Cellular cholesterol transport proteins in diabetic nephropathy

published_or_final_versio

Collisionally Activated Dissociation and Electron Capture Dissociation Provide Complementary Structural Information for Branched Permethylated Oligosaccharides

Doubly charged sodiated and permethylated linear malto-oligosaccharides ({Glc}6-{Glc}9), branched N-linked glycans (high-mannose type GlcNAc2Man5-9, and complex asialo- and disialylated-biantennary glycans) were analyzed by tandem mass spectrometry using collisionally-activated dissociation (CAD) and “hot” electron capture dissociation (ECD) available in a custom-built ESI FTICR mass spectrometer. For linear permethylated malto-oligosaccharides, both CAD and “hot” ECD produced glycosidic cleavages (B, Y, C, and Z ions), cross-ring cleavages (A- and X-type), and internal cleavages (B/Y and C/Y type) to provide sequence and linkage information. For the branched N-linked glycans, CAD and “hot” ECD provided complementary structural information. CAD generated abundant B and Y fragment ions by glycosidic cleavages, whereas “hot” ECD produced dominant C and Z ions. A-type cross-ring cleavages were present in CAD spectra. Complementary A- and X-type cross-ring fragmentation pairs were generated by “hot” ECD, and these delineated the branching patterns and linkage positions. For example, 0, 4An and 3, 5An ions defined the linkage position of the major branch as the 6-position of the central core mannose residue. The internal fragments observed in CAD were more numerous and abundant than in “hot” ECD spectra. Since the triply charged (sodiated) molecular ion of the permethylated disialylated-biantennary N-linked glycan has relatively high abundance, it was isolated and fragmented in a “hot” ECD experiment and extensive fragment ions (glycosidic and complementary pairs of cross-ring cleavages) were generated to fully confirm the sequence, branching, and linkage assignments for this glycan

Chlorophyll dephytylase 1 and chlorophyll synthase: a chlorophyll salvage pathway for the turnover of photosystems I and II

Chlorophyll (Chl) is made up of the tetrapyrrole chlorophyllide and phytol, a diterpenoid alcohol. The photosynthetic protein complexes utilize Chl for light harvesting to produce biochemical energy for plant development. However, excess light and adverse environmental conditions facilitate generation of reactive oxygen species, which damage photosystems I and II (PSI and PSII) and induce their turnover. During this process, Chl is released, and is thought to be recycled via dephytylation and rephytylation. We previously demonstrated that Chl recycling in Arabidopsis under heat stress is mediated by the enzymes chlorophyll dephytylase 1 (CLD1) and chlorophyll synthase (CHLG) using chlg and cld1 mutants. Here, we show that the mutants with high CLD1/CHLG ratio, by different combinations of chlg‐1 (a knock‐down mutant) and the hyperactive cld1‐1 alleles, develop necrotic leaves when grown under long‐ and short‐day, but not continuous light conditions, owing to the accumulation of chlorophyllide in the dark. Combination of chlg‐1 with cld1‐4 (a knock‐out mutant) leads to reduced chlorophyllide accumulation and necrosis. The operation of CLD1 and CHLG as a Chl salvage pathway was also explored in the context of Chl recycling during the turnover of Chl‐binding proteins of the two photosystems. CLD1 was found to interact with CHLG and the light‐harvesting complex‐like proteins OHP1 and LIL3, implying that auxiliary factors are required for this process.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Ministry of Science and Technology, Taiwan http://dx.doi.org/10.13039/501100004663Peer Reviewe

Zero-shot Domain-sensitive Speech Recognition with Prompt-conditioning Fine-tuning

In this work, we propose a method to create domain-sensitive speech recognition models that utilize textual domain information by conditioning its generation on a given text prompt. This is accomplished by fine-tuning a pre-trained, end-to-end model (Whisper) to learn from demonstrations with prompt examples. We show that this ability can be generalized to different domains and even various prompt contexts, with our model gaining a Word Error Rate (WER) reduction of up to 33% on unseen datasets from various domains, such as medical conversation, air traffic control communication, and financial meetings. Considering the limited availability of audio-transcript pair data, we further extend our method to text-only fine-tuning to achieve domain sensitivity as well as domain adaptation. We demonstrate that our text-only fine-tuned model can also attend to various prompt contexts, with the model reaching the most WER reduction of 29% on the medical conversation dataset.Comment: F-T Liao and Y-C Chan contributed equall

Polycythemia vera as a presentation of renal angiomyolipoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Angiomyolipoma is a common benign renal tumor composed of thick-walled blood vessels, smooth muscle, and adipose tissue. It may be found incidentally during workup for suspected renal disease. Although angiomyolipoma may present as a palpable, tender renal mass with flank pain and gross or microscopic hematuria, many patients are asymptomatic. Erythrocytosis is an unusual presentation, and malignant transformation may be suspected. This report describes a rare case of a woman diagnosed with renal angiomyolipoma and polycythemia vera. The report discusses the differential diagnosis using erythropoietin, erythropoietin-receptor and Janus kinase 2.</p> <p>Case presentation</p> <p>A 79-year-old Chinese woman was diagnosed with erythrocytosis according to World Health Organization criteria. An upper left renal pole angiomyolipoma was successfully ablated after multiple phlebotomy treatments. Red cell count immediately returned to normal, but gradually increased after 4 months. Polycythemia vera was finally diagnosed by positive mutation of Janus kinase 2 and negative erythropoietin protein expression. Her clinical symptoms improved with regular phlebotomy and hydroxyurea treatment.</p> <p>Conclusion</p> <p>Concurrent occurence of angiomyolipoma and polycythemia vera is rare. Polycythemia vera can be easily missed. Polycythemia vera can be confirmed with high specificity and sensitivity by the acquired somatic mutation. Surgical intervention for this renal tumor should be avoided unless malignancy or renal cell carcinoma is suspected or to prevent spontaneous rupture of larger tumors.</p

Pathological granuloma fibrosis induced by agar-embedded Mycobacterium abscessus in C57BL/6JNarl mice

IntroductionPulmonary granuloma diseases caused by Mycobacterium abscessus (M. abscessus) have increased in past decades, and drug-resistance in this pathogen is a growing public health concern. Therefore, an animal model of chronic granuloma disease is urgently needed.MethodsIn this study, M. abscessus embedded within agar beads (agar-AB) was used to develop such a model in C57BL/6JNarl mice.ResultsChronic infection was sustained for at least 3 months after agar-AB infection, visible granulomas spread in the lungs, and giant cells and foamy cells appeared in the granulomas. More importantly, pulmonary fibrosis progressed for 3 months, and collagen fibers were detected by Masson trichrome staining. Further, inducible nitric oxide synthase (iNOS) was highly expressed within the alveolar space, and the fibrosis-mediator transforming growth factor beta (TGF-β) began to be expressed at 1 month. Hypoxia-inducible factor (HIF-1α) expression also increased, which aided in normalizing oxygen partial pressure.DiscussionAlthough the transient fibrosis persisted for only 3 months, and the pulmonary structure resolved when the pathogen was cleard, this pulmonary fibrosis model for M. abscessus infection will provide a novel test platform for development of new drugs, regimens, and therapies

Effect of P to A Mutation of the N-Terminal Residue Adjacent to the Rgd Motif on Rhodostomin: Importance of Dynamics in Integrin Recognition

Rhodostomin (Rho) is an RGD protein that specifically inhibits integrins. We found that Rho mutants with the P48A mutation 4.4–11.5 times more actively inhibited integrin α5β1. Structural analysis showed that they have a similar 3D conformation for the RGD loop. Docking analysis also showed no difference between their interactions with integrin α5β1. However, the backbone dynamics of RGD residues were different. The values of the R2 relaxation parameter for Rho residues R49 and D51 were 39% and 54% higher than those of the P48A mutant, which caused differences in S2, Rex, and τe. The S2 values of the P48A mutant residues R49, G50, and D51 were 29%, 14%, and 28% lower than those of Rho. The Rex values of Rho residues R49 and D51 were 0.91 s−1 and 1.42 s−1; however, no Rex was found for those of the P48A mutant. The τe values of Rho residues R49 and D51 were 9.5 and 5.1 times lower than those of P48A mutant. Mutational study showed that integrin α5β1 prefers its ligands to contain (G/A)RGD but not PRGD sequences for binding. These results demonstrate that the N-terminal proline residue adjacent to the RGD motif affect its function and dynamics, which suggests that the dynamic properties of the RGD motif may be important in Rho's interaction with integrin α5β1