Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis

Mutations in the cilia-centrosomal protein CEP290 are frequently observed in autosomal recessive childhood blindness disorder Leber congenital amaurosis (LCA). No treatment or cure currently exists for this disorder. The Cep290(rd16) (retinal degeneration 16) mouse (a model of LCA) carries a mutation in the Cep290 gene. This mutation leads to shorter cilia formation and defective photoreceptor structure and function. A roadblock to developing a gene replacement strategy for CEP290 using conventional adeno-associated virus (AAV) vectors is its large size. The identification and characterization is reported of a miniCEP290 gene that is amenable to AAV2/8-mediated delivery and delaying retinal degeneration in the Cep290(rd16) mice. Using the ability of Cep290(rd16) mouse embryonic fibroblasts to from shorter cilia as a platform, a human CEP290 domain encoded by amino acids 580-1180 (miniCEP290(580-1180)) was identified that can recover the cilia length in vitro. Furthermore, subretinal injection of AAV particles carrying the cDNA expressing miniCEP290(580-1180) into neonatal Cep290(rd16) mice resulted in significantly improved photoreceptor survival, morphology, and function compared to control injected mice. These studies show the potential of using a truncated CEP290 to treat this fast progressing and devastating disease

Prenylated retinal ciliopathy protein RPGR regulates ciliary localization of Joubert Syndrome-associated protein INPP5E in cooperation with PDE6

Ciliary dysfunction is an underlying cause of severe human disorders (collectively called ciliopathies), such as retinitis pigmentosa (RP), Joubert Syndrome (JBTS), and Bardet-Biedl Syndrome. Ciliary proteins form distinct functional networks for localization to cilia as well as regulation of ciliary function. However, not much is known about the mechanism of ciliary localization and function of RPGR (retinitis pigmentosa GTPase regulator), a ciliary protein frequently associated with RP worldwide. Using tandem mass spectrometry analysis, we show that RPGR interacts with two JBTS-associated proteins: PDE6Π (delta subunit of Phosphodiesterase; a prenyl-binding protein) and INPP5E (inositol polyphosphate-5-phosphatase 5E; a ciliary cargo). Whereas PDE6Π binds in a prenylation-dependent manner to the C-terminus of RPGR, INPP5E associates with the N-terminus of RPGR. Prenylation and interaction of RPGR with PDE6Π are critical for its localization to cilia. We further show that loss of RPGR results in reduced amount of INPP5E in cilia of fibroblasts and in photoreceptor outer segment, a modified sensory cilium. Overall, our results suggest that RPGR, in complex with PDE6D, regulates the trafficking of ciliary cargo INPP5E and implicate reduction in ciliary INPP5E in the pathogenesis of RPGR-ciliopathy

Transcriptomic Shock Generates Evolutionary Novelty in a Newly Formed, Natural Allopolyploid Plant

SummaryNew hybrid species might be expected to show patterns of gene expression intermediate to those shown by parental species [1, 2]. “Transcriptomic shock” may also occur, in which gene expression is disrupted; this may be further modified by whole genome duplication (causing allopolyploidy) [3–16]. “Shock” can include instantaneous partitioning of gene expression between parental copies of genes among tissues [16–19]. These effects have not previously been studied at a population level in a natural allopolyploid plant species. Here, we survey tissue-specific expression of 144 duplicated gene pairs derived from different parental species (homeologs) in two natural populations of 40-generation-old allotetraploid Tragopogon miscellus (Asteraceae) plants. We compare these results with patterns of allelic expression in both in vitro “hybrids” and hand-crossed F1 hybrids between the parental diploids T. dubius and T. pratensis, and with patterns of homeolog expression in synthetic (S1) allotetraploids. Partitioning of expression was frequent in natural allopolyploids, but F1 hybrids and S1 allopolyploids showed less partitioning of expression than the natural allopolyploids and the in vitro “hybrids” of diploid parents. Our results suggest that regulation of gene expression is relaxed in a concerted manner upon hybridization, and new patterns of partitioned expression subsequently emerge over the generations following allopolyploidization

A smart chicken farming platform for chicken behavior identification and feed residual estimation

It is very potential to develop digital villages for promoting smart agriculture. As one of the important research fields of smart agriculture, smart chicken farms encounter management problems such as difficulties in quickly and accurately warning of sick and dead chickens and estimating feed residuals. Therefore, this study not only respectively proposed CKTrack and FRCM to detect sick and dead chickens and estimate feed residuals, but also developed a smart chicken farming platform for automagical management. Our main results include (1) the proposed CKTrack method can effectively identify sick and dead chickens under the condition of limited data volume and computing capacity; (2) the proposed FRCM method can accurately estimate the feed residuals; and (3) the smart chicken farming platform developed can provide farmers with functions such as early warning of sick and dead chickens, visualization of the chicken quantity inventory, and feed residual estimation.<br/

Change in sensory integration and regularity of postural sway with the suspensory strategy during static standing balance

Background and aimThe suspensory strategy, a method for controlling postural balance in the vertical direction of the center of mass (COM), is considered by the elderly as a means of balance control. The vertical COM control might alter the sensory integration and regularity of postural sway, which in turn impacts balance. However, to date, this was not confirmed. Thus, this study aimed at investigating the influence of the suspensory strategy achieved through knee flexion on the static standing balance.MethodsNineteen participants were monitored at knee flexion angles of 0°, 15°, and 65°. Time-frequency analysis and sample entropy were employed to analyze the COM data. Time-frequency analysis was utilized to assess the energy content across various frequency bands and corresponding percentage of energy within each frequency band. The outcomes of time-frequency are hypothesized to reflect the balance-related sensory input and sensory weights. Sample entropy was applied to evaluate the regularity of the COM displacement patterns.ResultsKnee flexion led to a decreased COM height. The highest energy content was observed at 65° knee flexion, in contrast with the lowest energy observed at 0° in both the anterior–posterior (AP) and medial-lateral (ML) directions. Additionally, the ultra-low-frequency band was more pronounced at 65° than that at 0° or 15° in the ML direction. Furthermore, the COM amplitudes were notably higher at 65° than those at 0° and 15° in the AP and ML directions, respectively. The sample entropy values were lower at 65° and 15° than those at 0° in the ML direction, with the lowest value observed at 65° in the vertical direction.ConclusionThe suspensory strategy could enhance the sensory input and cause sensory reweighting, culminating in a more regular balance control. Such suspensory strategy-induced postural control modifications may potentially provide balance benefits for people with declining balance-related sensory, central processing, and musculoskeletal system functions

SIPA1L3 methylation modifies the benefit of smoking cessation on lung adenocarcinoma survival: an epigenomic-smoking interaction analysis

Smoking cessation prolongs survival and decreases mortality of patients with non‐small‐cell lung cancer (NSCLC). In addition, epigenetic alterations of some genes are associated with survival. However, potential interactions between smoking cessation and epigenetics have not been assessed. Here, we conducted an epigenome‐wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival. We used a two‐stage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for early‐stage NSCLC. The discovery phase contained NSCLC patients from Harvard, Spain, Norway, and Sweden. A histology‐stratified Cox proportional hazards model adjusted for age, sex, clinical stage, and study center was used to test DNA methylation-smoking cessation interaction terms. Interactions with false discovery rate‐q ≤ 0.05 were further confirmed in a validation phase using The Cancer Genome Atlas database. Histology‐specific interactions were identified by stratification analysis in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients. We identified one CpG probe (cg02268510SIPA1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 × 10-7]. Further, the effect of smoking cessation on early‐stage LUAD survival varied across patients with different methylation levels of cg02268510SIPA1L3. Smoking cessation only benefited LUAD patients with low methylation (HR = 0.53; 95% CI: 0.34-0.82; P = 4.61 × 10-3) rather than medium or high methylation (HR = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510SIPA1L3. Moreover, there was an antagonistic interaction between elevated methylation of cg02268510SIPA1L3 and smoking cessation (HRinteraction = 2.1835; 95% CI: 1.27-3.74; P = 4.46 × 10−3). In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA1L3. The results have implications for not only smoking cessation after diagnosis, but also possible methylation‐specific drug targeting

Trans-omics biomarker model improves prognostic prediction accuracy for early-stage lung adenocarcinoma

Limited studies have focused on developing prognostic models with trans-omics biomarkers for early-stage lung adenocarcinoma (LUAD). We performed integrative analysis of clinical information, DNA methylation, and gene expression data using 825 early-stage LUAD patients from 5 cohorts. Ranger algorithm was used to screen prognosis-associated biomarkers, which were confirmed with a validation phase. Clinical and biomarker information was fused using an iCluster plus algorithm, which significantly distinguished patients into high- and low-mortality risk groups (Pdiscovery = 0.01 and Pvalidation = 2.71×10-3). Further, potential functional DNA methylation-gene expression-overall survival pathways were evaluated by causal mediation analysis. The effect of DNA methylation level on LUAD survival was significantly mediated through gene expression level. By adding DNA methylation and gene expression biomarkers to a model of only clinical data, the AUCs of the trans-omics model improved by 18.3% (to 87.2%) and 16.4% (to 85.3%) in discovery and validation phases, respectively. Further, concordance index of the nomogram was 0.81 and 0.77 in discovery and validation phases, respectively. Based on systematic review of published literatures, our model was superior to all existing models for early-stage LUAD. In summary, our trans-omics model may help physicians accurately identify patients with high mortality risk

Dual-Task Interference Slows Down Proprioception

It is well-known that multitasking impairs the performance of one or both of the concomitant ongoing tasks. Previous studies have mainly focused on how a secondary task can compromise visual or auditory information processing. However, despite dual tasking being critical to motor performance, the effects of dual-task performance on proprioceptive information processing have not been studied yet. The purpose of the present study was, therefore, to investigate whether sensorimotor task performance would be affected by the dual task and if so, in which phase of the sensorimotor task performance would this negative effect occur. The kinematic variables of passive and active knee movements elicited by the leg drop test were analyzed. Thirteen young adults participated in the study. The dual task consisted of performing serial subtractions. The results showed that the dual task increased both the reaction time to counteract passive knee-joint movements in the leg drop test and the threshold to detect those movements. The dual task did not affect the speed and time during the active knee movement and the absolute angle error between the final and the target knee angles. Furthermore, the results showed that the time to complete the sensorimotor task was prolonged in dual tasking. Our findings suggest that dual tasking reduces motor performance due to slowing down proprioceptive information processing without affecting movement execution