LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Synthesis of enantioenriched spirocyclic 2-arylpiperidines via kinetic resolution.

Kinetic resolution of N-Boc-spirocyclic 2-arylpiperidines with spiro substitution at C-4 was achieved with high enantiomeric ratios using the chiral base n-BuLi/sparteine. Cyclopropanation or metallaphotoredox catalysis were used to access the piperidines, which could be further functionalised without loss of enantiopurity, highlighting their use as potential 3D fragments for drug discovery.

Electrochemical Benzylic C(sp3)-H Direct Amidation.

Amide bonds are ubiquitous and found in a myriad of functional molecules. Although formed in a reliable and robust fashion, alternative amide bond disconnections provide flexibility and synthetic control. Herein we describe an electrochemical method to form the non-amide C-N bond from direct benzylic C(sp3)-H amidation. Our approach is applied toward the synthesis of secondary amides by coupling secondary benzylic substrates with substituted primary benzamides. The reaction has been scaled up to a multigram scale in flow.

Narrative review of management of cirrhosis during the treatment of hepatocellular carcinoma.

BACKGROUND AND OBJECTIVE: The management of hepatocellular carcinoma (HCC) and cirrhosis are closely linked. HCC most often occurs in the background of cirrhosis and can also lead to decompensation of underlying liver disease. The treatment of complications of cirrhosis is important to help reduce morbidity and mortality and allow for expanded treatment options of HCC. METHODS: We searched PubMed using search terms for cirrhosis and HCC. From this search, we selected references which appeared to be primary studies preferentially within the last 5 years, although also included select landmark studies which have shaped guidelines and recommendations. KEY CONTENT AND FINDINGS: The development of HCC and treatment of HCC can both cause decompensation of liver disease and worsening of liver function. For most patients, the development of HCC or progression of disease are the drivers of morbidity and mortality. However, it is important to closely monitor patients for complications of liver disease that develop either as a result of HCC or as a complication of HCC treatment, and this can have important implications on treatment options. Multidisciplinary team involvement including hepatologists, surgeons, radiologists, interventional radiologists, medical oncologists, and palliative care is essential in the care of patients with cirrhosis and HCC to help guide management decisions and treatment. CONCLUSIONS: The management of cirrhosis and HCC are both complex and interrelated. Through a multidisciplinary team approach we can best treat the complications of cirrhosis, allow for expanded treatment options, and improve quality of life through symptom management.

Kinetic Resolution of 2-Aryldihydroquinolines Using Lithiation - Synthesis of Chiral 1,2- and 1,4-Dihydroquinolines.

Highly enantiomerically enriched dihydrohydroquinolines were prepared in two steps from quinoline. Addition of aryllithiums to quinoline with tert-butoxycarbonyl (Boc) protection gave N-Boc-2-aryl-1,2-dihydroquinolines. These were treated with n-butyllithium and electrophilic trapping occurred exclusively at C-4 of the dihydroquinoline, a result supported by DFT studies. Variable temperature NMR spectroscopy gave kinetic data for the barrier to rotation of the carbonyl group (ΔG≠ ≈49 kJ mol-1 , 195 K). Lithiation using the diamine sparteine allowed kinetic resolutions with high enantioselectivities (enantiomer ratio up to 99 : 1). The enantioenriched 1,2-dihydroquinolines could be converted to 1,4-dihydroquinolines with retention of stereochemistry. Further functionalisation led to trisubstituted products. Reduction provided enantioenriched tetrahydroquinolines, whereas acid-promoted removal of Boc led to quinolines, and this was applied to a synthesis of the antimalarial compound M5717.

Photocatalysis and Kinetic Resolution by Lithiation to Give Enantioenriched 2-Arylpiperazines.

Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using n-BuLi/(+)-sparteine. This gave a range of piperazines with very high enantioselectivities. Further functionalizations gave enantioenriched 2,2-disubstituted piperazines, and either N-substituent can be removed selectively. Late-stage functionalizations of enantioenriched piperazine derivatives were demonstrated, including synthesis of a drug compound with glycogen synthase kinase (GSK)-3ß inhibitor activity with potential for treating Alzheimer's disease.

Kinetic Resolution of 2-Aryl-4-methylenepiperidines toward Enantioenriched Functionalizable Piperidine Fragments.

The base n-BuLi with sparteine allows a kinetic resolution of N-Boc-2-aryl-4-methylenepiperidines. The 2,2-disubstituted products and recovered starting materials were isolated with high enantiomeric ratios. From VT-NMR spectroscopy and DFT studies, the rate of rotation of the N-Boc group is fast. Lithiation and trapping of the enantioenriched starting materials gave 2,2-disubstituted piperidines with retention of stereochemistry. Functionalization of the 4-methylene group led to a variety of 2,4-disubstituted piperidines without loss of enantiopurity that could be useful building blocks for drug discovery.

Ultrasonic Sound Guide System with Eyeglass Device for the Visually Impaired.

The ultrasonic sound guide system presents the audio broadcasting system based on the inaudible ultrasonic sound to assist the indoor and outdoor navigation of the visually impaired. The transmitters are placed at the point of interest to propagate the frequency modulated voice signal in ultrasonic sound range. The dual channel receiver device is carried by the visually impaired person in the form of eyeglasses to receive the ultrasonic sound for the voice signal via demodulation. Since the ultrasonic sound demonstrates the acoustic properties, the velocity, directivity, attenuation, and superposition of ultrasonic sound provide the acoustic clue to the user for localizing the multiple transmitter positions by binaural localization capability. The visually impaired hear the designated voice signal and follow the signal attributions to arrive at the specific location. Due to the low microphone gain from side addressing, the time delay between the receiver channels demonstrates the high variance and high bias in end directions. However, the perception experiment shows the further prediction accuracy in end directions as compared to the center direction outcomes. The overall evaluations show the precise directional prediction for narrow- and wide-angle situations. The ultrasonic sound guide system is a useful device to localize places in the near field without touching braille.

Asymmetric Synthesis of 2-Arylindolines and 2,2-Disubstituted Indolines by Kinetic Resolution.

Kinetic resolution of 2-arylindolines (2,3-dihydroindoles) was achieved by treatment of their N-tert-butoxycarbonyl (Boc) derivatives with n-butyllithium and sparteine in toluene at -78 °C followed by electrophilic quench. The unreacted starting materials together with the 2,2-disubstituted products could be isolated with high enantiomer ratios. Variable temperature NMR spectroscopy showed that the rate of Boc rotation was fast (ΔG≠ ≈57 kJ/mol at 195 K). This was corroborated by DFT studies and by in situ ReactIR spectroscopy. The enantioenriched N-Boc-2-arylindolines were converted to 2,2-disubstituted products without significant loss in enantiopurity. Hence, either enantiomer of the 2,2-disubstituted products could be obtained with high selectivity from the same enantiomer of the chiral ligand sparteine (one from the kinetic resolution and the other from subsequent lithiation-trapping of the recovered starting material). Secondary amine products were prepared by removing the Boc group with acid to provide a way to access highly enantioenriched 2-aryl and 2,2-disubstituted indolines.

Single-Channel Multiple-Receiver Sound Source Localization System with Homomorphic Deconvolution and Linear Regression.

The conventional sound source localization systems require the significant complexity because of multiple synchronized analog-to-digital conversion channels as well as the scalable algorithms. This paper proposes a single-channel sound localization system for transport with multiple receivers. The individual receivers are connected by the single analog microphone network which provides the superimposed signal over simple connectivity based on asynchronized analog circuit. The proposed system consists of two computational stages as homomorphic deconvolution and machine learning stage. A previous study has verified the performance of time-of-flight estimation by utilizing the non-parametric and parametric homomorphic deconvolution algorithms. This paper employs the linear regression with supervised learning for angle-of-arrival prediction. Among the circular configurations of receiver positions, the optimal location is selected for three-receiver structure based on the extensive simulations. The non-parametric method presents the consistent performance and Yule-Walker parametric algorithm indicates the least accuracy. The Steiglitz-McBride parametric algorithm delivers the best predictions with reduced model order as well as other parameter values. The experiments in the anechoic chamber demonstrate the accurate predictions in proper ensemble length and model order.

Endoscopic Ultrasound Guided Gastroenterostomy: What Is the Learning Curve?

INTRODUCTION: Endoscopic ultrasound guided gastroenterostomy (EUS-GE) is a minimally invasive option for gastric outlet obstruction. It requires skills in endoscopic ultrasound, fluoroscopy, and lumen-apposing metal stent deployment. The aim of this study was to determine the learning curve for EUS-GE. METHODS: Consecutive patients undergoing EUS-GE by a single operator were included from a prospective registry over 3 years. Demographics, procedure info, postprocedure follow-up data, and adverse events were collected. Nonlinear regression and cumulative sum analyses were conducted for the learning curve. Clinical success was defined as tolerating a diet postprocedure. RESULTS: Twenty-three patients were included (39% male, mean age 65.8 y). Technical success was achieved in 22 (96%) patients. Clinical success was achieved in 21/22 (95%) patients. Average follow-up time 10.8 months (9.1 SD). Five patients had minor postprocedure complications; 1 patient had a periprocedural esophageal tear treated with clips. Four patients required repeat intervention for stent revision or removal if no longer needed.Median procedure time was 88 minutes (range: 45 to 140 min). Cumulative sum chart shows 88-minute procedure time was achieved at the seventh procedure indicating efficiency. Even with bridging of a misdeployed lumen-apposing metal stent, the procedure duration further reduced with consequent procedures indicating continued improvement with experience (nonlinear regression P<0.0001). CONCLUSIONS: Endoscopists experienced in EUS-GE achieve a reduction in procedure time over successive cases, with efficiency reached at 88 minutes and a learning rate of 7 cases. Misdeployed stents that require bridging add to the procedure time even after competency is achieved but do not affect the overall learning curve trend.