BTBR ob/ob mouse model of type 2 diabetes exhibits early loss of retinal function and retinal inflammation followed by late vascular changes

AIMS/HYPOTHESIS: Diabetic retinopathy is increasing in prevalence worldwide and is fast becoming a global epidemic and a leading cause of visual loss. Current therapies are limited, and the development of effective treatments for diabetic retinopathy requires a greater in-depth knowledge of disease progression and suitable modelling of diabetic retinopathy in animals. The aim of this study was to assess the early pathological changes in retinal morphology and neuronal, inflammatory and vascular features consistent with diabetic retinopathy in the ob/ob mouse model of type 2 diabetes, to investigate whether features similar to those in human diabetic retinopathy were present. METHODS: Male and female wild-type (+/+), heterozygous (+/−) and homozygous (−/−) BTBR ob/ob mice were examined at 6, 10, 15 and 20 weeks of age. Animals were weighed and blood glucose was measured. TUNEL and brain-specific homeobox/POU domain protein 3A (BRN3A) markers were used to examine retinal ganglion cells. We used immunostaining (collagen IV and platelet endothelial cell adhesion molecule [PECAM]/CD31), spectral domain optical coherence tomography and vitreous fluorophotometry to investigate vascular morphology and permeability. Oscillatory potential and photopic and scotopic electroretinograms helped to differentiate neuronal phenotypes. Concanavalin A leucostasis and immunostaining with glial fibrillary acidic protein (GFAP) and ionised calcium-binding adapter molecule 1 (IBA-1) identified differences in inflammatory status. Paraffin sections and transmission electron microscopy were used to reveal changes in the thickness and structure of the retinal layer. RESULTS: Following the development of obesity and hyperglycaemia (p < 0.001), early functional deficits (p < 0.001) and thinning of the inner retina (p < 0.001) were identified. Glial activation, leucostasis (p < 0.05) and a shift in microglia/macrophage phenotype were observed before microvascular degeneration (p < 0.05) and elevated vascular permeability occurred (p < 0.05). CONCLUSION/INTERPRETATION: The development of diabetic retinopathy in the ob/ob mouse represents a platform that will enable the development of new therapies, particularly for the early stages of disease

Sensitivity to musical emotion is influenced by tonal structure in congenital amusia

Emotional communication in music depends on multiple attributes including psychoacoustic features and tonal system information, the latter of which is unique to music. The present study investigated whether congenital amusia, a lifelong disorder of musical processing, impacts sensitivity to musical emotion elicited by timbre and tonal system information. Twenty-six amusics and 26 matched controls made tension judgments on Western (familiar) and Indian (unfamiliar) melodies played on piano and sitar. Like controls, amusics used timbre cues to judge musical tension in Western and Indian melodies. While controls assigned significantly lower tension ratings to Western melodies compared to Indian melodies, thus showing a tonal familiarity effect on tension ratings, amusics provided comparable tension ratings for Western and Indian melodies on both timbres. Furthermore, amusics rated Western melodies as more tense compared to controls, as they relied less on tonality cues than controls in rating tension for Western melodies. The implications of these findings in terms of emotional responses to music are discussed

Proteomic Analysis of the Dysferlin Protein Complex Unveils Its Importance for Sarcolemmal Maintenance and Integrity

Dysferlin is critical for repair of muscle membranes after damage. Mutations in dysferlin lead to a progressive muscular dystrophy. Recent studies suggest additional roles for dysferlin. We set out to study dysferlin's protein-protein interactions to obtain comprehensive knowledge of dysferlin functionalities in a myogenic context. We developed a robust and reproducible method to isolate dysferlin protein complexes from cells and tissue. We analyzed the composition of these complexes in cultured myoblasts, myotubes and skeletal muscle tissue by mass spectrometry and subsequently inferred potential protein functions through bioinformatics analyses. Our data confirm previously reported interactions and support a function for dysferlin as a vesicle trafficking protein. In addition novel potential functionalities were uncovered, including phagocytosis and focal adhesion. Our data reveal that the dysferlin protein complex has a dynamic composition as a function of myogenic differentiation. We provide additional experimental evidence and show dysferlin localization to, and interaction with the focal adhesion protein vinculin at the sarcolemma. Finally, our studies reveal evidence for cross-talk between dysferlin and its protein family member myoferlin. Together our analyses show that dysferlin is not only a membrane repair protein but also important for muscle membrane maintenance and integrity

Changing circumpolar distributions and isoscapes of Antarctic krill: Indo‐Pacific habitat refuges counter long‐term degradation of the Atlantic sector

The Southern Ocean provides strong contrasts in rates and directions of change in temperature and sea ice between its sectors, but it is unknown how these affect plankton species that are distributed right around Antarctica. Here, we quantify the changing circumpolar distributions of Antarctic krill, based on the CHINARE 2013/14 circum-Antarctic expedition, plus independent analyses of compiled abundance data (KRILLBASE:1926–2016). In the 1920s–1930s, average krill densities in the Atlantic-Bellingshausen sector were eight times those in the other sectors. More recently, however, the concentration factor has dropped to only about twofold. This reflects a rebalancing broadly commensurate with climatic forcing: krill densities declined in the Atlantic Bellingshausen sector which has warmed and lost sea ice, densities may have increased in the Ross-Pacific sector which showed the opposite climatic trend, while densities showed no significant changes in the more stable Lazarev-Indian sectors. Such changes would impact circumpolar food webs, so to better define these we examined circumpolar trends of isotopic values in krill and other zooplankton based on the CHINARE cruise and a literature meta-analysis. Krill δ15N values ranged significantly between sectors from 2.21‰ (Indian) to 3.59‰ (Ross-Pacific), about half a trophic level lower than another key euphausiid, Thysanoessa macrura. These isoscapes form a baseline for interpreting the reliance of predators on euphausiids, within the varying food webs around the continent. Overall, we suggest that the Indo-Pacific sector has acted as a refuge for the circumpolar krill stock while conditions for them deteriorated rapidly in the Atlantic sector

International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist

Acquired and congenital disorders of sung performance: A review.

Many believe that the majority of people are unable to carry a tune. Yet, this widespread idea underestimates the singing abilities of the layman. Most occasional singers can sing in tune and in time, provided that they perform at a slow tempo. Here we characterize proficient singing in the general population and identify its neuronal underpinnings by reviewing behavioral and neuroimaging studies. In addition, poor singing resulting from a brain injury or neurogenetic disorder (i.e., tone deafness or congenital amusia) is examined. Different lines of evidence converge in indicating that poor singing is not a monolithic deficit. A variety of poor-singing "phenotypes" are described, with or without concurrent perceptual deficits. In addition, particular attention is paid to the dissociations between specific abilities in poor singers (e.g., production of absolute vs. relative pitch, pitch vs. time accuracy). Such diversity of impairments in poor singers can be traced to different faulty mechanisms within the vocal sensorimotor loop, such as pitch perception and sensorimotor integration

Impact of direct‐acting antiviral agents on liver function in patients with chronic hepatitis C virus infection

© 2020 The Authors. Journal of Viral Hepatitis published by John Wiley & Sons Ltd Whilst the benefit of direct-acting antiviral agents (DAAs) in achieving sustained virological response (SVR) is now well-accepted, their impact on liver function, particularly in relation to achievement of SVR, has not been well documented. We studied 2394 patients with chronic HCV infection, 1276 receiving DAAs and 1118 interferon-based therapy. Liver function was assessed by the albumin-bilirubin (ALBI) score or grade. Overall survival according to SVR status and baseline ALBI grade was examined. We also studied time to first decompensation according to ALBI grade, as well as longitudinal changes in ALBI score over time according to SVR. Among the patients receiving DAAs, 89% achieved SVR (Japan=99%, UK=78%). Amongst the decompensated patients in the UK cohort, three distinct risk groups according to ALBI grade at baseline were observed. The UK patients receiving DAAs, who had predominantly decompensated disease, showed clear evidence of improvement of liver function detectable within 2years of the start of treatment, especially in those achieving SVR. These early changes in liver function were very similar to those observed in the first 2-3years after interferon-based therapy. DAAs improve liver function especially in those with decompensated disease who achieve SVR. Experience with interferon-based therapy suggests that failure to achieve SVR is associated with long-term decline in liver function and, in contrast, patients who do achieve SVR can expect long-term disease improvement and subsequent stabilization of liver function. Our initial analysis suggests that those receiving DAAs are likely, in the long term, to follow a similar course

The mechanism of speech processing in congenital amusia: Evidence from Mandarin speakers

Congenital amusia is a neuro-developmental disorder of pitch perception that causes severe problems with music processing but only subtle difficulties in speech processing. This study investigated speech processing in a group of Mandarin speakers with congenital amusia. Thirteen Mandarin amusics and thirteen matched controls participated in a set of tone and intonation perception tasks and two pitch threshold tasks. Compared with controls, amusics showed impaired performance on word discrimination in natural speech and their gliding tone analogs. They also performed worse than controls on discriminating gliding tone sequences derived from statements and questions, and showed elevated thresholds for pitch change detection and pitch direction discrimination. However, they performed as well as controls on word identification, and on statement-question identification and discrimination in natural speech. Overall, tasks that involved multiple acoustic cues to communicative meaning were not impacted by amusia. Only when the tasks relied mainly on pitch sensitivity did amusics show impaired performance compared to controls. These findings help explain why amusia only affects speech processing in subtle ways. Further studies on a larger sample of Mandarin amusics and on amusics of other language backgrounds are needed to consolidate these results