We describe the design, manufacture, and performance of bare-fiber integral field units (IFUs) for the SDSS-IV survey MaNGA (Mapping Nearby Galaxies at APO) on the the Sloan 2.5 m telescope at Apache Point Observatory (APO). MaNGA is a luminosity-selected integral-field spectroscopic survey of 10 4 local galaxies covering 360-1030 nm at R ∼ 2200. The IFUs have hexagonal dense packing of fibers with packing regularity of 3 µm (RMS), and throughput of 96±0.5% from 350 nm to 1 µm in the lab. Their sizes range from 19 to 127 fibers (3-7 hexagonal layers) using Polymicro FBP 120:132:150 µm core:clad:buffer fibers to reach a fill fraction of 56%. High throughput (and low focal-ratio degradation) is achieved by maintaining the fiber cladding and buffer intact, ensuring excellent surface polish, and applying a multi-layer AR coating of the input and output surfaces. In operations on-sky, the IFUs show only an additional 2.3% FRD-related variability in throughput despite repeated mechanical stressing during plate plugging (however other losses are present). The IFUs achieve on-sky throughput 5% above the single-fiber feeds used in SDSS-III/BOSS, attributable to equivalent performance compared to single fibers and additional gains from the AR coating. The manufacturing process is geared toward mass-production of high-multiplex systems. The low-stress process involves a precision ferrule with hexagonal inner shape designed to lead inserted fibers to settle in a dense hexagonal pattern. The ferrule inner diameter is tapered at progressively shallower angles toward its tip and the final 2 mm are straight and only a few micron larger than necessary to hold the desired number of fibers. Our IFU manufacturing process scales easily to accommodate other fiber sizes and can produce IFUs with substantially larger fiber counts. To assure quality, automated testing in a simple and inexpensive system enables complete characterization of throughput and fiber metrology. Future applications include larger IFUs, higher fill-factors with stripped buffer, de-cladding, and lenslet coupling.

The fourth generation of the Sloan

SummaryOnce melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy.

Recently the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune-microenvironment can act as source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNFα as a crucial melanoma-growth factor that provides resistance to MAPK pathway inhibitors through the lineage-transcription factor MITF. Most strikingly, in BRAF mutant melanomas of patients and BRafV600E-melanoma allografts MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNFα and MITF expression. Inhibiting TNFα-signaling with IκB-kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells, but also the microenvironment. In summary, we identify the immune-microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma.

Repeated methamphetamine (METH) administration to animals can result in long-lasting decreases in brain dopamine (DA) and serotonin (5-HT) content. Calcitriol, the active metabolite of vitamin D, has potent effects on brain cells, both in vitro and in vivo, including the ability to upregulate trophic factors and protect against various lesions. The present experiments were designed to examine the ability of calcitriol to protect against METH-induced reductions in striatal and nucleus accumbens levels of DA and 5-HT. Male Fischer-344 rats were administered vehicle or calcitriol (1 microg/kg, s.c.) once a day for eight consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline four times in 1 day at 2-h intervals. Seven days later the striata and accumbens were harvested from the animals for high-performance liquid chromatography (HPLC) analysis of monoamines and metabolites. In animals treated with vehicle and METH, there were significant reductions in DA, 5-HT, and their metabolites in both the striatum and accumbens. In animals treated with calcitriol and METH, the magnitude of the METH-induced reductions in DA, 5-HT, and metabolites was substantially and significantly attenuated. The calcitriol treatments did not reduce the hyperthermia associated with multiple injections of METH, indicating that the neuroprotective effects of calcitriol are not due to the prevention of increases in body temperature. These results suggest that calcitriol can provide significant protection against the DA- and 5-HT-depleting effects of neurotoxic doses of METH.

Our findings indicate a remarkable increase in bladder alpha1dAR mRNA and protein expression after 6 weeks of obstruction and resultant detrusor hypertrophy. This finding is potentially important since alpha1dARs have 10 to 100-fold higher affinity for the endogenous neurotransmitter norepinephrine than the alpha1a or alpha1bAR subtypes. These findings imply that targeting alpha1d may provide a new therapeutic approach for controlling bladder irritative symptoms and possibly detrusor overactivity associated with bladder outlet obstruction.

Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a “MITF‐high” phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance “AXL‐high” phenotype. > 50% of melanomas progress with enriched “AXL‐high” populations, and because AXL is linked to de‐differentiation and invasiveness avoiding an “AXL‐high relapse” is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF‐induced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK re‐activation in a paracrine manner. Most importantly, EDN1 not only supports MITF‐high populations through the endothelin receptor B (EDNRB), but also AXL‐high populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXL‐high‐expressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXL‐high cells.

Calcitriol has been implicated as an agent that has neuroprotective effects in various animal models of diseases, possibly by upregulating glial cell line-derived neurotrophic factor (GDNF). The present study examined the neuroprotective effects of calcitriol in a model of early Parkinson's disease. Rats were treated daily with calcitriol or saline for 7 days before an intraventricular injection of 6-hydroxydopamine (6-OHDA), and then for 1 day or daily for 3(1/2) to 4 weeks after lesioning. Evoked overflow and tissue content of dopamine (DA) were determined 3(1/2) to 4 weeks post lesion. The 8-day calcitriol treatment did not attenuate 6-OHDA-induced decreases in evoked overflow of DA, nor did it protect against 6-OHDA-induced reductions in tissue levels of DA in the striatum or substantia nigra. However, the long-term calcitriol treatment did significantly increase evoked overflow of DA, as well as the amount of DA in the striatum, compared to saline treated animals. GDNF was significantly increased in the substantia nigra, but not in the striatum, of non-lesioned, calcitriol treated rats. These results suggest that long-term treatment with calcitriol can provide partial protection for dopaminergic neurons against the effects of intraventricularly administered 6-OHDA.