Strategies for revision surgery after primary double-bundle anterior cruciate ligament (ACL) reconstruction

The purpose of this article was to discuss pre- and intra-operative considerations as well as surgical strategies for different femoral and tibial tunnel scenarios in revision surgery following primary double-bundle anterior cruciate ligament (ACL) reconstruction. Based on the current literature of ACL revision surgery and surgical experience, an algorithm for revision surgery after primary double-bundle ACL reconstruction was created. A guideline and flowchart were created using a case-based approached for revision surgery after primary double-bundle ACL reconstruction. Revision surgery after primary double-bundle ACL reconstruction can be a challenging procedure that requires flexibility and a repertoire of surgical techniques. The combination of pre-operative planning with 3D-CT reconstruction, in addition to careful intra-operative assessment, and the use of this flowchart can simplify the ACL revision procedure.

The neural correlates of visual and auditory cross-modal selective attention in aging

Age-related deficits in selective attention have been demonstrated to depend on the sensory modality through which targets and distractors are presented. Some of these investigations suggest a specific impairment of cross-modal auditory selective attention. For the first time, this study is taking on a whole brain approach while including a passive perception baseline, to investigate the neural underpinnings of selective attention across age groups, and taking the sensory modality of relevant and irrelevant (i.e., distracting) stimuli into account. Sixteen younger (mean age = 23.3 years) and 14 older (mean age = 65.3 years), healthy participants performed a series of delayed match-to-sample tasks, in which participants had to selectively attend to visual stimuli, selectively attend to auditory stimuli, or passively view and hear both types of stimuli, while undergoing 3T fMRI. The imaging analyses showed that areas recruited by cross-modal visual and auditory selective attention in both age groups included parts of the dorsal attention and frontoparietal control networks (i.e., intraparietal sulcus, insula, fusiform gyrus, anterior cingulate, and inferior frontal cortex). Most importantly, activation throughout the brain did not differ across age groups, suggesting intact brain function during cross-modal selective attention in older adults. Moreover, stronger brain activation during cross-modal visual vs. cross-modal auditory selective attention was found in both age groups, which is consistent with earlier accounts of visual dominance. In conclusion, these results do not support the hypothesized age-related deficit of cross-modal auditory selective attention. Instead, they suggest that the underlying neural correlates of cross-modal selective attention are similar in younger and older adults

The effect of hearing loss on age-related differences in neural distinctiveness

Age differences in cognitive performance have been shown to be overestimated if age-related hearing loss is not taken into account. Here, we investigated the role of age-related hearing loss on age differences in functional brain organization by assessing its impact on previously reported age differences in neural differentiation. To this end, we analyzed the data of 36 younger adults, 21 older adults with clinically normal hearing, and 21 older adults with mild-to-moderate hearing loss who had taken part in a functional localizer task comprising visual (i.e., faces, scenes) and auditory stimuli (i.e., voices, music) while undergoing functional magnetic resonance imaging. Evidence for reduced neural distinctiveness in the auditory cortex was observed only in older adults with hearing loss relative to younger adults, whereas evidence for reduced neural distinctiveness in the visual cortex was observed both in older adults with normal hearing and in older adults with hearing loss relative to younger adults. These results indicate that age-related dedifferentiation in the auditory cortex is exacerbated by age-related hearing loss

Allele-specific quantitative proteomics unravels molecular mechanisms modulated by cis-regulatory PPARG locus variation

Abstract Genome-wide association studies identified numerous disease risk loci. Delineating molecular mechanisms influenced by cis-regulatory variants is essential to understand gene regulation and ultimately disease pathophysiology. Combining bioinformatics and public domain chromatin information with quantitative proteomics supports prediction of cis-regulatory variants and enabled identification of allele-dependent binding of both, transcription factors and coregulators at the type 2 diabetes associated PPARG locus. We found rs7647481A nonrisk allele binding of Yin Yang 1 (YY1), confirmed by allele-specific chromatin immunoprecipitation in primary adipocytes. Quantitative proteomics also found the coregulator RING1 and YY1 binding protein (RYBP) whose mRNA levels correlate with improved insulin sensitivity in primary adipose cells carrying the rs7647481A nonrisk allele. Our findings support a concept with diverse cis-regulatory variants contributing to disease pathophysiology at one locus. Proteome-wide identification of both, transcription factors and coregulators, can profoundly improve understanding of mechanisms underlying genetic associations

TFG binds LC3C to regulate ULK1 localization and autophagosome formation

The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy

TFG binds LC3C to regulate ULK1 localization and autophagosome formation

The early secretory pathway and autophagy are two essential and evolutionarily conserved endomembrane processes that are finely interlinked. Although growing evidence suggests that intracellular trafficking is important for autophagosome biogenesis, the molecular regulatory network involved is still not fully defined. In this study, we demonstrate a crucial effect of the COPII vesicle-related protein TFG (Trk-fused gene) on ULK1 puncta number and localization during autophagy induction. This, in turn, affects formation of the isolation membrane, as well as the correct dynamics of association between LC3B and early ATG proteins, leading to the proper formation of both omegasomes and autophagosomes. Consistently, fibroblasts derived from a hereditary spastic paraparesis (HSP) patient carrying mutated TFG (R106C) show defects in both autophagy and ULK1 puncta accumulation. In addition, we demonstrate that TFG activity in autophagy depends on its interaction with the ATG8 protein LC3C through a canonical LIR motif, thereby favouring LC3C-ULK1 binding. Altogether, our results uncover a link between TFG and autophagy and identify TFG as a molecular scaffold linking the early secretion pathway to autophagy

Quantitative single-molecule localization microscopy combined with rule-based modeling reveals ligand-induced TNF-R1 reorganization toward higher-order oligomers

We report on the assembly of tumor necrosis factor receptor 1 (TNF-R1) prior to ligand activation and its ligand-induced reorganization at the cell membrane. We apply single-molecule localization microscopy to obtain quantitative information on receptor cluster sizes and copy numbers. Our data suggest a dimeric pre-assembly of TNF-R1, as well as receptor reorganization toward higher oligomeric states with stable populations comprising three to six TNF-R1. Our experimental results directly serve as input parameters for computational modeling of the ligand-receptor interaction. Simulations corroborate the experimental finding of higher-order oligomeric states. This work is a first demonstration how quantitative, super-resolution and advanced microscopy can be used for systems biology approaches at the single-molecule and single-cell level