The kinetic landscape of an RNA-binding protein in cells.

Gene expression in higher eukaryotic cells orchestrates interactions between thousands of RNA-binding proteins (RBPs) and tens of thousands of RNAs1. The kinetics by which RBPs bind to and dissociate from their RNA sites are critical for the coordination of cellular RNA-protein interactions2. However, these kinetic parameters have not been experimentally measured in cells. Here we show that time-resolved RNA-protein cross-linking with a pulsed femtosecond ultraviolet laser, followed by immunoprecipitation and high-throughput sequencing, allows the determination of binding and dissociation kinetics of the RBP DAZL for thousands of individual RNA-binding sites in cells. This kinetic cross-linking and immunoprecipitation (KIN-CLIP) approach reveals that DAZL resides at individual binding sites for time periods of only seconds or shorter, whereas the binding sites remain DAZL-free for markedly longer. The data also indicate that DAZL binds to many RNAs in clusters of multiple proximal sites. The effect of DAZL on mRNA levels and ribosome association correlates with the cumulative probability of DAZL binding in these clusters. Integrating kinetic data with mRNA features quantitatively connects DAZL-RNA binding to DAZL function. Our results show how kinetic parameters for RNA-protein interactions can be measured in cells, and how these data link RBP-RNA binding to the cellular function of RBPs.

A PAK family kinase and the Hippo/Yorkie pathway modulate WNT signaling to functionally integrate body axes during regeneration.

Successful regeneration of missing tissues requires seamless integration of positional information along the body axes. Planarians, which regenerate from almost any injury, use conserved, developmentally important signaling pathways to pattern the body axes. However, the molecular mechanisms which facilitate cross talk between these signaling pathways to integrate positional information remain poorly understood. Here, we report a p21-activated kinase (smed-pak1) which functionally integrates the anterior-posterior (AP) and the medio-lateral (ML) axes. pak1 inhibits WNT/ß-catenin signaling along the AP axis and, functions synergistically with the ß-catenin-independent WNT signaling of the ML axis. Furthermore, this functional integration is dependent on warts and merlin-the components of the Hippo/Yorkie (YKI) pathway. Hippo/YKI pathway is a critical regulator of body size in flies and mice, but our data suggest the pathway regulates body axes patterning in planarians. Our study provides a signaling network integrating positional information which can mediate coordinated growth and patterning during planarian regeneration.

Drugst.One - a plug-and-play solution for online systems medicine and network-based drug repurposing.

In recent decades, the development of new drugs has become increasingly expensive and inefficient, and the molecular mechanisms of most pharmaceuticals remain poorly understood. In response, computational systems and network medicine tools have emerged to identify potential drug repurposing candidates. However, these tools often require complex installation and lack intuitive visual network mining capabilities. To tackle these challenges, we introduce Drugst.One, a platform that assists specialized computational medicine tools in becoming user-friendly, web-based utilities for drug repurposing. With just three lines of code, Drugst.One turns any systems biology software into an interactive web tool for modeling and analyzing complex protein-drug-disease networks. Demonstrating its broad adaptability, Drugst.One has been successfully integrated with 21 computational systems medicine tools. Available at https://drugst.one, Drugst.One has significant potential for streamlining the drug discovery process, allowing researchers to focus on essential aspects of pharmaceutical treatment research.

Financial burden following adult liver transplantation is common and associated with adverse recipient outcomes.

The financial impact of liver transplantation has been underexplored. We aimed to identify associations between high financial burden (≥10% annual income spent on out-of-pocket medical costs) and work productivity, financial distress (coping behaviors in response to the financial burden), and financial toxicity (health-related quality of life, HRQOL) among adult recipients of liver transplant. Between June 2021 and May 2022, we surveyed 207 adult recipients of liver transplant across 5 US transplant centers. Financial burden and distress were measured by 25 items adapted from national surveys of cancer survivors. Participants also completed the Work Productivity and Activity Impairment and EQ-5D-5L HRQOL questionnaires. In total, 23% of recipients reported high financial burden which was significantly associated with higher daily activity impairment (32.9% vs. 23.3%, p =0.048). In adjusted analyses, the high financial burden was significantly and independently associated with delayed or foregone medical care (adjusted odds ratio, 3.95; 95% CI, 1.85-8.42) and being unable to afford basic necessities (adjusted odds ratio, 5.12; 95% CI: 1.61-16.37). Recipients experiencing high financial burden had significantly lower self-reported HRQOL as measured by the EQ-5D-5L compared to recipients with low financial burden (67.8 vs. 76.1, p =0.008) and an age-matched and sex-matched US general population (67.8 vs. 79.1, p <0.001). In this multicenter cohort study, nearly 1 in 4 adult recipients of liver transplant experienced a high financial burden, which was significantly associated with delayed or foregone medical care and lower self-reported HRQOL. These findings underscore the need to evaluate and address the financial burden in this population before and after transplantation.

Identification of novel neutralizing determinants for protection against HCV.

BACKGROUND AND AIMS: HCV evasion of neutralizing antibodies (nAb) results in viral persistence and poses challenges to the development of an urgently needed vaccine. N-linked glycosylation of viral envelope proteins is a key mechanism for such evasion. To facilitate rational vaccine design, we aimed to identify determinants of protection of conserved neutralizing epitopes. APPROACH AND RESULTS: Using a reverse evolutionary approach, we passaged genotype 1a, 1b, 2a, 3a, and 4a HCV with envelope proteins (E1 and E2) derived from chronically infected patients without selective pressure by nAb in cell culture. Compared with the original viruses, HCV recombinants, engineered to harbor substitutions identified in polyclonal cell culture-passaged viruses, showed highly increased fitness and exposure of conserved neutralizing epitopes in antigenic regions 3 and 4, associated with protection from chronic infection. Further reverse genetic studies of acquired E1/E2 substitutions identified positions 418 and 532 in the N1 and N6 glycosylation motifs, localizing to adjacent E2 areas, as key regulators of changes of the E1/E2 conformational state, which governed viral sensitivity to nAb. These effects were independent of predicted glycan occupancy. CONCLUSIONS: We show how N-linked glycosylation motifs can trigger dramatic changes in HCV sensitivity to nAb, independent of glycan occupancy. These findings aid in the understanding of HCV nAb evasion and rational vaccine design, as they can be exploited to stabilize the structurally flexible envelope proteins in an open conformation, exposing important neutralizing epitopes. Finally, this work resulted in a panel of highly fit cell culture infectious HCV recombinants.

Click synthesis of dendronized malonates for the preparation of amphiphilic dendro[60]fullerenes.

Fullerene C60 and its malonate derivatives, produced via the Bingel-Hirsch reaction, have displayed promising properties against various diseases. These molecules have great therapeutic potential, but their broad use has been limited due to poor aqueous solubility and toxicity caused by accumulation. In this study, we synthesized new malonates and malonamides attached to first- and second-generation polyester dendrons using click chemistry (CuAAC). These dendrons were then linked at C60 through the Bingel-Hirsch reaction, resulting in an amphiphilic system that retains the hydrophobic nature of C60. The dendronized malonate derivatives showed good reaction yields for the Bingel-Hirsch mono-adducts and were easier to work with than the corresponding malonamides. However, the malonamide derivatives, which were obtained through a multistep reaction sequence, showed moderate yields in the Bingel-Hirsch reaction. Surprisingly, removing acetonide protecting groups from dendritic architectures was more challenging than anticipated, likely due to product decomposition. Only the corresponding free malonate derivatives 25 and 26 were obtained, but in a low yield due to decomposition under the reaction conditions. Meanwhile, it was not possible to obtain the corresponding malonamide derivatives 27 and 28. Currently, efforts are being made to improve the production of the desired molecules and to design new synthesis routes that allow direct access to the desired poly-hydroxylated derivatives. These derivatives will be evaluated as multitarget ligands against Alzheimer's disease, through their use as inhibitors of amyloid ß-peptide aggregation, acetylcholinesterase modulators, and antioxidants.

Ametropia detection using a novel, compact wavefront autorefractor.

INTRODUCTION: Despite the well-known reproducibility issues of subjective refraction, most studies evaluating autorefractors compared differences between the device and subjective refraction. This work evaluated the performance of a novel handheld Hartmann-Shack-based autorefractor using an alternative protocol, which considered the inherent variability of subjective refraction. METHODS: Participants underwent an initial measurement with a desktop autorefractor, two subjective refractions (SR1 and SR2) and a final measurement with the QuickSee Free (QSFree) portable autorefractor. Autorefractor performance was evaluated by comparing the differences between the QSFree and each of the subjective refractions with the difference between the subjective refractions (SR1 vs. SR2) using Bland-Altman analysis and percentage of agreement. RESULTS: A total of 75 subjects (53 ± 14 years) were enrolled in the study. The average difference in the absolute spherical equivalent (M) between the QSFree and the SR1 and SR2 was ±0.24 and ±0.02 D, respectively, that is, very similar or smaller than the SR1 versus SR2 difference (±0.26 D). Average differences in astigmatic components were found to be negligible. The results demonstrate that differences between QSFree and both subjective refractions in J0 and J45 were within ±0.50 D for at least 96% of the measurements. The limits of agreement (LOAs) of the differences between QSFree and SR1, as well as QSFree and SR2, were higher than those observed between SR1 and SR2 for M, J0 and J45 . CONCLUSIONS: A protocol was designed and validated for the evaluation of a refractive device to account for the variability of subjective refraction. This protocol was used to evaluate a novel portable autorefractor and observed a smaller difference between the device and subjective refractions than the difference between the two subjective refraction measurements in terms of mean bias error, although the standard deviation was higher.

Microbiome-mediated incapacitation of interferon lambda production in the oral mucosa.

Here, we show that Porphyromonas gingivalis (Pg), an endogenous oral pathogen, dampens all aspects of interferon (IFN) signaling in a manner that is strikingly similar to IFN suppression employed by multiple viral pathogens. Pg suppressed IFN production by down-regulating several IFN regulatory factors (IRFs 1, 3, 7, and 9), proteolytically degrading STAT1 and suppressing the nuclear translocation of the ISGF3 complex, resulting in profound and systemic repression of multiple interferon-stimulated genes. Pg-induced IFN paralysis was not limited to murine models but was also observed in the oral tissues of human periodontal disease patients, where overabundance of Pg correlated with suppressed IFN generation. Mechanistically, multiple virulence factors and secreted proteases produced by Pg transcriptionally suppressed IFN promoters and also cleaved IFN receptors, making cells refractory to exogenous IFN and inducing a state of broad IFN paralysis. Thus, our data show a bacterial pathogen with equivalence to viruses in the down-regulation of host IFN signaling.

An isolated bioinductive repair vs. sutured repair for full-thickness rotator cuff tears: 2-year results of a double blinded, randomized controlled trial.

BACKGROUND: Partial-thickness rotator cuff tears treated with an isolated bioinductive repair (IBR) in lieu of a completion-and-repair have shown complete healing. This treatment option is afforded by the remaining tendon's structural integrity, which is similar to that present in small/medium full-thickness tears (FTTs) when the rotator cable remains intact. This randomized controlled trial (RCT) investigated whether an IBR for small/medium FTTs resulted in superior healing and patient-reported outcomes (PROs) compared with a sutured repair. METHODS: This prospective, double blinded (patients and outcome assessors), single-center RCT enrolled patients ≥18 years with a small/medium (≤2.5cm) full thickness supraspinatus tear and intact rotator cable. Patients were randomized and blinded to arthroscopic transosseous-equivalent repair (control, n = 30) or IBR (n = 30). The primary outcome was tendon quality on biopsy at 6 months. Secondary outcomes were PROs (American Shoulder and Elbow Surgeons [ASES], Constant-Murley Shoulder [CMS], and pain visual analogue scale scores) and tendon thickness and healing measured via MRI at 6, 12, and 24 months; satisfaction at 12 and 24 months; and time to return to work. RESULTS: Baseline demographic, tear, and surgical characteristics were comparable between the groups (IBR: mean age, 54.2 years, 14 male; control: mean age, 56.4 years, 16 male). Measured via 6 month biopsy, highly organized, parallel bundles of collagen, without inflammation, were present in all IBR patients, whereas poorly organized, non-parallel collagen fibers were present in 24/30 (80%) of control patients (P < .0001), with 28/30 having minimal to mild inflammation. The increase in tendon thickness measured via MRI at 6 months from baseline was greater in the IBR group (2.0 mm) than in the control group (0.8 mm) (P < .0001). All IBR patients had 100% healing on MRI at 12 and 24 months. Compared with the control group, the IBR group had higher ASES and CMS scores at each evaluation, less pain at 6 and 12 months, and greater satisfaction at 12 and 24 months (P < .0003). The IBR group returned to work significantly faster (median 90 days [IQR, 25] vs. median 163.5 days [IQR, 24]; P < .0001) than the control group. CONCLUSION: Compared with a sutured repair, the IBR treatment resulted in superior tendon quality, patient outcomes, satisfaction, and return to work. The IBR enabled a robust healing response evident through MRI and biopsy evaluation, demonstrating superior tendon quality and healing.

Parent-Youth Attachment Insecurity and Informant Discrepancies of Intrafamilial Aggression.

This study investigated how youth attachment anxiety and avoidance are associated with informant discrepancies of intrafamilial aggression within families where youth have clinically significant mental health challenges (N = 510 youth-parent dyads). Using polynomial regressions, we tested whether youth attachment avoidance and anxiety moderated the absolute magnitude of the association between youth- and parent-reports of aggression toward each other. Furthermore, difference scores were computed to test whether youth attachment was associated with the direction of youths' reports of the frequency of aggression relative to parents (i.e., did youth under- or over-report). Dyads' reports of youth-to-parent aggression were more strongly related at high than low levels of attachment anxiety. Results also revealed that youth attachment anxiety was associated with youth over-reporting of youth-to-parent and parent-to-youth aggression (relative to parents), whereas attachment avoidance was associated with youth over-reporting parent-to-youth aggression (relative to parents). These findings highlight the importance of understanding the source of informant discrepancies in social-emotional development and family functioning.

Early and annual projected savings from anti-CGRP monoclonal antibodies in migraine prevention: a cost-benefit analysis in the working-age population.

BACKGROUND: Migraine is one of the main causes of disability worldwide. Anti-CGRP monoclonal antibodies (MAbs) have proven to be safe and efficacious as preventive migraine treatments. However, their use is restricted in many countries due to their apparently high cost. Cost-benefit studies are needed. OBJECTIVE: To study the cost-benefit of anti-CGRP MAbs in working-age patients with migraine. METHODS: This is a prospective cohort study of consecutive migraine patients treated with anti-CGRP MAbs (erenumab, fremanezumab and galcanezumab) following National reimbursement policy in a specialized headache clinic. Migraine characteristics and the work impact scale (WPAI) were compared between baseline (M0) and after 3 (M3) and 6 months (M6) of treatment. Using WPAI and the municipal average hourly wage, we calculated indirect costs (absenteeism and presenteeism) at each time point. Direct costs (emergency visits, acute medication use) were also analysed. A cost-benefit study was performed considering the different costs and savings of treating with MAbs. Based on these data an annual projection was conducted. RESULTS: From 256 treated working-age patients, 148 were employed (89.2% women; mean age 48.0 ± 8.5 years), of which 41.2% (61/148) were responders (> 50% reduction in monthly headache days (MHD)). Statistically significant reductions between M0 and M3/M6 were found in absenteeism (p < 0.001) and presenteeism (p < 0.001). Average savings in indirect costs per patient at M3 were absenteeism 105.4 euros/month and presenteeism 394.3 euros/month, similar for M6. Considering the monthly cost of anti-CGRP MAbs, the cost-benefit analysis showed savings of 159.8 euros per patient at M3, with an annual projected savings of 639.2 euros/patient. Both responders and partial responders (30-50% reduction in MHD) presented a positive cost-benefit balance. The overall savings of the cohort at M3/M6 compensated the negative cost-benefit balance for non-responders (< 30% reduction in MHD). CONCLUSION: Anti-CGRP MAbs have a positive impact in the workforce significantly reducing absenteeism and presenteeism. In Spain, this benefit overcomes the expenses derived from their use already at 3 months and is potentially sustainable at longer term; also in patients who are only partial responders, prompting reconsideration of current reimbursement criteria and motivating the extension of similar cost-benefit studies in other countries.

Arsenic and mercury exposure in different insect trophic guilds from mercury mining areas in Mexico.

The exposure to arsenic and mercury in various insect trophic guilds from two mercury mining sites in Mexico was assessed. The two study sites were La Laja (LL) and La Soledad (LS) mines. Additionally, a reference site (LSR) was evaluated for LS. The terrestrial ecosystem was studied at LL, whereas both the terrestrial ecosystem and a stream called El Cedral (EC) were assessed at LS. The study sites are situated in the Biosphere Reserve Sierra Gorda (BRSG). Mercury vapor concentrations were measured with a portable analyzer, and concentrations of arsenic and mercury in environmental and biological samples were determined through atomic absorption spectrophotometry. Both pollutants were detected in all terrestrial ecosystem components (soil, air, leaves, flowers, and insects) from the two mines. The insect trophic guilds exposed included pollinivores, rhizophages, predators, coprophages, and necrophages. In LS, insects accumulated arsenic at levels 29 to 80 times higher than those found in specimens from LSR, and 10 to 46 times higher than those from LL. Similarly, mercury exposure in LS was 13 to 62 times higher than LSR, and 15 to 54 times higher than in LL. The analysis of insect exposure routes indicated potential exposure through air, soil, leaves, flowers, animal prey, carrion, and excrement. Water and sediment from EC exhibited high levels of arsenic and mercury compared to reference values, and predatory aquatic insects were exposed to both pollutants. In conclusion, insects from mercury mining sites in the BRSG are at risk.

An International Consensus Survey among Pediatric Surgeons on the Role of Appendectomy in Malrotation.

Introduction: Ladd's procedure, originally described in 1936 for the treatment of malrotation, does not traditionally include appendectomy as a standard step. We conducted a multinational survey to investigate the current consensus on the role of appendectomy in Ladd's procedure. Methodology: An anonymous online survey was distributed to pediatric surgeons worldwide. The survey collected demographic data and explored surgical preferences related to the management of malrotation. Open-ended questions were used to assess the opinions regarding the necessity of appendectomy, decision-making factors, and complications associated with appendectomy during Ladd's procedure. Results: A total of 343 responses were received from 46 countries. Of the respondents, 319 (93%) were consultants and 24 (7%) were residents/trainees. When asked about the choice between open and laparoscopic Ladd's procedure, 292 (85%) preferred open surgery. Overall, 184 (53%) respondents favored appendectomy in both open and laparoscopic Ladd's procedure. Furthermore, 172 (50%) surgeons advocated for appendectomy in all malrotation cases, citing concerns about potential future appendicitis. While differences existed between all comparisons, none of them reached statistical significance. The factors influencing the decision to preserve the appendix included the risk of postoperative complications and the potential future use of the appendix as a surgical conduit. The surgical complications following appendectomy included surgical site infections in 14 (33%) patients, adhesive obstruction in 13 (31%) patients, intrabdominal abscesses in 10 (24%) patients, and fecal fistulas in 5 (12%) patients. Conclusion: The majority of surgeons aim to perform appendectomy in all malrotation cases, considering the potential risks and benefits of this approach. These findings offer valuable insights for clinical practice and may inform future guidelines and decision-making algorithms.

Inactivated genotype 1a, 2a and 3a HCV vaccine candidates induced broadly neutralising antibodies in mice.

OBJECTIVE: A prophylactic vaccine is needed to control the HCV epidemic, with genotypes 1-3 causing >80% of worldwide infections. Vaccine development is hampered by HCV heterogeneity, viral escape including protection of conserved neutralising epitopes and suboptimal efficacy of HCV cell culture systems. We developed cell culture-based inactivated genotype 1-3 HCV vaccine candidates to present natively folded envelope proteins to elicit neutralising antibodies. DESIGN: High-yield genotype 1a, 2a and 3a HCV were developed by serial passage of TNcc, J6cc and DBN3acc in Huh7.5 cells and engineering of acquired mutations detected by next-generation sequencing. Neutralising epitope exposure was determined in cell-based neutralisation assays using human monoclonal antibodies AR3A and AR4A, and polyclonal antibody C211. BALB/c mice were immunised with processed and inactivated genotype 1a, 2a or 3a viruses using AddaVax, a homologue of the licenced adjuvant MF-59. Purified mouse and patient serum IgG were assayed for neutralisation capacity; mouse IgG and immune-sera were assayed for E1/E2 binding. RESULTS: Compared with the original viruses, high-yield viruses had up to ~1000 fold increased infectivity titres (peak titres: 6-7 log10 focus-forming units (FFU)/mL) and up to ~2470 fold increased exposure of conserved neutralising epitopes. Vaccine-induced IgG broadly neutralised genotype 1-6 HCV (EC50: 30-193 µg/mL; mean 71 µg/mL), compared favourably with IgG from chronically infected patients, and bound genotype 1-3 E1/E2; immune-sera endpoint titres reached up to 32 000. CONCLUSION: High-yield genotype 1-3 HCV could be developed as basis for inactivated vaccine candidates inducing broadly neutralising antibodies in mice supporting further preclinical development.

Molecular characterization of a flatworm Girardia isolate from Guanajuato, Mexico.

Planarian flatworms are best known for their impressive regenerative capacity, yet this trait varies across species. In addition, planarians have other features that share morphology and function with the tissues of many other animals, including an outer mucociliary epithelium that drives planarian locomotion and is very similar to the epithelial linings of the human lung and oviduct. Planarians occupy a broad range of ecological habitats and are known to be sensitive to changes in their environment. Yet, despite their potential to provide valuable insight to many different fields, very few planarian species have been developed as laboratory models for mechanism-based research. Here we describe a previously undocumented planarian isolate, Girardia sp. (Guanajuato). After collecting this isolate from a freshwater habitat in central Mexico, we characterized it at the morphological, cellular, and molecular level. We show that Girardia sp. (Guanajuato) not only shares features with animals in the Girardia genus but also possesses traits that appear unique to this isolate. By thoroughly characterizing this new planarian isolate, our work facilitates future comparisons to other flatworms and further molecular dissection of the unique and physiologically-relevant traits observed in this Girardia sp. (Guanajuato) isolate.

APGW/AKH Precursor from Rotifer Brachionus plicatilis and the DNA Loss Model Explain Evolutionary Trends of the Neuropeptide LWamide, APGWamide, RPCH, AKH, ACP, CRZ, and GnRH Families.

In the year 2002, DNA loss model (DNA-LM) postulated that neuropeptide genes to emerged through codons loss via the repair of damaged DNA from ancestral gene namely Neuropeptide Precursor Predictive (NPP), which organization correspond two or more neuropeptides precursors evolutive related. The DNA-LM was elaborated according to amino acids homology among LWamide, APGWamide, red pigment-concentrating hormone (RPCH), adipokinetic hormones (AKHs) and in silico APGW/RPCH NPPAPGW/AKH NPP were proposed. With the above principle, it was proposed the evolution of corazonin (CRZ), gonadotropin-releasing hormone (GnRH), AKH, and AKH/CRZ (ACP), but any NPP never was considered. However, the evolutive relation via DNA-LM among these neuropeptides precursors not has been established yet. Therefore, the transcriptomes from crabs Callinectes toxotes and Callinectes arcuatus were used to characterized ACP and partial CRZ precursors, respectively. BLAST alignment with APGW/RPCH NPP and APGW/AKH NPP allow identified similar NPP in the rotifer Brachionus plicatilis and other invertebrates. Moreover, three bioinformatics algorithms and manual verification were used to purify 13,778 sequences, generating a database with 719 neuropeptide precursors. Phylogenetic trees with the DNA-LM parameters showed that some ACP, CRZ, AKH2 and two NPP share nodes with GnRH from vertebrates and some of this neuropeptide had nodes in invertebrates. Whereas the phylogenetic tree with standard parameters do not showed previous node pattern. Robinson-Foulds metric corroborates the differences among phylogenetic trees. Homology relationship showed four putative orthogroups; AKH4, CRZ, and protostomes GnRH had individual group. This is the first demonstration of NPP in species and would explain the evolution neuropeptide families by the DNA-LM.

Asthma and incident coronary heart disease: an observational and Mendelian randomisation study.

BACKGROUND: Observational studies suggest asthma is a risk factor for coronary heart disease (CHD) and sex modifies the risk, but they may suffer from methodological limitations. To overcome these, we applied a "triangulation approach", where different methodologies, with different potential biases, were leveraged to enhance confidence in findings. METHODS: First, we conducted an observational study using UK medical records to match asthma patients 1:1, by age, sex and general practitioner (GP) practice, to the general population. We measured the association between asthma and incident CHD (myocardial infarction: hospitalisation/death) by applying minimal sufficient adjustment: model 1, smoking, body mass index, oral corticosteroids, atopy and deprivation; model 2, additionally adjusting for healthcare behaviour (GP consultation frequency). Second, we conducted a Mendelian randomisation (MR) study using data from the UK Biobank, Trans-National Asthma Genetic Consortium (TAGC) and Coronary Artery Disease Genome-wide Replication and Meta-analysis consortium (CARDIoGRAM). Using 64 asthma single nucleotide polymorphisms, the effect of asthma on CHD was estimated with inverse variance-weighted meta-analysis and methods that adjust for pleiotropy. RESULTS: In our observational study (n=1 522 910), we found asthma was associated with 6% increased risk of CHD (model 1: HR 1.06, 95% CI 1.01-1.13); after accounting for healthcare behaviour, we found no association (model 2: HR 0.99, 95% CI 0.94-1.05). Asthma severity did not modify the association, but sex did (females: HR 1.11, 95% CI 1.01-1.21; males: HR 0.91, 95% CI 0.84-0.98). Our MR study (n=589 875) found no association between asthma and CHD (OR 1.01, 95% CI 0.98-1.04) and no modification by sex. CONCLUSIONS: Our findings suggest that asthma is not a risk factor for CHD. Previous studies may have suffered from detection bias or residual confounding.

Trajectories of cardiac troponin in the decades before cardiovascular death: a longitudinal cohort study.

BACKGROUND: High-sensitivity cardiac troponin testing is a promising tool for cardiovascular risk prediction, but whether serial testing can dynamically predict risk is uncertain. We evaluated the trajectory of cardiac troponin I in the years prior to a cardiovascular event in the general population, and determine whether serial measurements could track risk within individuals. METHODS: In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on three occasions over a 15-year period. Time trajectories of troponin were constructed in those who died from cardiovascular disease compared to those who survived or died from other causes during follow up and these were externally validated in the HUNT Study. A joint model that adjusts for cardiovascular risk factors was used to estimate risk of cardiovascular death using serial troponin measurements. RESULTS: In 7,293 individuals (mean 58 ± 7 years, 29.4% women) cardiovascular and non-cardiovascular death occurred in 281 (3.9%) and 914 (12.5%) individuals (median follow-up 21.4 years), respectively. Troponin concentrations increased in those dying from cardiovascular disease with a steeper trajectory compared to those surviving or dying from other causes in Whitehall and HUNT (Pinteraction < 0.05 for both). The joint model demonstrated an independent association between temporal evolution of troponin and risk of cardiovascular death (HR per doubling, 1.45, 95% CI,1.33-1.75). CONCLUSIONS: Cardiac troponin I concentrations increased in those dying from cardiovascular disease compared to those surviving or dying from other causes over the preceding decades. Serial cardiac troponin testing in the general population has potential to track future cardiovascular risk.

Shellfish industrial waste reuse.

The global production of aquatic organisms has grown steadily in recent decades. This increase in production results in high volumes of by-products and waste, generally considered to be of low commercial value and part of them are consequently discarded in landfills or in the sea, causing serious environmental problems when not used. Currently, a large part of the reused aquaculture waste is destined for the feed industry. This generally undervalued waste presents an important source of bioactive compounds in its composition, such as: amino acids, carotenoids, chitin and its derivatives, fatty acids and minerals. These compounds are capable of offering numerous benefits due to their bioactive properties. However, the applicability of these compounds may be opportune in several other sectors. This review describes studies that seek to obtain and apply bioactive compounds from different sources of aquaculture waste, thus adding commercial value to these underutilized biomasses.HIGHLIGHTSVolume of aquaculture industrial waste from crustaceans and mollusks.Quantity and quality of bioactive components in aquaculture waste.Applications of recovered proteins, lipids, chitin, carotenoids and minerals.Future prospects for the destination of aquaculture waste.

Photophysical Characterization of Isoguanine in a Prebiotic-Like Environment.

It is intriguing how a mixture of organic molecules survived the prebiotic UV fluxes and evolved into the actual genetic building blocks. Scientists are trying to shed light on this issue by synthesizing nucleic acid monomers and their analogues under prebiotic Era-like conditions and by exploring their excited state dynamics. To further add to this important body of knowledge, this study discloses new insights into the photophysical properties of protonated isoguanine, an isomorph of guanine, using steady-state and femtosecond broadband transient absorption spectroscopies, and quantum mechanical calculations. Protonated isoguanine decays in ultrafast time scales following 292 nm excitation, consistently with the barrierless paths connecting the bright S1 (ππ*) state with different internal conversion funnels. Complementary calculations for neutral isoguanine predict similar photophysical properties. These results demonstrate that protonated isoguanine can be considered photostable in contrast to protonated guanine, which exhibits 40-fold longer excited state lifetimes.