Adaptation of turnip mosaic virus to Arabidopsis thaliana involves rewiring of VPg-host proteome interactions.

The outcome of a viral infection depends on a complex interplay between the host physiology and the virus, mediated through numerous protein-protein interactions. In a previous study, we used high-throughput yeast two-hybrid (HT-Y2H) to identify proteins in Arabidopsis thaliana that bind to the proteins encoded by the turnip mosaic virus (TuMV) genome. Furthermore, after experimental evolution of TuMV lineages in plants with mutations in defense-related or proviral genes, most mutations observed in the evolved viruses affected the VPg cistron. Among these mutations, D113G was a convergent mutation selected in many lineages across different plant genotypes, including cpr5-2 with constitutive expression of systemic acquired resistance. In contrast, mutation R118H specifically emerged in the jin1 mutant with affected jasmonate signaling. Using the HT-Y2H system, we analyzed the impact of these two mutations on VPg's interaction with plant proteins. Interestingly, both mutations severely compromised the interaction of VPg with the translation initiation factor eIF(iso)4E, a crucial interactor for potyvirus infection. Moreover, mutation D113G, but not R118H, adversely affected the interaction with RHD1, a zinc-finger homeodomain transcription factor involved in regulating DNA demethylation. Our results suggest that RHD1 enhances plant tolerance to TuMV infection. We also discuss our findings in a broad virus evolution context.

Alterations in Gray Matter Structural Networks in Amnestic Mild Cognitive Impairment: A Source-Based Morphometry Study.

Background: Amnestic mild cognitive impairment (aMCI), considered as the prodromal stage of Alzheimer's disease, is characterized by isolated memory impairment and cerebral gray matter volume (GMV) alterations. Previous structural MRI studies in aMCI have been mainly based on univariate statistics using voxel-based morphometry. Objective: We investigated structural network differences between aMCI patients and cognitively normal older adults by using source-based morphometry, a multivariate approach that considers the relationship between voxels of various parts of the brain. Methods: Ninety-one aMCI patients and 80 cognitively normal controls underwent structural MRI and neuropsychological assessment. Spatially independent components (ICs) that covaried between participants were estimated and a multivariate analysis of covariance was performed with ICs as dependent variables, diagnosis as independent variable, and age, sex, education level, and site as covariates. Results: aMCI patients exhibited reduced GMV in the precentral, temporo-cerebellar, frontal, and temporal network, and increased GMV in the left superior parietal network compared to controls (pFWER < 0.05, Holm-Bonferroni correction). Moreover, we found that diagnosis, more specifically aMCI, moderated the positive relationship between occipital network and Mini-Mental State Examination scores (pFWER < 0.05, Holm-Bonferroni correction). Conclusions: Our results showed GMV alterations in temporo-fronto-parieto-cerebellar networks in aMCI, extending previous results obtained with univariate approaches.

Towards Sustainable Temperature Sensor Production through CO2-Derived Polycarbonate-Based Composites.

The steep increase in carbon dioxide (CO2) emissions has created great concern due to its role in the greenhouse effect and global warming. One approach to mitigate CO2 levels involves its application in specific technologies. In this context, CO2 can be used for a more sustainable synthesis of polycarbonates (CO2-PCs). In this research, CO2-PC films and composites with multiwalled carbon nanotubes (MWCNTs, ranging from 0.2 to 7.0 wt.%) have been prepared to achieve more sustainable multifunctional sensing devices. The inclusion of the carbonaceous fillers allows for the electrical conductivity to be enhanced, reaching the percolation threshold (Pc) at 0.1 wt.% MWCNTs and a maximum electrical conductivity of 0.107 S·m-1 for the composite containing 1.5 wt.% MWCNTs. The composite containing 3.0 wt.% MWCNTs was also studied, showing a stable and linear response under temperature variations from 40 to 100 °C and from 30 to 45 °C, with a sensitivity of 1.3 × 10-4 °C-1. Thus, this investigation demonstrates the possibility of employing CO2-derived PC/MWCNT composites as thermoresistive sensing materials, allowing for the transition towards sustainable polymer-based electronics.

ß-Amino Acids Reduce Ternary Complex Stability and Alter the Translation Elongation Mechanism.

Templated synthesis of proteins containing non-natural amino acids (nnAAs) promises to expand the chemical space available to biological therapeutics and materials, but existing technologies are still limiting. Addressing these limitations requires a deeper understanding of the mechanism of protein synthesis and how it is perturbed by nnAAs. Here we examine the impact of nnAAs on the formation and ribosome utilization of the central elongation substrate: the ternary complex of native, aminoacylated tRNA, thermally unstable elongation factor, and GTP. By performing ensemble and single-molecule fluorescence resonance energy transfer measurements, we reveal that both the (R)- and (S)-ß2 isomers of phenylalanine (Phe) disrupt ternary complex formation to levels below in vitro detection limits, while (R)- and (S)-ß3-Phe reduce ternary complex stability by 1 order of magnitude. Consistent with these findings, (R)- and (S)-ß2-Phe-charged tRNAs were not utilized by the ribosome, while (R)- and (S)-ß3-Phe stereoisomers were utilized inefficiently. (R)-ß3-Phe but not (S)-ß3-Phe also exhibited order of magnitude defects in the rate of translocation after mRNA decoding. We conclude from these findings that non-natural amino acids can negatively impact the translation mechanism on multiple fronts and that the bottlenecks for improvement must include the consideration of the efficiency and stability of ternary complex formation.

Management and Outcomes of Hepatoblastoma in Patients With Trisomy 18: A Systematic Review and Pooled Analysis of 70 Patients.

INTRODUCTION: Predicted 1-year survival of children with trisomy 18 (T18) has increased to 59.3%. We aimed to systematically review the characteristics, management, and outcomes of children with T18 and hepatoblastoma. METHODS: A systematic literature review of the PubMed, Embase, Scopus, Web of Science, and Cochrane Library databases was performed according to the PRISMA 2020 statement (end-of-search date: 03/03/2024). RESULTS: Fifty studies reporting on 70 patients were included. The median age at diagnosis was 11.5 months, 85.9% were female (n = 55/64), and 15.0% had mosaic T18 (n = 6/40). Diagnosis was made during symptom evaluation (most commonly hepatomegaly or abdominal mass) in 45.5% (n = 15/33), incidentally in 24.2% (n = 8/33), during surveillance with abdominal ultrasound in 18.2% (n = 6/33), and at autopsy in 12.1% (n = 4/33). The median tumor size was 6.4 cm, 33.3% had multiple tumors (n = 14/42), and metastasis was present in one patient (3.8%; n = 1/26). Neoadjuvant chemotherapy was administered in 42.6% (n = 26/61) and adjuvant chemotherapy in 31.6% (n = 18/57). Surgical treatment was performed in 64.2% (n = 43/67). Of the patients not diagnosed on autopsy, overall mortality was 35.5% (n = 22/62) over a median follow-up of 11.0 months. Among the 26 deceased patients (including those diagnosed on autopsy), the most common causes of death were cardiopulmonary disease (38.5%, n = 10/26) and tumor progression (30.8%, n = 8/26). CONCLUSIONS: T18 does not preclude resection with curative intent for hepatoblastoma. Combination of surgery and chemotherapy should be considered in children on an individualized basis depending on tumor characteristics and underlying cardiopulmonary comorbidities. Locoregional modalities may have a role in the setting of severe comorbidities. LEVEL OF EVIDENCE: Level IV evidence.

Epidemiology, Treatment Patterns, and Cost Analysis of Immune Thrombocytopenia in Spain between 2014 and 2020: A Population-based Study.

Background Immune thrombocytopenia (ITP) is characterised by low platelet counts and often leads to bleeding, fatigue, and reduced health-related quality of life. Methods This observational, retrospective, population-based study using BIG-PAC® database included Spanish paediatric and adult patients with primary ITP diagnosed in primary care and hospitals between 2014 and 2020 (median follow-up: 4 years). Epidemiology, baseline/clinical characteristics, treatment trends, healthcare resources and costs were analysed. Results The BIG-PAC® database contains records of 1,818,588 patients; 170 adults and 27 children with ITP were included in our analysis. ITP prevalence and annual incidence per 100,000 were estimated in 10.8 (2.8 in chronic ITP [cITP] patients) and 1.5 (0.3 in cITP patients), respectively. Epistaxis was the most common bleeding event, followed by genitourinary and gastrointestinal bleeding; >50%/> 75% of ITP/cITP patients reported fatigue. Chronic patients had lower platelet counts at baseline and required more transfusions. Corticosteroids, immunosuppressants, and thrombopoietin receptor agonists were the most used agents in first-, second- and third-line treatment, respectively. Thirty-five patients, all of them in chronic phase, underwent splenectomy. Patients had on average 13.9, 6.6, and 1.2 visits/year to primary care, haematology/internal medicine, and emergency departments, respectively. More than one-fourth of adult patients took on average 16.3 days of sick leave annually. Mean annual total health care costs were €10,741 (ITP patients) and €19,809 (cITP patients). Conclusion This is the first study to provide an overall perspective on the situation of the Spanish ITP population in terms of epidemiology, treatment trends, health care resources and costs, highlighting unmet patient needs, and direct and indirect costs/resource use between 2014 and 2020.

Arresting dissolution of two-dimensional metal-organic frameworks enables long life in electrochemical devices.

Two-dimensional conjugated metal-organic frameworks (2D cMOFs) are emerging as promising materials for electrochemical energy storage (EES). Despite considerable interest, an understanding of their electrochemical stability and the factors contributing to their degradation during cycling is largely lacking. Here we investigate three Cu-based MOFs and report that the dissolution of 2D cMOFs into electrolytes is a prevalent and significant degradation pathway. Several factors, such as the inherent solubility of ligands in electrolyte solvents and the duration of charge-discharge cycling exert a strong influence on the dissolution process. When these factors combine within a MOF, severely limited cycling stability is observed, with dissolution accounting for up to 80% of capacity degradation. Conversely, excellent cycling stability is observed when testing a Cu-MOF with a sparingly soluble ligand within an optimized potential window. Overall, these findings represent essential insights into the electrochemical stability of 2D cMOFs, offering crucial guidelines for their targeted development in EES applications.

Computational approaches for lead compound discovery in dipeptidyl peptidase-4 inhibition using machine learning and molecular dynamics techniques.

The prediction of possible lead compounds from already-known drugs that may present DPP-4 inhibition activity imply a advantage in the drug development in terms of time and cost to find alternative medicines for the treatment of Type 2 Diabetes Mellitus (T2DM). The inhibition of dipeptidyl peptidase-4 (DPP-4) has been one of the most explored strategies to develop potential drugs against this condition. A diverse dataset of molecules with known experimental inhibitory activity against DPP-4 was constructed and used to develop predictive models using different machine-learning algorithms. Model M36 is the most promising one based on the internal and external performance showing values of Q2CV = 0.813, and Q2EXT = 0.803. The applicability domain evaluation and Tropsha's analysis were conducted to validate M36, indicating its robustness and accuracy in predicting pIC50 values for organic molecules within the established domain. The physicochemical properties of the ligands, including electronegativity, polarizability, and van der Waals volume were relevant to predict the inhibition process. The model was then employed in the virtual screening of potential DPP4 inhibitors, finding 448 compounds from the DrugBank and 9 from DiaNat with potential inhibitory activity. Molecular docking and molecular dynamics simulations were used to get insight into the ligand-protein interaction. From the screening and the favorable molecular dynamic results, several compounds including Skimmin (pIC50 = 3.54, Binding energy = -8.86 kcal/mol), bergenin (pIC50 = 2.69, Binding energy = -13.90 kcal/mol), and DB07272 (pIC50 = 3.97, Binding energy = -25.28 kcal/mol) seem to be promising hits to be tested and optimized in the treatment of T2DM. This results imply a important reduction in cost and time on the application of this drugs because all the information about the its metabolism is already available.

Carcinoid crisis: The challenge is still there.

Carcinoid crisis (CC) has classically been considered the extreme end of the spectrum of carcinoid syndrome (CS). However, this presumption and other aspects of CC remain poorly understood. Consequently, current clinical guidelines are based on a low quality of evidence. There is no standard definition of CC and its incidence is unknown. Patients with florid CS and elevated serotonin (or its derivatives) which develop CC have been reported during decades. Nevertheless, the hypothesis that CC is due to the sudden massive release of serotonin or other vasoactive substances is unproven. Many triggers of CC (surgery, anaesthesia, peptide receptor radionuclide therapy, tumour biopsy or liver-directed treatments) have been proposed. However, data from studies are heterogeneous and even contradictory. Finally, the role of octreotide in the prevention of CC has been questioned. Herein, we report a clinical case and perform a critical review of the evidence available today on this topic.

Efficacy and safety of regorafenib as a first-line agent alone or in combination with an immune checkpoint inhibitor for advanced hepatocellular carcinoma: a retrospective cohort study.

Background: The RESORCE-III trial demonstrated that advanced hepatocellular carcinoma (HCC) patients who progressed on sorafenib and had second-line therapy with regorafenib improved overall survival compared with placebo. Later, immunotherapy with immune checkpoint inhibitors (ICIs) combined with antiangiogenetic antibodies has evolved as the preferred first-line treatment for fit patients. We aimed to explore the efficacy and safety of regorafenib as a first-line agent alone or in combination with ICIs in patients with advanced HCC. Methods: We identified 50 patients with advanced HCC treated with regorafenib as a first-line agent. Two patients were lost to follow-up and excluded. Baseline factors, dosing, concomitant use of ICIs, toxicity and outcome of treatment were recorded from electronic medical records. Results: Twenty-six patients received regorafenib as monotherapy and twenty-two received regorafenib + ICI in combination. In the total cohort, the median progression-free survival (mPFS) was 7.7 months and the median overall survival (mOS) was 16.7 months (P=0.02). Objective response rate (ORR) and disease control rate (DCR) assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were 21% and 73%. In the regorafenib monotherapy group, mPFS was 5.9 months, and mOS was 13.9 months; in the combination group, mPFS was 7.8 months, and mOS was 23.6 months. ORR and DCR were 15% and 65% in the monotherapy group, and 27% and 82% in the combined treatment group, respectively. Conclusions: Regorafenib used in combination with ICIs had a mild safety profile and resulted in improved response and an almost doubling of mOS compared to monotherapy, warranting further prospective evaluation in a randomized study.

MINIstock: Model for INsect Inclusion in sustainable agriculture: USDA-ARS's research approach to advancing insect meal development and inclusion in animal diets.

Animal agriculture is under pressure to increase efficiency, sustainability, and innovation to meet the demands of a rising global population while decreasing adverse environmental effects. Feed cost and availability are 2 of the biggest hurdles to sustainable production. Current diets depend on sources of grain and animal byproduct protein for essential amino acids which have limited sustainability. Insects have arisen as an attractive, sustainable alternative protein source for animal diets due to their favorable nutrient composition, low space and water requirements, and natural role in animal diets. Additionally, insects are capable of bioremediating waste streams including agricultural and food waste, manure, and plastics helping to increase their sustainability. The insect rearing industry has grown rapidly in recent years and shows great economic potential. However, state-of-the-art research is urgently needed to overcome barriers to adoption in commercial animal diets such as regulatory restrictions, production scale issues, and food safety concerns. To address this need, the USDA Agricultural Research Service "MINIstoc: Model for INsect Inclusion" project was created to bring together diverse scientists from across the world to synergistically advance insect meal production and inclusion in animal diets. Here, we provide a short review of insects as feed while describing the MINIstock project which serves as the inspiration for the Journal of Economic Entomology Special Collection "Insects as feed: sustainable solutions for food waste and animal production practices."

Context-dependent reduction in corticomuscular coupling for balance control in chronic stroke survivors.

Balance control is an important indicator of mobility and independence in activities of daily living. How the functional coupling between the cortex and the muscle for balance control is affected following stroke remains to be known. We investigated the changes in coupling between the cortex and leg muscles during a challenging balance task over multiple frequency bands in chronic stroke survivors. Fourteen participants with stroke and ten healthy controls performed a challenging balance task. They stood on a computerized support surface that was either fixed (low difficulty condition) or sway-referenced with varying gain (medium and high difficulty conditions). We computed corticomuscular coherence between electrodes placed over the sensorimotor area (electroencephalography) and leg muscles (electromyography) and assessed balance performance using clinical and laboratory-based tests. We found significantly lower delta frequency band coherence in stroke participants when compared with healthy controls under medium difficulty condition, but not during low and high difficulty conditions. These differences were found for most of the distal but not for proximal leg muscle groups. No differences were found at other frequency bands. Participants with stroke showed poor balance clinical scores when compared with healthy controls, but no differences were found for laboratory-based tests. The observation of effects at distal but not at proximal muscle groups suggests differences in the (re)organization of the descending connections across two muscle groups for balance control. We argue that the observed group difference in delta band coherence indicates balance context-dependent alteration in mechanisms for the detection of somatosensory modulation resulting from sway-referencing of the support surface for balance maintenance following stroke.

Lifestyle predictors of colorectal cancer in European populations: a systematic review.

Background: Colorectal cancer (CRC) is the second most prevalent cancer in Europe, with one-fifth of cases attributable to unhealthy lifestyles. Risk prediction models for quantifying CRC risk and identifying high-risk groups have been developed or validated across European populations, some considering lifestyle as a predictor. Purpose: To identify lifestyle predictors considered in existing risk prediction models applicable for European populations and characterise their corresponding parameter values for an improved understanding of their relative contribution to prediction across different models. Methods: A systematic review was conducted in PubMed and Web of Science from January 2000 to August 2021. Risk prediction models were included if (1) developed and/or validated in an adult asymptomatic European population, (2) based on non-invasively measured predictors and (3) reported mean estimates and uncertainty for predictors included. To facilitate comparison, model-specific lifestyle predictors were visualised using forest plots. Results: A total of 21 risk prediction models for CRC (reported in 16 studies) were eligible, of which 11 were validated in a European adult population but developed elsewhere, mostly USA. All models but two reported at least one lifestyle factor as predictor. Of the lifestyle factors, the most common predictors were body mass index (BMI) and smoking (each present in 13 models), followed by alcohol (11), and physical activity (7), while diet-related factors were less considered with the most commonly present meat (9), vegetables (5) or dairy (2). The independent predictive contribution was generally greater when they were collected with greater detail, although a noticeable variation in effect size estimates for BMI, smoking and alcohol. Conclusions: Early identification of high-risk groups based on lifestyle data offers the potential to encourage participation in lifestyle change and screening programmes, hence reduce CRC burden. We propose the commonly shared lifestyle predictors to be further used in public health prediction modelling for improved uptake of the model.

Ultrasound-Guided External Oblique Intercostal Block as Part of Multimodal Analgesia for Unplanned Open Cholecystectomy.

We present the case of a 56-year-old female with a significant medical history of cholelithiasis and recurrent choledocholithiasis. Following an elective cholecystectomy, an obstructing gallstone in the common bile duct led to a series of interventions, including endoscopic retrograde cholangiopancreatography and stent placement. The patient was scheduled for a robot-assisted laparoscopic common bile duct exploration. Due to severe adhesions, the procedure was converted to open with a large right upper quadrant incision. Intraoperative continuous external oblique block and catheter placement were performed at the end of surgery in the OR. Peripheral nerve blocks have become an integral part of multimodal pain management strategies. This case report describes the successful implementation of an ultrasound-guided right external oblique intercostal block and catheter placement for postoperative pain control and minimization of opioids. This case highlights the efficacy and safety of ultrasound-guided peripheral nerve blocks for postoperative pain management. Successful pain control contributed to the patient's overall postoperative recovery.

Acute Pain Management in a Multi-site Trauma Patient.

Pain management is often difficult in the setting of multi-site trauma such as that caused by motor vehicle accidents (MVA), which is especially compounded in the setting of polysubstance abuse. This often results in patients with poor pain tolerance requiring escalating doses of opioid therapy, which creates a vicious cycle. The use of peripheral nerve blocks (PNB) has been shown to decrease overall opioid consumption and can be used effectively to manage postoperative pain in this patient population. Our case report aims to highlight the importance of PNBs as part of a multimodal approach to pain management in patients with polytrauma in the setting of polysubstance abuse.

Rationale and design of the SPREAD study: Sport Practice and its Effects on Aortic Size and Valve Function in Bicuspid Aortic Valve Disease.

The bicuspid aortic valve (BAV) is the most common congenital heart defect among adults, often leading to severe valve dysfunction and aortic complications. Despite its clinical significance, uncertainties persist regarding the impact of sports participation on the natural course of BAV disease. The SPREAD (Sport PRactice and its Effects on Bicuspid Aortic valve Disease) study is a multicenter and multinational project designed to investigate this relationship. This paper outlines the study's design, and objectives. The study is divided into two phases; phase one involves a cross-sectional analysis comparing aortic dimensions and valve function among competitive athletes with BAV, athletes with tricuspid aortic valves (TAV), and sedentary individuals with BAV. The second phase is a prospective, longitudinal follow-up aiming to evaluate the impact of regular sports training on disease progression. The SPREAD study seeks to provide evidence-based insights into the effects of sports participation on BAV disease progression, guiding clinical decision-making regarding sports eligibility and risk stratification for individuals with BAV.

Regulatory compliance of PCDD/F emissions by a municipal solid waste incinerator. A case study in Sant Adrià de Besòs, Catalonia, Spain.

Despite incineration is an important emission source of toxic pollutants, such as heavy metals and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), it is still one of the most widely used methods for the management of municipal solid waste. The current paper summarizes the results of a 20-year follow-up study of the emissions of PCDD/Fs by a municipal solid waste incinerator (MSWI) in Sant Adrià de Besòs (Catalonia, Spain). Samples of ambient air, soils and herbage were periodically collected near the facility and the content of PCDD/Fs was analyzed. In the last (2017) survey, mean levels in soil were 3.60 ng WHO-TEQ/kg (range: 0.40-10.6), being considerably higher than the mean concentrations of PCDD/Fs in soil samples collected near other MSWIs in Catalonia. Moreover, air PCDD/F concentrations were even higher than those found in a previous (2014) survey, as they increased from 0.026 to 0.044 pg WHO-TEQ/m3. Ultimately, the PCDD/F exposure would be associated to a cancer risk (2.5 × 10-6) for the population living in the surrounding area. Globally, this information indicates that the MSWI of Sant Adrià de Besòs could have had a negative impact on the environment and potentially on public health, being an example of a possible inappropriate management for years. The application of Best Available Techniques to minimize the emission of PCDD/Fs and other chemicals is critical.

Levels of Rare Earth Elements in Food and Human Dietary Exposure: A Review.

Rare earth elements (REEs) are a group consisting of the following 17 metals: Ce, Dy, Er, Eu, Gd, Ho, La, Lu, Nd, Pr, Pm, Sc, Sm, Tb, Tm, Y and Yb. In the current century, the number of applications of REEs has significantly increased. They are being used as components in high technology devices of great importance industrial/economic. However, information on the risk of human exposure to REEs, as well as the potential toxic effects of these elements is still limited. In general terms, dietary intake is the main route of exposure to metals for non-occupationally exposed individuals, which should be also expected for REEs. The current paper aimed at reviewing the studies -conducted over the world- that focused on determining the levels of REEs in foods, as well as the dietary intake of these elements. Most studies do not suggest potential health risk for consumers of freshwater and marine species of higher consumption, or derived from the intake of a number of vegetables, fruits, mushrooms, as well as other various foodstuffs (honey, tea, rice, etc.). The current estimated daily intake (EDI) of REEs does not seem to be of concern. However, considering the expected wide use of these elements in the next years, it seems to be clearly recommendable to assess periodically the potential health risk of the dietary exposure to REEs. This is already being done with well-known toxic elements such as As, Cd, Pb and Hg, among other potentially toxic metals.