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Introduction Mirizzi syndrome is an infrequent complication of long-standing cholelithiasis. Extrinsic compression of the common hepatic duct is usually caused by an impacted stone in Hartmann's pouch or cystic duct resulting in the development of cholecystobiliary fistula. This syndrome is classified based on the presence and severity of cholecystobiliary fistula. Mirizzi syndrome is challenging to diagnose preoperatively and may require complex biliary surgical procedures for resolution. Results We present three patients with Mirizzi syndrome with different clinical presentations. All were successfully treated by cholangioscopy with electrohydraulic lithotripsy. Endoscopic treatment is a safe alternative with a high success rate. Single-operator cholangioscopy combined with lithotripsy has been shown to have a 90–100% success rate in the treatment of biliary stones. Conclusion Herein, we present our experience treating Mirizzi syndrome with single-operator cholangioscopy guided electrohydraulic lithotripsy. Difficult management of Mirizzi syndrome has led to research of new treatment options to minimize the risk of high-rate complications. Single-operator cholangioscopy in combination with laser lithotripsy is an adequate and safe alternative for the treatment of this condition., Highlights • Mirizzi syndrome has no current gold-standard for treatment. Avoiding damage to the biliary tract has been a challenge. • Adequate management is achieved with direct visualization aided of cholangioscopy and lithotripsy. • Mirizzi syndrome can have different clinical presentations.

Lambert-Eaton syndrome is a rare paraneoplastic disorder of the neuromuscular junction, characterized by impaired release of acetylcholine, which causes proximal muscle weakness, depressed tendon reflexes, and autonomic changes. Most cases of Lambert-Eaton syndrome present in small-cell lung carcinoma, and only a few cases have been reported in other lung subtypes. Herein, we report a case of 69 years old male patient with Lambert-Eaton syndrome as a rare association with a pulmonary large-cell neuroendocrine carcinoma, which presented 5 months before neoplasm diagnosis. A lobectomy was auspiciously performed. A review of the literature is also presented.

We present a fully-automated CCD testbench. The system performs all the tests in about 12 hours, and when done reduces the data, grading the device and presenting the results in the form of both a pdf report and web-based tables . All the data goes automatically to a database where both the raw and processed data can be visualized and compared with other devices, allowing for detector statistical graphs (number of devices over certain threshold in any given parameter, etc). The testbench was developed in the context of a FermiLab and CTIO collaboration for the packaging and characterization of the red and NIR science ccds for the Dark Energy Spectroscopic Instrument (DESI), where over 40 devices were tested. The system was further expanded at CTIO to be used with any ccd or detector controller. The characterization includes non-linearity (high and low), full well, flats and darks cosmetics (hot and dark pixels, bad columns,etc), dark current, noise, CTE, absolute QE and lateral diffusion.

The Coherent Neutrino-Nucleus Interaction Experiment (CONNIE) uses low-noise fully depleted charge-coupled devices (CCDs) with the goal of measuring low-energy recoils from coherent elastic scattering (CE$\nu$NS) of reactor antineutrinos with silicon nuclei and testing nonstandard neutrino interactions (NSI). We report here the first results of the detector array deployed in 2016, considering an active mass 47.6 g (8 CCDs), which is operating at a distance of 30 m from the core of the Angra 2 nuclear reactor, with a thermal power of 3.8 GW. A search for neutrino events is performed by comparing data collected with reactor on (2.1 kg-day) and reactor off (1.6 kg-day). The results show no excess in the reactor-on data, reaching the world record sensitivity down to recoil energies of about 1 keV (0.1 keV electron-equivalent). A 95% confidence level limit for new physics is established at an event rate of 40 times the one expected from the standard model at this energy scale. The results presented here provide a new window to low-energy neutrino physics, allowing one to explore for the first time the energies accessible through the low threshold of CCDs. They will lead to new constrains on NSI from the CE$\nu$NS of antineutrinos from nuclear reactors., Comment: Updated to match the version accepted for publication in Physical Review D

Undocumented Latina/o college students face obstacles and stressors; their stressful experiences and academic strengths merit empirical attention. This cross-sectional, mixed-methods study explored stress, depression, grit, and grade point average (GPA) of 84 non-citizen, Latina/o first-generation college students with a comparison group of 180 citizen, Latina/o first-generation college students in Maryland. Qualitative interviews were conducted with 21 non-citizens and 26 citizens, after conducting a quantitative online survey. Immigrant status moderated the relation between depression and GPA in addition to grit and depression. Qualitative findings suggested that stress for citizens and non-citizens centered on financing college, but non-citizens faced additional stress due to policies pertaining to immigration status. Both groups displayed grit in navigating obstacles and contained their emotions with positive self-talk, but most non-citizens did not turn to anyone outside of the family for support. Findings hold implications for ecological processes and achievement among Latina/o undocumented college students.

Student affairs practitioners at a large, mid-Atlantic research university created a learning community directed by the student union to support community college transfer students. The authors examined qualitative data and pre/post surveys from 40 learning community participants in the program’s pilot year. Results suggested favorable effects of participation with regard to civic engagement and mental health and descriptions of major challenges and supports encountered among this group of community college transfer students.

The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5,PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥ 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure–activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with >80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.

Both JNK and LRRK2 are associated with Parkinson's disease (PD). Here we report a reasonably selective and potent kinase inhibitor (compound 6) that bound to both JNK and LRRK2 (a dual inhibitor). A bidentate-binding strategy that simultaneously utilized the ATP hinge binding and a unique protein surface site outside of the ATP pocket was applied to the design and identification of this kind of inhibitor. Compound 6 was a potent JNK3 and modest LRRK2 dual inhibitor with an enzyme IC50 value of 12 nM and 99 nM (LRRK2-G2019S), respectively. Compound 6 also exhibited good cell potency, inhibited LRRK2:G2019S-induced mitochondrial dysfunction in SHSY5Y cells, and was demonstrated to be reasonably selective against a panel of 116 kinases from representative kinase families. Design of such a probe molecule may help enable testing if dual JNK and LRRK2 inhibitions have added or synergistic efficacy in protecting against neurodegeneration in PD.

In this study, we exposed adult rats to chronic variable stress and tested the hypothesis that previous early-life exposure to stress changes the manner in which older subjects respond to aversive conditions. To this end, we analyzed the cytogenic changes in the hippocampus and hippocampal-dependent spatial learning performance. The experiments were performed on 18-month-old male rats divided into 4 groups as follows: Control (old rats under standard laboratory conditions), Early-life stress (old rats who were exposed to environmental noise from postnatal days 21 to 35), Chronic variable stress + Early-life stress (old rats exposed to a chronic stress protocol who were previously exposed to the early-life noise stress) and Chronic variable stress (old rats who were exposed only to the chronic stress protocol). The Morris Water Maze (MWM) was employed to evaluate the spatial learning abilities of the rats at the end of the experiment. Immunohistochemistry against 5’Bromodeoxiuridine (BrdU) and glial fibrillar acidic protein (GFAP) was also conducted in the DG, CA1, CA2 and CA3 regions of the hippocampus. We confocally analyzed the cytogenic (BrdU-labeled cells) and astrogenic (BrdU+GFAP-labeled cells) changes produced by these conditions. Using this procedure, we found that stress diminished the total number of BrdU+ cells over the main proliferative area of the hippocampus (i.e., the dentate gyrus) but increased the astrocyte phenotypes (GFAP+BrdU). The depleted BrdU+ cells were restored when the senile rats also experienced stress at the early stages of life. The MWM assessment demonstrated that stress also impairs the ability of the rats to learn the task. This impairment was not present when the stressful experience was preceded by the early-life exposure. Thus, our results support the idea that previous exposure to mild stressing agents may have beneficial effects on aged subjects.

Three JNK isoforms, JNK1, JNK2, and JNK3 have been reported and unique biological function has been ascribed to each. It is unknown if selective inhibition of these isoforms would confer therapeutic or safety benefit. To probe JNK isoform function we designed JNK2/3 inhibitors that have >30-fold selectivity over JNK1. Utilizing site-directed mutagenesis and x-ray crystallography we identified L144 in JNK3 as a key residue for selectivity. To test whether JNK2/3 selective inhibitors protect human dopaminergic neurons against neurotoxin-induced mitochondrial dysfunction, we monitored reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP). The results showed that JNK2/3 selective inhibitors protected against 6-hydroxydopamine-induced ROS generation and MMP depolarization. These results suggest that it was possible to develop JNK2/3 selective inhibitors and that residues in hydrophobic pocket I were responsible for selectivity. Moreover, the findings also suggest that inhibition of JNK2/3 likely contributed to protecting mitochondrial function and prevented ultimate cell death.

The effect of blanching and drying on water loss and oil uptake during potato slice frying was studied. Two pretreatments were carried out for the slices: (i) blanching in hot water at 85°C for 3.5 min; (ii) blanching in hot water at 85°C for 3.5 min and then, air-dried until a moisture content of 60 % (wet basis) was obtained. A control treatment, consisting of unblanched potato slices not air-dried was also conducted. After the pretreatments, potato slices were deep-fried in sunflower oil at 120, 150, and 180°C. With respect to the control treatment, blanching provided an increase while blanching-drying a decrease of the oil uptake. Two models, based on Fick's law, were used to describe water loss during frying. The first one is the classic model with an effective moisture diffusion coefficient, which assumed a constant value. The second model considers that the diffusion coefficient varies during the frying process. The variable diffusivity model adjusted the experimental data much better than the cons...

A novel series of 2-aminopyridopyrimidinone based JNK (c-jun N-terminal kinase) inhibitors were discovered and developed. Structure–activity relationships (SARs) were systematically developed utilizing biochemical and cell based assays and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies. Through the optimization of lead compound 1, several potent and selective JNK inhibitors with high oral bioavailability were developed. Inhibitor 13 was a potent JNK3 inhibitor (IC50 = 15 nM), had high selectivity against p38 (IC50 > 10 μM), had high potency in functional cell based assays, and had high stability in human liver microsome (t1/2 = 76 min), a clean CYP-450 inhibition profile, and excellent oral bioavailability (%F = 87). Moreover, cocrystal structures of compounds 13 and 22 in JNK3 were solved at 2.0 A. These structures elucidated the binding mode (Type-I binding) and can pave the way for further inhibitor design of this pyridopyrimidinone scaffold for JNK inhibition.

The c-jun N-terminal kinase 3 (JNK3) is expressed primarily in the brain. Numerous reports have shown that inhibition of JNK3 is a promising strategy for treatment of neurodegeneration. The optimization of aminopyrazole-based JNK3 inhibitors with improved potency, isoform selectivity, and pharmacological properties by structure-activity relationship (SAR) studies utilizing biochemical and cell-based assays, and structure-based drug design is reported. These inhibitors had high selectivity over JNK1 and p38α, minimal cytotoxicity, potent inhibition of 6-OHDA-induced mitochondrial membrane potential dissipation and ROS generation, and good drug metabolism and pharmacokinetic (DMPK) properties for iv dosing. 26n was profiled against 464 kinases and was found to be highly selective hitting only seven kinases with80% inhibition at 10 μM. Moreover, 26n showed good solubility, good brain penetration, and good DMPK properties. Finally, the crystal structure of 26k in complex with JNK3 was solved at 1.8 Å to explore the binding mode of aminopyrazole based JNK3 inhibitors.