 72% NR; P = .2), and beta-blockers (71% HR vs 60% NR; P = .2) was similar; in the EVAR-2 trial, the corresponding use of these medications was 58%, 42%, and not available, respectively. Perioperative mortality (0% HR vs 1.2% NR; P = 1.0) and early complication rates (4% HR vs 6% NR; P = .8) were similar. In contrast, perioperative mortality in the EVAR-2 trial was 9%. At a mean follow-up of 3 years, the incidence rates of delayed secondary interventions for aneurysm- or graft-related complications were 7% for HR patients and 10% for NR patients ( P = .5). The 1-, 2-, and 4-year survival rates in HR patients (85%, 77%, 65%) were lower than those in NR patients (97%, 97%, 93%; P < .001), but this was more favorable compared with a 36% 4-year survival in the EVAR-2 trial. No difference was seen in long-term reintervention-free survival in HR and NR patients ( P = .8). Backward stepwise logistic regression analysis identified five prognostic indicators for post-EVAR death: age, chronic kidney disease stages 4 and 5, congestive heart failure, home oxygen use, and current cancer therapy. Conclusions EVAR can be performed in patients unfit for open surgical repair with excellent early survival and long-term durability. These outcomes in the HR group compare more favorably to the EVAR-2 trial data. However, not all HR patients for open surgical repair derive the benefit from EVAR. The decision to proceed with EVAR in HR patients should be individualized, depending on the number and severity of risk factors. [ABSTRACT FROM AUTHOR]

Vesicular glutamate transporter 3 (VGLUT3) plays a major role in hearing, and mice lacking the VGLUT3 are congenitally deaf due to absence of glutamate release at the inner hair cell afferent synapses. However, whether VGLUT3 is expressed normally in the cochleae of developing circling mice (homozygous ( cir / cir ) mice), the animal model for human deafness type DFNB6, has not been established. In this study, we investigated the developmental expression of VGLUT3 in cochlear inner hair cells (IHCs) and spiral ganglion cells (SGCs) of homozygous ( cir / cir ) mice from postnatal day (P)1 to P14 using immunofluorescence (IF) staining and Western blot. VGLUT3 immunoreactivity (IR) and protein expression increased progressively with age in homozygous ( cir / cir ) and control mice (heterozygous (+/ cir ) mice and ICR mice). The rank order of VGLUT3 IR in IHCs and SGCs in P14 mice was homozygous ( cir / cir ) mice = heterozygous ( + / cir ) mice > ICR mice. The rank order of total protein expression was homozygous ( cir/cir ) mice > heterozygous (+/ cir ) mice = ICR mice at P14. IF staining and Western blot analysis indicated that developmental VGLUT3 expression in cochleae was most prominent in homozygous ( cir / cir ) mice. The possible contribution of VGLUT3 upregulation in the cochlear degeneration is discussed. [ABSTRACT FROM AUTHOR]

Novel CAR T cells targeting mesothelin (MSLN) expressed on pancreatic cancer cells were developed to overcome the limit of the clinical efficacy of CAR T cell therapy for pancreatic cancer patients. Optimal single-chain variable fragments (scFv) binding to MSLN were selected based on the binding activity and the functional effectiveness of various scFv containing CAR-expressing T cells. Engineered MSLN CAR T cells showed successful anti-tumor activity specific to MSLN expression level. Furthermore, MSLN CAR T cells were evaluated for the anti-cancer efficacy in orthotopic mouse models bearing pancreatic cancer cells, MIA Paca-2, MSLN-overexpressed MIA Paca-2 or endogenously MSLN-expressing AsPC-1. Mice were randomized into control, mock treated, MS501 BBz treated, MS501 28z treated or MS501 28BBz treated group. Mice were monitored by weekly IVIS imaging and tumors were harvested and analyzed by immunohistochemical analyses. MSLN CAR T cells produced the therapeutic effect in orthotopic animal models with complete remission in significant number of mice. Histopathological analysis indicated that CD4+ and CD8+ MSLN CAR T cells infiltrated pancreatic tumor tissue and led to cancer cell eradication. Our results demonstrated the anti-tumor efficacy of MSLN CAR T cell therapy against pancreatic cancer, suggesting its therapeutic potential. [ABSTRACT FROM AUTHOR]

New degradable cationic ester lipids with `T-shape'' configurations were synthesized and tested for gene delivery carrier. Their transfection efficiency and toxicity were compared with commercially available cationic lipids, DOTMA, DOSPA, and DC-Chol. They showed efficient transfection activity and almost no toxicity on mammalian cell lines. Their ester bond degradation was monitored by 1H NMR. [Copyright &y& Elsevier]

B Introduction: b The prognostic significance of R1 resection for pancreatic ductal adenocarcinoma (PDAC) has varied in the literature due to a lack of consensus on the definition of various resection margin/surfaces. The safety margins for all circumferential margin/surfaces (anterior, posterior, SMV/PV groove, SMA) were recorded in millimeters. In contrast, involvement of the SMA margin and SMV/PV groove by both 0mm and 1mm rules was correlated with significantly decreased OS and DFS. [Extracted from the article]