Niemann-Pick type C disease as proof-of-concept for intelligent biomarker panel selection in neurometabolic disorders.

AIM: Using Niemann-Pick type C disease (NPC) as a paradigm, we aimed to improve biomarker discovery in patients with neurometabolic disorders. METHOD: Using a multiplexed liquid chromatography tandem mass spectrometry dried bloodspot assay, we developed a selective intelligent biomarker panel to monitor known biomarkers N-palmitoyl-O-phosphocholineserine and 3ß,5α,6ß-trihydroxy-cholanoyl-glycine as well as compounds predicted to be affected in NPC pathology. We applied this panel to a clinically relevant paediatric patient cohort (n = 75; 35 males, 40 females; mean age 7 years 6 months, range 4 days-19 years 8 months) presenting with neurodevelopmental and/or neurodegenerative pathology, similar to that observed in NPC. RESULTS: The panel had a far superior performance compared with individual biomarkers. Namely, NPC-related established biomarkers used individually had 91% to 97% specificity but the combined panel had 100% specificity. Moreover, multivariate analysis revealed long-chain isoforms of glucosylceramide were elevated and very specific for patients with NPC. INTERPRETATION: Despite advancements in next-generation sequencing and precision medicine, neurological non-enzymatic disorders remain difficult to diagnose and lack robust biomarkers or routine functional testing for genetic variants of unknown significance. Biomarker panels may have better diagnostic accuracy than individual biomarkers in neurometabolic disorders, hence they can facilitate more prompt disease identification and implementation of emerging targeted, disease-specific therapies. WHAT THIS PAPER ADDS: Intelligent biomarker panel design can help expedite diagnosis in neurometabolic disorders. In Niemann-Pick type C disease, such a panel performed better than individual biomarkers. Biomarker panels are easy to implement and widely applicable to neurometabolic conditions.

The chemosensory system of the Drosophila larva: an overview of current understanding.

Animals must sense their surroundings and be able to distinguish between relevant and irrelevant cues. An enticing area of research aims to uncover the mechanisms by which animals respond to chemical signals that constitute critical sensory input. In this review, we describe the principles of a model chemosensory system: the Drosophila larva. While distinct in many ways, larval behaviour is reminiscent of the dogmatic goals of life: to reach a stage of reproductive potential. It takes into account a number of distinct and identifiable parameters to ultimately provoke or modulate appropriate behavioural output. In this light, we describe current knowledge of chemosensory anatomy, genetic components, and the processing logic of chemical cues. We outline recent advancements and summarize the hypothesized neural circuits of sensory systems. Furthermore, we note yet-unanswered questions to create a basis for further investigation of molecular and systemic mechanisms of chemosensation in Drosophila and beyond.

Taste sensing and sugar detection mechanisms in Drosophila larval primary taste center.

Despite the small number of gustatory sense neurons, Drosophila larvae are able to sense a wide range of chemicals. Although evidence for taste multimodality has been provided in single neurons, an overview of gustatory responses at the periphery is missing and hereby we explore whole-organ calcium imaging of the external taste center. We find that neurons can be activated by different combinations of taste modalities, including opposite hedonic valence and identify distinct temporal dynamics of response. Although sweet sensing has not been fully characterized so far in the external larval gustatory organ, we recorded responses elicited by sugar. Previous findings established that larval sugar sensing relies on the Gr43a pharyngeal receptor, but the question remains if external neurons contribute to this taste. Here, we postulate that external and internal gustation use distinct and complementary mechanisms in sugar sensing and we identify external sucrose sensing neurons.

Pulsed X-ray source with the pulse duration of 50 ns and the peak power of 70 MW for capturing moving objects.

BACKGROUND: Traditionally, X-ray systems for capturing moving objects consist of a continuous X-ray source and a detector that operates at a predetermined frame rate. OBJECTIVE: This study investigates the possibility of using pulsed X-ray source with an inductive energy storage device and a semiconductor opening switch for shooting moving objects. METHODS: The study uses a high-voltage pulse generator that has the following parameters namely, the pulse voltage amplitude up to 320 kV, the pulse current up to 240 A, the current pulse duration of about 50 ns, and the pulse repetition rate up to 2 kHz. The duration and intensity of glow for standard CsI:Tl and Gd2O2S:Tb X-ray phosphors after their irradiation with X-ray flashes of about 50 ns duration are investigated. After X-ray radiation is converted into light, the signal is recorded using semiconductor detectors. We acquired several images of an object moving at a speed of about 20 m/s. A semiconductor detector with phosphor, which operates in the mode of continuous signal accumulation, is used. RESULTS: When using the pulsed X-ray source and phosphors with a short afterglow, the individual frames can be obtained at the pulse repetition rate of several kilohertz, and the detector does not contain the residual luminescence from the previous frame by the arrival of the next frame. CONCLUSIONS: The X-ray source shows good pulse-to-pulse reproducibility of X-rays, and can be used to capture objects in motion at a frame rate of several kHz.