A mutation in the Warburg syndrome gene, <i>RAB3GAP1</i>, causes a similar syndrome with polyneuropathy and neuronal vacuolation in Black Russian Terrier dogs

AbstractAn autosomal recessive disease of Black Russian Terriers was previously described as a juvenile-onset, laryngeal paralysis and polyneuropathy similar to Charcot Marie Tooth disease in humans. We found that in addition to an axonal neuropathy, affected dogs exhibit microphthalmia, cataracts, and miotic pupils. On histopathology, affected dogs exhibit a spongiform encephalopathy characterized by accumulations of abnormal, membrane-bound vacuoles of various sizes in neuronal cell bodies, axons and adrenal cells. DNA from an individual dog with this polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV) was used to generate a whole genome sequence which contained a homozygous RAB3GAP1:c.743delC mutation that was absent from 73 control canine whole genome sequences. An additional 12 Black Russian Terriers with POANV were RAB3GAP1:c.743delC homozygotes. DNA samples from 249 Black Russian Terriers with no known signs of POANV were either heterozygotes or homozygous for the reference allele. Mutations in human RAB3GAP1 cause Warburg micro syndrome (WARBM), a severe developmental disorder characterized by abnormalities of the eye, genitals and nervous system including a predominantly axonal peripheral neuropathy. RAB3GAP1 encodes the catalytic subunit of a GTPase activator protein and guanine exchange factor for Rab3 and Rab18 respectively. Rab proteins are involved in membrane trafficking in the endoplasmic reticulum, axonal transport, autophagy and synaptic transmission. The neuronal vacuolation and membranous inclusions and vacuoles in axons seen in this canine disorder likely reflect alterations of these processes. Thus, this canine disease could serve as a model for WARBM and provide insight into its pathogenesis and treatment

Supplement: "Localization and broadband follow-up of the gravitational-wave transient GW150914" (2016, ApJL, 826, L13)

This Supplement provides supporting material for Abbott et al. (2016a). We briefly summarize past electromagnetic (EM) follow-up efforts as well as the organization and policy of the current EM follow-up program. We compare the four probability sky maps produced for the gravitational-wave transient GW150914, and provide additional details of the EM follow-up observations that were performed in the different bands

A physical approach to protein structure prediction.

We describe our global optimization method called Stochastic Perturbation with Soft Constraints (SPSC), which uses information from known proteins to predict secondary structure, but not in the tertiary structure predictions or in generating the terms of the physics-based energy function. Our approach is also characterized by the use of an all atom energy function that includes a novel hydrophobic solvation function derived from experiments that shows promising ability for energy discrimination against misfolded structures. We present the results obtained using our SPSC method and energy function for blind prediction in the 4th Critical Assessment of Techniques for Protein Structure Prediction competition, and show that our approach is more effective on targets for which less information from known proteins is available. In fact our SPSC method produced the best prediction for one of the most difficult targets of the competition, a new fold protein of 240 amino acids

Entwicklung und Validierung einer Checkliste zur Bewertung von Medizin- und Pflegestudierenden aus Sicht von Simulationspatient*innen in OSCEs

Fragestellung/Zielsetzung: Obwohl der*die Patient*in im Mittelpunkt der ärztlichen Behandlung oder Pflege steht, fehlt die Patient*Innenperspektive häufig in der Bewertung der ärztlichen und pflegerischen Fähigkeiten von Studierenden. Um eine solche Bewertung zu ermöglichen, werden wir eine geeignete Checkliste entwickeln und validieren. Bei der Bewertung steht vor allem der Beziehungsaufbau von den Studierenden mit den Simulationspatient*innen (SPs) im Vordergrund. Methoden: Die Checkliste wird basierend auf einer eigenen Vorstudie [1] und der Literatur [2], [3] entwickelt (Inhaltsvalidität). Nach einem Vortest im formativen OSCE für Humanmedizinstudierende im 3. Studienjahr, wird die Checkliste entsprechend der Rückmeldungen der SPs finalisiert (Antwortprozess). Die finale Checkliste wird in drei summativen OSCEs getestet werden (im Juni 2021 mit Humanmedizinstudierenden im 3. Studienjahr in Bern; im August 2021 mit Pflegestudierenden im 3. Studienjahr am Bildungszentrum Pflege in Bern und mit Humanmedizinstudierenden im 3. Studienjahr an der Universität Tübingen). Mit diesen Daten werden wir die interne Struktur, die Beziehung zu anderen Variablen (Jefferson’s Empathie-Skala: Sicht der Patient*innen) und die Konsequenzen der neuen Bewertung auf die Messgenauigkeit des OSCEs und die Resultate der Studierenden analysieren. Ergebnisse: An der Tagung werden wir die finale Checkliste vorstellen, sowie unsere Ergebnisse bezüglich der Validierung der Checkliste. Die finale Checkliste wird aus etwa 5 Checklisten Items und einer Globalbeurteilung bestehen. Wir erwarten, dass sie moderat bis hoch mit der Jefferson’s Empathie-Skala aus Sicht der Patient*innen korrelieren wird. Durch den Einbezug der Patient*Innenperspektive erwarten wir eine verbessere Validität des OSCEs. Die Resultate der Kandidat*innen sollten sich leicht verändern und besser ihren tatsächlichen Leistungen entsprechen. Diskussion: Mittels unserer neuen Checkliste können SPs Medizin- und Pflegestudierende in OSCEs bewerten. Hierdurch kann die Patientenperspektive in die Bewertung der Studierenden miteinbezogen werden. Zu diskutieren bleibt die Frage, wie hoch die Bewertung durch die SPs im Vergleich zu der Bewertung durch die Examinatoren gewichtet werden soll

MRI-Guided Motion-Corrected PET Image Reconstruction for Cardiac PET/MRI

Simultaneous PET/MRI has shown potential for the comprehensive assessment of myocardial health from a single examination. Furthermore, MRI-derived respiratory motion information, when incorporated into the PET image reconstruction, has been shown to improve PET image quality. Separately, MRI-based anatomically guided PET image reconstruction has been shown to effectively denoise images, but this denoising has so far been demonstrated mainly in brain imaging. To date, the combined benefits of motion compensation and anatomic guidance have not been demonstrated for myocardial PET/MRI. This work addressed this lack by proposing a single cardiac PET/MR image reconstruction framework that fully utilizes MRI-derived information to allow both motion compensation and anatomic guidance within the reconstruction. Methods: Fifteen patients underwent an (18)F-FDG cardiac PET/MRI scan with a previously introduced acquisition framework. The MRI data processing and image reconstruction pipeline produces respiratory motion fields and a high-resolution respiratory motion–corrected MR image with good tissue contrast. This MRI-derived information was then included in a respiratory motion–corrected, cardiac-gated, anatomically guided image reconstruction of the simultaneously acquired PET data. Reconstructions were evaluated by measuring myocardial contrast and noise and were compared with images from several comparative intermediate methods using the components of the proposed framework separately. Results: Including respiratory motion correction, cardiac gating, and anatomic guidance significantly increased contrast. In particular, myocardium–to–blood pool contrast increased by 143% on average (P < 0.0001), compared with conventional uncorrected, nonguided PET images. Furthermore, anatomic guidance significantly reduced image noise, by 16.1%, compared with nonguided image reconstruction (P < 0.0001). Conclusion: The proposed framework for MRI-derived motion compensation and anatomic guidance of cardiac PET data significantly improved image quality compared with alternative reconstruction methods. Each component of the reconstruction pipeline had a positive impact on the final image quality. These improvements have the potential to improve clinical interpretability and diagnosis based on cardiac PET/MR images