Innovative, combinatorial and high-throughput approaches to degrader synthesis.

Targeted protein degraders such as PROTACs and molecular glues are a rapidly emerging therapeutic modality within industry and academia. Degraders possess unique mechanisms of action that lead to the removal of specific proteins by co-opting the cell's natural degradation mechanisms via induced proximity. Their optimisation thus far has often been largely empirical, requiring the synthesis and screening of a large number of analogues. In addition, the synthesis and development of degraders is often challenging, leading to lengthy optimisation campaigns to deliver candidate-quality compounds. This review highlights how the synthesis of degraders has evolved in recent years, in particular focusing on means of applying high-throughput chemistry and screening approaches to expedite these timelines, which we anticipate to be valuable in shaping the future of degrader optimisation campaigns.

A genome-wide association study based on the China Kadoorie Biobank identifies genetic associations between snoring and cardiometabolic traits.

Despite the high prevalence of snoring in Asia, little is known about the genetic etiology of snoring and its causal relationships with cardiometabolic traits. Based on 100,626 Chinese individuals, a genome-wide association study on snoring was conducted. Four novel loci were identified for snoring traits mapped on SLC25A21, the intergenic region of WDR11 and FGFR, NAA25, ALDH2, and VTI1A, respectively. The novel loci highlighted the roles of structural abnormality of the upper airway and craniofacial region and dysfunction of metabolic and transport systems in the development of snoring. In the two-sample bi-directional Mendelian randomization analysis, higher body mass index, weight, and elevated blood pressure were causal for snoring, and a reverse causal effect was observed between snoring and diastolic blood pressure. Altogether, our results revealed the possible etiology of snoring in China and indicated that managing cardiometabolic health was essential to snoring prevention, and hypertension should be considered among snorers.

Association of physical activity with risk of chronic kidney disease in China: A population-based cohort study.

BACKGROUND: Information on the association between physical activity (PA) and the risk of chronic kidney disease (CKD) is limited. We aimed to explore the associations of total, domain-specific, and intensity-specific PA with CKD and its subtypes in China. METHODS: The study included 475,376 adults from the China Kadoorie Biobank aged 30-79 years during 2004-2008 at baseline. An interviewer-administered questionnaire was used to collect the information about PA, which was quantified as metabolic equivalent of task hours per day (MET-h/day) and categorized into 4 groups based on quartiles. Cox regression was used to analyze the association between PA and CKD risk. RESULTS: During a median follow-up of 12.1 years, 5415 incident CKD cases were documented, including 1159 incident diabetic kidney disease (DKD) cases and 362 incident hypertensive nephropathy (HTN) cases. Total PA was inversely associated with CKD risk, with an adjusted hazard ratio (HR, 95% confidence interval (95%CI)) of 0.83 (0.75-0.92) for incident CKD in the highest quartile of total PA as compared with participants in the lowest quartile. Similar results were observed for risk of DKD and HTN, and the corresponding HRs (95%CIs) were 0.75 (0.58-0.97) for DKD risk and 0.56 (0.37-0.85) for HTN risk. Increased nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA were significantly associated with a decreased risk of CKD, with HRs (95%CIs) of 0.80 (0.73-0.88), 0.85 (0.77-0.94), and 0.85 (0.76-0.95) in the highest quartile, respectively. CONCLUSION: PA, including nonoccupational PA, low-intensity PA, and moderate-to-vigorous-intensity PA, was inversely associated with the risk of CKD, including DKD, HTN, and other CKD, and such associations were dose dependent.

Associations of diabetes, circulating protein biomarkers, and risk of pancreatic cancer.

BACKGROUND: Type 2 diabetes (T2D) is associated with higher risk of pancreatic cancer (PC), but the underlying mechanisms are not fully understood. METHODS: We conducted a case-subcohort study involving 610 PC cases and 623 subcohort participants with 92 protein biomarkers measured in baseline plasma samples. Genetically-instrumented T2D was derived using 86 single-nucleotide polymorphisms (SNPs), including insulin resistance (IR) SNPs. RESULTS: In observational analyses of 623 subcohort participants (mean age, 52 years; 61% women), T2D was positively associated with 13 proteins (SD difference: IL6: 0.52 [0.23-0.81]; IL10: 0.41 [0.12-0.70]), of which 8 were nominally associated with incident PC. The 8 proteins potentially mediated 36.9% (18.7-75.0%) of the association between T2D and PC. In MR, no associations were observed for genetically-determined T2D with proteins, but there were positive associations of genetically-determined IR with IL6 and IL10 (SD difference: 1.23 [0.05-2.41] and 1.28 [0.31-2.24]). In two-sample MR, fasting insulin was associated with both IL6 and PC, but no association was observed between IL6 and PC. CONCLUSIONS: Proteomics were likely to explain the association between T2D and PC, but were not causal mediators. Elevated fasting insulin driven by insulin resistance might explain the associations of T2D, proteomics, and PC.

Integrated Direct-to-Biology Platform for the Nanoscale Synthesis and Biological Evaluation of PROTACs.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that co-opt the cell's natural proteasomal degradation mechanisms to degrade undesired proteins. A challenge associated with PROTACs is the time and resource-intensive optimization; thus, the development of high-throughput platforms for their synthesis and biological evaluation is required. In this study, we establish an ultra-high-throughput experimentation (ultraHTE) platform for PROTAC synthesis, followed by direct addition of the crude reaction mixtures to cellular degradation assays without any purification. This 'direct-to-biology' (D2B) approach was validated and then exemplified in a medicinal chemistry campaign to identify novel BRD4 PROTACs. Using the D2B platform, the synthesis of 650 PROTACs was carried out in a 1536-well plate, and subsequent biological evaluation was performed by a single scientist in less than 1 month. Due to its ability to hugely accelerate the optimization of new degraders, we anticipate our platform will transform the synthesis and testing of PROTACs.

Sleep duration and risk of stroke and coronary heart disease: a 9-year community-based prospective study of 0.5 million Chinese adults.

BACKGROUND: There is uncertainty about the optimum sleep duration for risk of different subtypes of stroke and ischaemic heart disease. METHODS: The present analyses involved 409,156 adults in the China Kadoorie Biobank study without a prior history of coronary heart disease or stroke or insomnia symptoms. The mean age of study participants was 52 years and 59% were women. Self-reported sleep duration including daytime napping was recorded using a questionnaire. The adjusted hazard ratios (HRs) for disease outcomes associated with sleep duration were estimated by Cox proportional hazards after adjustment for confounding factors. RESULTS: The overall mean (SD) sleep duration was 7.4 (1.4) hours. The associations of sleep duration with CVD types were U-shaped, with individuals reporting 7-8 h of sleep having the lowest risks. Compared with those who typically slept 7-8 h, individuals with very short sleep duration (≤ 5 h) had adjusted HRs of 1.10 (95% CI 1.04-1.16), 1.07 (1.01-1.13), 1.19 (1.06-1.33) and 1.23 (1.10-1.37) for total stroke, ischaemic stroke (IS), Intracerebral haemorrhage (ICH) and major coronary events (MCE), respectively. Likewise, individuals with very long sleep duration (≥ 10 h) had HRs of 1.12 (1.07-1.17), 1.08 (1.03-1.14), 1.23 (1.12-1.35) and 1.22 (1.10-1.34) for the same diseases, respectively, with little differences by sex and age. The patterns were similar for all-cause mortality. CONCLUSIONS: While abnormal sleep duration (≤ 6 h or ≥ 9 h) was associated with higher risks of CVD, the risks were more extreme for those reporting ≤ 5 or ≥ 10 h, respectively and such individuals should be prioritised for more intensive treatment for CVD prevention.

Association between fresh fruit consumption and the risk of chronic obstructive pulmonary disease-related hospitalization and death in Chinese adults: A prospective cohort study.

BACKGROUND: Existing evidence suggests that fruit consumption is a significant influencing factor for chronic obstructive pulmonary disease (COPD), but this is unclear in the Chinese population. We examined the association of fresh fruit consumption with the risk of COPD-related hospitalization and death in a nationwide, population-based prospective cohort from China. METHODS: Between 2004 and 2008, the China Kadoorie Biobank recruited >0.5 million adults aged 30 to 79 years from ten diverse regions across China. After excluding individuals diagnosed with major chronic diseases and prevalent COPD, the prospective analysis included 421,428 participants. Cox regression was used to calculate the hazard ratios (HRs) for the association between fresh fruit consumption and risk of COPD-related hospitalization and death, with adjustment for established and potential confounders. RESULTS: During a mean follow-up of 10.9 years, 11,292 COPD hospitalization events and deaths were documented, with an overall incidence rate of 2.47/1000 person-years. Participants who consumed fresh fruit daily had a 22% lower risk of COPD-related hospitalization and death compared with non-consumers (HR = 0.78, 95% confidence interval [CI]: 0.71-0.87). The inverse association between fresh fruit consumption and COPD-related hospitalization and death was stronger among non-current smokers and participants with normal body mass index (BMI) (18.5 kg/m 2 ≤ BMI < 24.0 kg/m 2 ); the corresponding HRs for daily fresh fruit consumption were 0.78 (95% CI: 0.68-0.89) and 0.69 (95% CI: 0.59-0.79) compared with their counterparts, respectively. CONCLUSIONS: High-frequency fruit consumption was associated with a lower risk of COPD in Chinese adults. Increasing fruit consumption, together with cigarette cessation and weight control, should be considered in the prevention and management of COPD.

Characterising personal, household, and community PM2.5 exposure in one urban and two rural communities in China.

BACKGROUND: Cooking and heating in households contribute importantly to air pollution exposure worldwide. However, there is insufficient investigation of measured fine particulate matter (PM2.5) exposure levels, variability, seasonality, and inter-spatial dynamics associated with these behaviours. METHODS: We undertook parallel measurements of personal, household (kitchen and living room), and community PM2.5 in summer (May-September 2017) and winter (November 2017-Janauary 2018) in 477 participants from one urban and two rural communities in China. After stringent data cleaning, there were 67,326-80,980 person-hours (ntotal = 441; nsummer = 384; nwinter = 364; 307 had repeated PM2.5 data in both seasons) of processed data per microenvironment. Age- and sex-adjusted geometric means of PM2.5 were calculated by key participant characteristics, overall and by season. Spearman correlation coefficients between PM2.5 levels across different microenvironments were computed. FINDINGS: Overall, 26.4 % reported use of solid fuel for both cooking and heating. Solid fuel users had 92 % higher personal and kitchen 24-h average PM2.5 exposure than clean fuel users. Similarly, they also had a greater increase (83 % vs 26 %) in personal and household PM2.5 from summer to winter, whereas community levels of PM2.5 were 2-4 times higher in winter across different fuel categories. Compared with clean fuel users, solid fuel users had markedly higher weighted annual average PM2.5 exposure at personal (78.2 [95 % CI 71.6-85.3] µg/m3 vs 41.6 [37.3-46.5] µg/m3), kitchen (102.4 [90.4-116.0] µg/m3 vs 52.3 [44.8-61.2] µg/m3) and living room (62.1 [57.3-67.3] µg/m3 vs 41.0 [37.1-45.3] µg/m3) microenvironments. There was a remarkable diurnal variability in PM2.5 exposure among the participants, with 5-min moving average from 10 µg/m3 to 700-1200 µg/m3 across different microenvironments. Personal PM2.5 was moderately correlated with living room (Spearman r: 0.64-0.66) and kitchen (0.52-0.59) levels, but only weakly correlated with community levels, especially in summer (0.15-0.34) and among solid fuel users (0.11-0.31). CONCLUSION: Solid fuel use for cooking and heating was associated with substantially higher personal and household PM2.5 exposure than clean fuel users. Household PM2.5 appeared a better proxy of personal exposure than community PM2.5.

Minimal improvement in coronary artery disease risk prediction in Chinese population using polygenic risk scores: evidence from the China Kadoorie Biobank.

BACKGROUND: Several studies have reported that polygenic risk scores (PRSs) can enhance risk prediction of coronary artery disease (CAD) in European populations. However, research on this topic is far from sufficient in non-European countries, including China. We aimed to evaluate the potential of PRS for predicting CAD for primary prevention in the Chinese population. METHODS: Participants with genome-wide genotypic data from the China Kadoorie Biobank were divided into training ( n = 28,490) and testing sets ( n = 72,150). Ten previously developed PRSs were evaluated, and new ones were developed using clumping and thresholding or LDpred method. The PRS showing the strongest association with CAD in the training set was selected to further evaluate its effects on improving the traditional CAD risk-prediction model in the testing set. Genetic risk was computed by summing the product of the weights and allele dosages across genome-wide single-nucleotide polymorphisms. Prediction of the 10-year first CAD events was assessed using hazard ratios (HRs) and measures of model discrimination, calibration, and net reclassification improvement (NRI). Hard CAD (nonfatal I21-I23 and fatal I20-I25) and soft CAD (all fatal or nonfatal I20-I25) were analyzed separately. RESULTS: In the testing set, 1214 hard and 7201 soft CAD cases were documented during a mean follow-up of 11.2 years. The HR per standard deviation of the optimal PRS was 1.26 (95% CI:1.19-1.33) for hard CAD. Based on a traditional CAD risk prediction model containing only non-laboratory-based information, the addition of PRS for hard CAD increased Harrell's C index by 0.001 (-0.001 to 0.003) in women and 0.003 (0.001 to 0.005) in men. Among the different high-risk thresholds ranging from 1% to 10%, the highest categorical NRI was 3.2% (95% CI: 0.4-6.0%) at a high-risk threshold of 10.0% in women. The association of the PRS with soft CAD was much weaker than with hard CAD, leading to minimal or no improvement in the soft CAD model. CONCLUSIONS: In this Chinese population sample, the current PRSs minimally changed risk discrimination and offered little improvement in risk stratification for soft CAD. Therefore, this may not be suitable for promoting genetic screening in the general Chinese population to improve CAD risk prediction.

WHO cardiovascular disease risk prediction model performance in 10 regions, China.

Objective: To validate the World Health Organization (WHO) non-laboratory-based cardiovascular disease risk prediction model in regions of China. Methods: We performed an external validation of the WHO model for East Asia using the data set of China Kadoorie Biobank, an ongoing cohort study with 512 725 participants recruited from 10 regions of China from 2004-2008. We also recalculated the recalibration parameters for the WHO model in each region and evaluated the predictive performance of the model before and after recalibration. We assessed discrimination performance by Harrell's C index. Findings: We included 412 225 participants aged 40-79 years. During a median follow-up of 11 years, 58 035 and 41 262 incident cardiovascular disease cases were recorded in women and men, respectively. Harrell's C of the WHO model was 0.682 in women and 0.700 in men but varied among regions. The WHO model underestimated the 10-year cardiovascular disease risk in most regions. After recalibration in each region, discrimination and calibration were both improved in the overall population. Harrell's C increased from 0.674 to 0.749 in women and from 0.698 to 0.753 in men. The ratios of predicted to observed cases before and after recalibration were 0.189 and 1.027 in women and 0.543 and 1.089 in men. Conclusion: The WHO model for East Asia yielded moderate discrimination for cardiovascular disease in the Chinese population and had limited prediction for cardiovascular disease risk in different regions in China. Recalibration for diverse regions greatly improved discrimination and calibration in the overall population.

Impacts of solid fuel use versus smoking on life expectancy at age 30 years in the rural and urban Chinese population: a prospective cohort study.

Background: The impact of solid fuel use on life expectancy (LE) in less-developed countries remains unclear. We aimed to evaluate the potential impact of household solid fuel use on LE in the rural and urban Chinese population, with the effect of smoking as a reference. Methods: We used data from China Kadoorie Biobank (CKB) of 484,915 participants aged 30-79 free of coronary heart disease, stroke, or cancer at baseline. Analyses were performed separately for solid fuel use for cooking, solid fuel use for heating, and smoking, with participants exposed to the other two sources excluded. Solid fuels refer to coal and wood, and clean fuels refer to electricity, gas, and central heating. We used a flexible parametric Royston-Parmar model to estimate hazard ratios of all-cause mortality and predict LE at age 30. Findings: Totally, 185,077, 95,228, and 230,995 participants were included in cooking-, heating-, and smoking-related analyses, respectively. During a median follow-up of approximately 12.1 years, 12,725, 7,531, and 18,878 deaths were recorded in the respective analysis. Compared with clean fuel users who reported cooking with ventilation, participants who used solid fuels with ventilation and without ventilation had a difference in LE (95% confidence interval [CI]) at age 30 of -1.72 (-2.88, -0.57) and -2.62 (-4.16, -1.05) years for men and -1.33 (-1.85, -0.81) and -1.35 (-2.02, -0.67) years for women, respectively. The difference in LE (95% CI) for heating was -2.23 (-3.51, -0.95) years for men and -1.28 (-2.08, -0.48) years for women. In rural men, the LE reduction (95% CI) related to solid fuel use for cooking (-2.55; -4.51, -0.58) or heating (-3.26; -6.09, 0.44) was more than that related to smoking (-1.71; -2.54, -0.89). Conversely, in urban men, the LE reduction (95% CI) related to smoking (-3.06; -3.56, -2.56) was more than that related to solid fuel use for cooking (-1.28; -2.61, 0.05) and heating (-1.90; -3.16, -0.65). Similar results were observed in women but with a smaller magnitude. Interpretation: In this Chinese population, the harm to LE from household use of solid fuels was greater than that from smoking in rural residents. Conversely, the negative impact of smoking was greater than solid fuel use in urban residents. Our findings highlight the complexity and diversity of the factors affecting LE in less-developed populations. Funding: National Natural Science Foundation of China, National Key R&D Program of China, Kadoorie Charitable Foundation, UK Wellcome Trust.

Modeling biological age using blood biomarkers and physical measurements in Chinese adults.

BACKGROUND: This study aimed to: 1) assess the associations of biological age acceleration based on Klemera and Doubal's method (KDM-AA) with long-term risk of all-cause mortality; and 2) compare the association of KDM-AA with all-cause mortality among participants potentially at different stages of the cardiovascular disease (CVD) continuum. METHODS: The present study was based on a subpopulation of the China Kadoorie Biobank, with baseline survey during 2004-08. A total of 12,377 participants free of ischemic heart disease, stroke, or cancer at baseline were included, in which 8180 participants were identified to develop major coronary event (MCE), ischemic stroke (IS), intracerebral hemorrhage (ICH) or subarachnoid hemorrhage (SAH), and 4197 remained free of these cardiovascular diseases before 1 January 2014. These participants were followed up until 1 Jan 2018. KDM-AA was calculated by regressing biological age measurement, which was constructed based on baseline 16 physical and 9 biochemical markers using Klemera and Doubal's method, on chronological age. We estimated the associations of KDM-AA with the mortality risk using the hazard ratio (HR) and 95% confidence interval (CI) from Cox proportional hazard models. We assessed discrimination performance by Harrell's C-index and net reclassification index (NRI). FINDINGS: The participants who developed MCE (mean KDM-AA = 0.1 year, standard deviation [SD] = 1.6 years) or ICH/SAH (0.3 ± 1.5 years) during subsequent follow-up showed accelerated aging at baseline compared to those of IS (0.0 ± 1.2 years) and control (-0.3 ± 1.3 years) groups. The KDM-AA was positively associated with long-term risk of all-cause mortality (HR = 1.20; 95% CI: 1.17, 1.23), and the association was robust for participants potentially at different stages of the CVD continuum. Adding KDM-AA improved mortality prediction compared to the model only with sociodemographic and lifestyle factors in whole participants, with the Harrell's C-index increasing from 0.813 (0.807, 0.819) to 0.821 (0.815, 0.826) (NRI = 0.011; 95% CI: 0.003, 0.019). INTERPRETATION: In this middle-aged and elderly Chinese population, the KDM-AA is a promising measurement for biological age, and can capture the difference in cardiovascular health and predict the risk of all-cause mortality over a decade. FUNDING: This work was supported by National Natural Science Foundation of China (82192904, 82192901, 82192900, 81941018). The CKB baseline survey and the first re-survey were supported by a grant from the Kadoorie Charitable Foundation Hong Kong. The long-term follow-up is supported by grants from the UK Wellcome Trust (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z), grants (2016YFC0900500) from the National Key R&D Program of China, National Natural Science Foundation of China (81390540, 91846303), and Chinese Ministry of Science and Technology (2011BAI09B01).

Dystrophin-Deficient Muscular Dystrophy in Two Male Juvenile Brittanys.

A 6 mo old and a 7 mo old male intact Brittany were presented for progressive exercise intolerance, failure to grow, and dysphagia. Creatine kinase activity was markedly and persistently elevated in both dogs. Based on the neurological examination, clinical signs localized to the neuromuscular system. Electromyography revealed complex repetitive discharges in multiple muscle groups. Immunofluorescence of biopsies confirmed dystrophin-deficient muscular dystrophy. This is the first report describing dystrophin-deficient muscular dystrophy in the Brittany breed. Currently, no specific therapies are available for this form of myopathy. The presence of dystrophin deficiency in the two dogs suggests an inherited myopathy rather than a spontaneous mutation. The location of the dogs in the United States and Japan suggests a wide distribution of this dystrophy and should alert clinicians to the existence of this myopathy in the Brittany breed. A mutation in the DMD gene has not yet been identified.

The role of lifestyle factors on comorbidity of chronic liver disease and cardiometabolic disease in Chinese population: A prospective cohort study.

Background: Lifestyle factors are associated with chronic liver disease (CLD) and death after CLD diagnosis. However, their associations with pathways of CLD progression have been unclear, particularly transition to cardiometabolic disease (CMD), a major comorbid condition with CLD. We assessed the associations of lifestyle factors with CLD progression. Methods: The study population involved 486,828 participants of the prospective China Kadoorie Biobank (CKB) aged 30-79 years without a history of cardiovascular disease, diabetes, CLD, or cancer at baseline. Liver-cardiometabolic comorbidity (LCC) was defined as developing CMD subsequently after first CLD (FCLD) in an individual. A multi-state model was used to estimate the associations of high-risk lifestyle factors (smoking, alcohol, physical inactivity, and central adiposity) with CLD progression from healthy to FCLD, subsequently to LCC, and further to death. Findings: During a median follow-up of 11 years, 5046 participants developed FCLD, 519 developed LCC, and 157 died afterwards. There were positive associations between the number of high-risk lifestyle factors and risks of all transitions. The hazard ratios (95% CIs) per 1-factor increase were 1.30 (1.25-1.35) for transitions from baseline to FCLD, 1.21 (1.09-1.34) for FCLD to LCC, 1.20 (1.17-1.23) for baseline to death, 1.15 (1.09-1.22) for FCLD to death, and 1.17 (1.06-1.31) for LCC to death. For CLD subtypes, lifestyle factors showed different associations with disease-specific transitions even within the same transition stage. Interpretation: High-risk lifestyle factors played a key role in all disease transition stages from healthy to FCLD, subsequently to LCC, and then to death, with different magnitude of associations. Funding: Kadoorie Charitable Foundation, Chinese MoST and NSFC.

The INRAE Centre for Vegetable Germplasm: Geographically and Phenotypically Diverse Collections and Their Use in Genetics and Plant Breeding.

The French National Research Institute for Agriculture, Food and the Environment (INRAE) conserves and distributes five vegetable collections as seeds: the aubergine* (in this article the word aubergine refers to eggplant), pepper, tomato, melon and lettuce collections, together with their wild or cultivated relatives, are conserved in Avignon, France. Accessions from the collections have geographically diverse origins, are generally well-described and fixed for traits of agronomic or scientific interest and have available passport data. In addition to currently conserving over 10,000 accessions (between 900 and 3000 accessions per crop), the centre maintains scientific collections such as core collections and bi- or multi-parental populations, which have also been genotyped with SNP markers. Each collection has its own merits and highlights, which are discussed in this review: the aubergine collection is a rich source of crop wild relatives of Solanum; the pepper, melon and lettuce collections have been screened for resistance to plant pathogens, including viruses, fungi, oomycetes and insects; and the tomato collection has been at the heart of genome-wide association studies for fruit quality traits and environmental stress tolerance.

Specialty-Specific Diagnoses in Pediatric Patients With Postconcussion Syndrome: Experience From a Multidisciplinary Concussion Clinic.

OBJECTIVE: To describe the collaborative findings across a broad array of subspecialties in children and adolescents with postconcussion syndrome (PCS) in a pediatric multidisciplinary concussion clinic (MDCC) setting. DESIGN: Retrospective analysis. SETTING: Multidisciplinary concussion clinic at a pediatric tertiary-level hospital. PATIENTS: Fifty-seven patients seen in MDCC for evaluation and management of PCS between June 2014 and January 2016. INTERVENTIONS: Clinical evaluation by neurology, sports medicine, otolaryngology, optometry, ophthalmology, physical therapy, and psychology. MAIN OUTCOME MEASURES: Specialty-specific clinical findings and specific, treatable diagnoses relevant to PCS symptoms. RESULTS: A wide variety of treatable, specialty-specific diagnoses were identified as potential contributing factors to patients' postconcussion symptoms. The most common treatable diagnoses included binocular vision dysfunction (76%), anxiety, (57.7%), depression (44.2%), new or change in refractive error (21.7%), myofascial pain syndrome (19.2%), and benign paroxysmal positional vertigo (17.5%). CONCLUSIONS: Patients seen in a MDCC setting receive a high number of treatable diagnoses that are potentially related to patients' PCS symptoms. The MDCC approach may (1) increase access to interventions for PCS-related impairments, such as visual rehabilitation, physical therapy, and psychological counseling; (2) provide patients with coordinated medical care across specialties; and (3) hasten recovery from PCS.

Get the Balance Right: ROS Homeostasis and Redox Signalling in Fruit.

Plant central metabolism generates reactive oxygen species (ROS), which are key regulators that mediate signalling pathways involved in developmental processes and plant responses to environmental fluctuations. These highly reactive metabolites can lead to cellular damage when the reduction-oxidation (redox) homeostasis becomes unbalanced. Whilst decades of research have studied redox homeostasis in leaves, fundamental knowledge in fruit biology is still fragmentary. This is even more surprising when considering the natural profusion of fruit antioxidants that can process ROS and benefit human health. In this review, we explore redox biology in fruit and provide an overview of fruit antioxidants with recent examples. We further examine the central role of the redox hub in signalling during development and stress, with particular emphasis on ascorbate, also referred to as vitamin C. Progress in understanding the molecular mechanisms involved in the redox regulations that are linked to central metabolism and stress pathways will help to define novel strategies for optimising fruit nutritional quality, fruit production and storage.

Characterisation of class VI TRIM RING domains: linking RING activity to C-terminal domain identity.

TRIM E3 ubiquitin ligases regulate multiple cellular processes, and their dysfunction is linked to disease. They are characterised by a conserved N-terminal tripartite motif comprising a RING, B-box domains, and a coiled-coil region, with C-terminal domains often mediating substrate recruitment. TRIM proteins are grouped into 11 classes based on C-terminal domain identity. Class VI TRIMs, TRIM24, TRIM33, and TRIM28, have been described as transcriptional regulators, a function linked to their C-terminal plant homeodomain and bromodomain, and independent of their ubiquitination activity. It is unclear whether E3 ligase activity is regulated in family members where the C-terminal domains function independently. Here, we provide a detailed biochemical characterisation of the RING domains of class VI TRIMs and describe the solution structure of the TRIM28 RING. Our study reveals a lack of activity of the isolated RING domains, which may be linked to the absence of self-association. We propose that class VI TRIMs exist in an inactive state and require additional regulatory events to stimulate E3 ligase activity, ensuring that associated chromatin-remodelling factors are not injudiciously degraded.