Responses of fine particulate matter (PM2.5) air quality to future climate, land use, and emission changes: Insights from modeling across shared socioeconomic pathways.

Air pollution induced by fine particulate matter with diameter ≤ 2.5 µm (PM2.5) poses a significant challenge for global air quality management. Understanding how factors such as climate change, land use and land cover change (LULCC), and changing emissions interact to impact PM2.5 remains limited. To address this gap, we employed the Community Earth System Model and examined both the individual and combined effects of these factors on global surface PM2.5 in 2010 and projected scenarios for 2050 under different Shared Socioeconomic Pathways (SSPs). Our results reveal biomass-burning and anthropogenic emissions as the primary drivers of surface PM2.5 across all SSPs. Less polluted regions like the US and Europe are expected to experience substantial PM2.5 reduction in all future scenarios, reaching up to ~5 µg m-3 (70 %) in SSP1. However, heavily polluted regions like India and China may experience varied outcomes, with a potential decrease in SSP1 and increase under SSP3. Eastern China witness ~20 % rise in PM2.5 under SSP3, while northern India may experience ~70 % increase under same scenario. Depending on the region, climate change alone is expected to change PM2.5 up to ±5 µg m-3, while the influence of LULCC appears even weaker. The modest changes in PM2.5 attributable to LULCC and climate change are associated with aerosol chemistry and meteorological effects, including biogenic volatile organic compound emissions, SO2 oxidation, and NH4NO3 formation. Despite their comparatively minor role, LULCC and climate change can still significantly shape future air quality in specific regions, potentially counteracting the benefits of emission control initiatives. This study underscores the pivotal role of changes in anthropogenic emissions in shaping future PM2.5 across all SSP scenarios. Thus, addressing all contributing factors, with a primary focus on reducing anthropogenic emissions, is crucial for achieving sustainable reduction in surface PM2.5 levels and meeting sustainable pollution mitigation goals.

Isolation and Total Synthesis of PM170453, a New Cyclic Depsipeptide Isolated from Lyngbya sp.

In our continuing search for biologically active new chemical entities from marine organisms, we have isolated a new cyclic depsipeptide, PM170453 (1), from a cyanobacterium of the genus Lyngbya sp., collected in the Indo-Pacific Ocean. Structure elucidation of the isolated compound was determined by spectroscopic methods including MS, 1H, 13C and 2D-NMR. To solve the supply problem for 1 and progress pharmaceutical development, the total synthesis of 1 that involves a total of 20 chemical steps in a convergent process was carried out. Its in vitro cytotoxic activity against four human tumor cell lines, as well as the inhibition of the interaction between the programmed cell death protein 1 PD-1 and its ligand PD-L1 were also evaluated.

Relationship of body composition with middle cerebral artery hemodynamic using compositional data analysis: Toledo Study for Healthy Ageing in middle age.

Excess adipose tissue may promote chronic systemic inflammation and oxidative stress, causing endothelial damage. Early evidence indicates that obesity may be associated with poorer cerebral perfusion. The purpose of this study was to examine the relationship between body composition and cerebral hemodynamics. A total of 248 middle-aged adults (50-58 years old; 55% women) underwent a ramp test on a cycle-ergometer until volitional exhaustion. Gas exchange was assessed on a breath-by-breath basis. Mean middle cerebral artery velocity (MCAv) was measured using transcranial Doppler, and pulsatility index (PI) calculated. Body composition was assessed by dual X-ray absorptiometry. Statistical analyses were performed using a compositional data approach including a three-compartment model for body composition (trunk fat mass, extremities fat mass, and fat-free mass). The unadjusted models for the whole sample showed that trunk fat mass relative to other compartments was negatively associated with MCAvrest, MCAvmax, and gain, and positively associated with PImax; extremities fat mass relative to other compartments was positively associated with MCAvrest and MCAvmax, and negatively associated with PImax; and fat-free mass relative to other compartments was positively associated with PImax. These associations were sex-dependent, remaining in the women's subgroup. However, after adjusting for confounders, these associations became non-significant, except for PImax in the whole sample and women's subgroup. These findings suggest a possible association between cerebral hemodynamics and body composition in middle-aged adults, highlighting sex-specific differences. Moreover, our results indicate that higher trunk fat mass relative to other compartments may negatively impact cerebral hemodynamics, reducing MCAv and increasing PImax.

Circadian Transcriptome Oscillations In Human Adipose Tissue Depend On Napping Status And Link To Metabolic And Inflammatory Pathways.

STUDY OBJECTIVES: Napping is a common habit in many countries. Nevertheless, studies about the chronic effects of napping on obesity are contradictory, and the molecular link between napping and metabolic alterations has yet to be studied. We aim to identify molecular mechanisms in adipose tissue (AT) that may connect napping and abdominal obesity. METHODS: In this cross-sectional study, we extracted the RNA repeatedly across 24h from cultured AT explants and performed RNA sequencing. Circadian rhythms were analyzed using 6 consecutive time points across 24 hours. We also assessed global gene expression in each group (nappers vs. non-nappers). RESULTS: With napping, there was a loss of rhythmicity in 88% of genes that showed circadian rhythmicity among non-nappers, a reduction in rhythm amplitudes of 29%, and significant phase changes from a coherent unimodal acrophase in non-nappers, towards a scattered and bimodal acrophase in nappers. Those genes that lost rhythmicity with napping were mainly involved in pathways of glucose and lipid metabolism, and of the circadian clock. Additionally, we found differential global gene expression between nappers and non-nappers with 34 genes down- and 32 genes up-regulated in nappers. The top up-regulated gene (IER3) and top down-regulated pseudogene (VDAC2P2) in nappers have been previously shown to be involved in inflammation. CONCLUSION: These new findings may have implications for our understanding of napping's effects on obesity and metabolic disorders.

Dynamic Adhesive Behavior and Biofilm Formation of Staphylococcus aureus on Polylactic Acid Surfaces in Diabetic Environments.

Interest in biodegradable implants has focused attention on the resorbable polymer polylactic acid. However, the risk of these materials promoting infection, especially in patients with existing pathologies, needs to be monitored. The enrichment of a bacterial adhesion medium with compounds that are associated with human pathologies can help in understanding how these components affect the development of infectious processes. Specifically, this work evaluates the influence of glucose and ketone bodies (in a diabetic context) on the adhesion dynamics of S. aureus to the biomaterial polylactic acid, employing different approaches and discussing the results based on the physical properties of the bacterial surface and its metabolic activity. The combination of ketoacidosis and hyperglycemia (GK2) appears to be the worst scenario: this system promotes a state of continuous bacterial colonization over time, suppressing the stationary phase of adhesion and strengthening the attachment of bacteria to the surface. In addition, these supplements cause a significant increase in the metabolic activity of the bacteria. Compared to non-enriched media, biofilm formation doubles under ketoacidosis conditions, while in the planktonic state, it is glucose that triggers metabolic activity, which is practically suppressed when only ketone components are present. Both information must be complementary to understand what can happen in a real system, where planktonic bacteria are the ones that initially colonize a surface, and, subsequently, these attached bacteria end up forming a biofilm. This information highlights the need for good monitoring of diabetic patients, especially if they use an implanted device made of PLA.

Sacha Inchi (Plukenetia volubilis L.) Protein Hydrolysate as a New Ingredient of Functional Foods.

Sacha inchi (Plukenetia volubilis L.) is an under-exploited crop with great potential due to its nutritional and medicinal characteristics. A Sacha inchi protein isolate (SII), obtained from defatted Sacha inchi flour (SIF), was hydrolyzed by Bioprotease LA 660 under specific conditions. The hydrolysates were characterized chemically, and their digestibility and antioxidant capacity were evaluated by in vitro cell-free experiments to select the hydrolysate with major antioxidant activity. Sacha inchi protein hydrolysate at 20 min (SIH20B) was selected, and the anti-inflammatory capacity was evaluated by RT-qPCR and ELISA techniques, using two different doses in monocytes THP-1 stimulated with lipopolysaccharide (LPS). The results obtained showed that the in vitro administration of SIH20B down-regulated the TNF-α gene and reduced the release of this cytokine, whereas the anti-inflammatory cytokines IL-10 and IL-4 were up-regulated in LPS-stimulated monocytes and co-administrated with SIH20B. The peptides contained in SIH20B were identified, and the 20 more relatively abundant peptides with a mass by 1 kDa were subjected to in silico analysis to hypothesize those that could be responsible for the bioactivity reported in the hydrolysate. From the identified peptides, the peptides AAGALKKFL and LGVKFKGGL, among others, are proposed as the most biologically actives. In conclusion, SIH20B is a novel, natural source of high-value-added biopeptides that could be used as an ingredient in formulations of food or nutraceutical compounds.

Synthesis and Properties of Hydrophilic and Hydrophobic Deep Eutectic Solvents via Heating-Stirring and Ultrasound.

Deep eutectic solvents (DESs) have emerged as a greener alternative to other more polluting traditional solvents and have attracted a lot of interest in the last two decades. The DESs are less toxic dissolvents and have a lower environmental footprint. This paper presents an alternative synthesis method to the classical heating-stirring method. The ultrasound method is one of the most promising synthesis methods for DESs in terms of yield and energy efficiency. Therefore, the ultrasound synthesis method was studied to obtain hydrophobic (Aliquat 336:L-Menthol (3:7); Lidocaine:Decanoic acid (1:2)) and hydrophilic DESs based on choline chloride, urea, ethylene glycol and oxalic acid. The physical characterization of DESs via comparison of Fourier transform infrared (FTIR) spectra showed no difference between the DESs obtained by heating-stirring and ultrasound synthesis methods. The study and comparison of all the prepared DESs were carried out via nuclear magnetic resonance spectroscopy (NMR). The density and viscosity properties of DESs were evaluated. The density values were similar for both synthesis methods. However, differences in viscosity values were detected due to the presence of some water in hygroscopic DESs.

GUANIN: An all-in-one GUi-driven Analyzer for NanoString Interactive Normalization.

SUMMARY: Most tools for normalizing NanoString gene expression data, apart from the default NanoString nCounter software, are R packages that focus on technical normalization and lack configurable parameters. However, content normalization is the most sensitive, experiment-specific, and relevant step to preprocess NanoString data. Currently this step requires the use of multiple tools and a deep understanding of data management by the researcher. We present GUANIN, a comprehensive normalization tool that integrates both new and well-established methods, offering a wide variety of options to introduce, filter, choose, and evaluate reference genes for content normalization. GUANIN allows the introduction of genes from and endogenous subset as reference genes, addressing housekeeping-related selection problems. It performs a specific and straightforward normalization approach for each experiment, using a wide variety of parameters with suggested default values. GUANIN provides a large number of informative output files that enable the iterative refinement of the normalization process. In terms of normalization, GUANIN matches or outperforms other available methods. Importantly, it allows researchers to interact comprehensively with the preprocessing process without programming knowledge, thanks to its easy-to-use Graphical User Interface (GUI). AVAILABILITY AND IMPLEMENTATION: GUANIN can be installed with pip install guanin and it is available at https://pypi.org/project/guanin/. Source code, documentation and case studies are available at https://github.com/julimontoto/guanin under the GPLv3 license. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Viroporin-like activity of the hairpin transmembrane domain of African swine fever virus B169L protein.

African swine fever virus (ASFV) is the causative agent of a contagious disease affecting wild and domestic swine. The function of B169L protein, as a potential integral structural membrane protein, remains to be experimentally characterized. Using state-of-the-art bioinformatics tools, we confirm here earlier predictions indicating the presence of an integral membrane helical hairpin, and further suggest anchoring of this protein to the ER membrane, with both terminal ends facing the lumen of the organelle. Our evolutionary analysis confirmed the importance of purifying selection in the preservation of the identified domains during the evolution of B169L in nature. Also, we address the possible function of this hairpin transmembrane domain (HTMD) as a class IIA viroporin. Expression of GFP fusion proteins in the absence of a signal peptide supported B169L insertion into the ER as a Type III membrane protein and the formation of oligomers therein. Overlapping peptides that spanned the B169L HTMD were reconstituted into ER-like membranes and the adopted structures analyzed by infrared spectroscopy. Consistent with the predictions, B169L transmembrane sequences adopted α-helical conformations in lipid bilayers. Moreover, single vesicle permeability assays demonstrated the assembly of lytic pores in ER-like membranes by B169L transmembrane helices, a capacity confirmed by ion-channel activity measurements in planar bilayers. Emphasizing the relevance of these observations, pore-forming activities were not observed in the case of transmembrane helices derived from EP84R, another ASFV protein predicted to anchor to membranes through a α-helical HTMD. Overall, our results support predictions of viroporin-like function for the B169L HTMD.IMPORTANCEAfrican swine fever (ASF), a devastating disease affecting domestic swine, is widely spread in Eurasia, producing significant economic problems in the pork industry. Approaches to prevent/cure the disease are mainly restricted to the limited information concerning the role of most of the genes encoded by the large (160-170 kba) virus genome. In this report, we present the experimental data on the functional characterization of the African swine fever virus (ASFV) gene B169L. Data presented here indicates that the B169L gene encodes for an essential membrane-associated protein with a viroporin function.

Mild behavioral impairment domains are longitudinally associated with pTAU and metabolic biomarkers in dementia-free older adults.

BACKGROUND: The mechanisms linking mild behavioral impairment (MBI) and Alzheimer's disease (AD) have been insufficiently explored, with conflicting results regarding tau protein and few data on other metabolic markers. We aimed to evaluate the longitudinal association of the MBI domains and a spectrum of plasma biomarkers. METHODS: Our study is a secondary analysis of data from NOLAN. The longitudinal association of the MBI domains with plasma biomarkers, including pTau181, was tested using adjusted linear mixed-effects models. RESULTS: The sample comprised 359 participants (60% female, mean age: 78.3, standard deviation: 0.3 years). After 1 year, the MBI domain of abnormal perception was associated with steeper increases in plasma pTau181. Abnormal perception, decreased motivation, and impulse dyscontrol were associated with homocysteine or insulin dysregulation. DISCUSSION: Apart from the association with plasma pTau181, our results suggest that MBI might also represent metabolic dysregulation, probably contributing to dementia transition among older adults with subjective cognitive decline or mild cognitive impairment. HIGHLIGHTS: Mild behavioral impairment (MBI) psychosis was associated with steeper increases in plasma p. pTau could be a pharmacological target to treat agitation and psychosis symptoms. MBI domains were linked to metabolic dysregulation involving insulin and homocysteine.

ACR Appropriateness Criteria® Workup of Pleural Effusion or Pleural Disease.

Pleural effusions are categorized as transudative or exudative, with transudative effusions usually reflecting the sequala of a systemic etiology and exudative effusions usually resulting from a process localized to the pleura. Common causes of transudative pleural effusions include congestive heart failure, cirrhosis, and renal failure, whereas exudative effusions are typically due to infection, malignancy, or autoimmune disorders. This document summarizes appropriateness guidelines for imaging in four common clinical scenarios in patients with known or suspected pleural effusion or pleural disease. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer's disease.

Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer's Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.

Children with obesity have poorer circadian health as assessed by a global circadian health score.

BACKGROUND: Circadian health refers to individuals' well-being and balance in terms of their circadian rhythm. It is influenced by external cues. In adults, a close relationship between circadian-related alterations and obesity has been described. However, studies in children are scarce, and circadian health and its association with obesity have not been evaluated globally. We aimed to assess whether circadian health differed between children with and without obesity as determined by a global circadian score (GCS) in a school-age population. METHODS: Four hundred and thirty-two children (7-12 years) were recruited in Spain. Non-invasive tools were used to calculate the GCS: (1) 7-day rhythm of wrist temperature (T), activity (A), position (P), an integrative variable that combines T, A, and P (TAP); (2) cortisol; and (3) 7-day food and sleep records. Body mass index, body fat percentage, waist circumference (WC), melatonin concentration, and cardiometabolic marker levels were determined. RESULTS: Circadian health, as assessed by the GCS, differed among children with obesity, overweight, and normal weight, with poorer circadian health among children with obesity. Children with obesity and abdominal obesity had 3.54 and 2.39 greater odds of having poor circadian health, respectively, than did those with normal weight or low WC. The percentage of rhythmicity, a marker of the robustness of the TAP rhythm, and the amplitude, both components of the GCS, decreased with increasing obesity. Different lifestyle behaviors were involved in the association between circadian health and obesity, particularly protein intake (P = 0.024), physical activity level (P = 0.076) and chronotype (P = 0.029). CONCLUSIONS: The GCS can capture the relationship between circadian health and obesity in school-age children. Protein intake, physical activity level, and chronotype were involved in this association. Early intervention based on improving circadian health may help to prevent childhood obesity.

Tramadol intoxication in children: An emerging issue.

BACKGROUND: Prescribing tramadol in children raises safety concerns. In Europe, tramadol is still approved and licensed for use in children over 1-3 years of age, depending on the country. In this context, the authors report a case of a tramadol overdose in a 5-year-old-child with a medical history of homozygous sickle cell disease. METHODS: Tramadol and M1 were quantified using liquid chromatography with a diode array detection method. CYP2D6 genotype was determined using a next generation sequencing platform (MISeq, Illumina). RESULTS: Tramadol and M1 were quantified in blood respectively at 5.48 and 1.32µg/mL at admission, at 0.77 and 0.35µg/mL 12hours later, and at 0.32 and 0.18µg/mL 20hours later. The patient was predicted as a CYP2D6 normal metabolizer (*35/*29). CONCLUSION: One of the most important difficulties with the use of tramadol in children relates to its pharmacokinetic (PK) properties. Indeed, tramadol's PK is characterized by a great variability related to: (i) anatomical/physiological factors that impact the volume of distribution (Vd); (ii) CYP2D6 genetic polymorphisms. Considering such an issue is particularly relevant to prevent poisoning. In the reported case, the plasma elimination half-life was estimated at 6.3h, significantly more than those reported in 2-8 year-old children (about 3h). This discrepancy does not seem related to genetic polymorphisms but rather to the Vd. Indeed, the patient was predicted to be a CYP2D6 normal metabolizer (*35/*29). The case presented here highlights the risk associated with the tramadol use in children and emphasizes the importance of considering PK variability among this population. Such variability necessitates greater caution in prescribing tramadol in children and highlights the importance of therapeutic education for families of children treated with this painkiller.

Effectiveness of repeated injections of botulinum toxin A on gait and fatigue in adults with spastic paraparesis secondary to multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is the most common neurologic disease in young adults. Spasticity is one of its most disabling symptoms, with botulinum toxin A type A (BoNT-A) being one of the treatments of choice for this symptom. OBJECTIVE: We assessed the response to abobotulinumtoxinA in improving walking ability and fatigue in patients with spastic paraparesis caused by MS. METHODS: We performed a real-world, multicenter, prospective, open-label low-intervention trial in 84 patients with MS and spastic paraparesis of the lower limbs infiltrated with abobotulinumtoxinA (LINITOX study). The response of spasticity, walking ability and fatigue is analyzed in 4 cycles of ultrasound-guided injection in the lower limbs. RESULTS: The patients improved their walking ability by an average of 11.34% meters measured with 6-Minute Walk Test (6MWT), and decreased the percentage of fatigue by 6.86% (4.66 percentage points less), in the 12-Item Multiple Sclerosis Walking Scale (MSWS-12) 4 weeks after abobotulinumtoxinA injection, both values are statistically significant. This improvement seems to persist over time, throughout the cycles. CONCLUSION: We found improved walking ability and less fatigue in patients with MS-related spastic paresis of the lower limbs after injection of abobotulinumtoxinA.

Primary Healthcare Case Management Nurses and Assistance Provided to Chronic Patients: A Narrative Review.

Population aging is causing increases in the numbers of chronic diseases, with the consequent need for changes in health systems to better assist patients with chronic conditions. A narrative review was conducted in this study with the objective of analysing the scientific evidence on the care and assistance provided by Case Management Nurses (CMNs) to chronic patients in primary healthcare. A total of 15 articles published in English, Spanish, and Portuguese were selected in the following databases: PubMed, Embase, Cochrane Library, Scopus, Dialnet, Cinahl, and Web of Science. In total, 46.6% of the studies showed the assistance provided by CMNs for chronic pathologies. Most of the articles selected (80%) considered that the assistance offered by case management nurses in relation to chronic diseases is effective, enabling cost reductions, which supposes benefits at the economic and political levels. It was concluded that CMNs have proven to be efficient in caring for people with chronic diseases, improving the quality of life of these people and their caregivers; therefore, they have a fundamental role in the PHC.

Sustainable agricultural practices influence s-metolachlor, foramsulfuron and thiencarbazone-methyl degradation and their metabolites formation.

The effect of sustainable agricultural practices, such as mulching or the application of straw residues as an organic amendment, on the degradation, dissipation and persistence in the soil of S-metolachlor (SMOC), foramsulfuron (FORAM) and thiencarbazone-methyl (TCM) is still unclear. The objective here was to conduct a laboratory experiment to evaluate the impact of milled wheat straw (WS) simulating its individual use as mulch or applied as an organic amendment to two agricultural soils: unamended and WS-amended soils on the degradation kinetics of the herbicides SMOC, FORAM and TCM, and on the formation of their major metabolites at two incubation temperatures (14 °C and 24 °C). The degradation rate of SMOC on WS was 6.9-16.7 times faster than that observed for FORAM and TCM at both temperatures. The half-life (DT50) values were 1.1-10.6 times lower for FORAM than for SMOC and TCM in the unamended and WS-amended soils at 14 °C and 24 °C. The application of WS to soils increased the DT50 values from 1.1 to 11.2 times for all the herbicides at both incubation temperatures due to their higher adsorption and lower bioavailability. The herbicides recorded a faster degradation at 24 °C (1.2-3.9 times) than at 14 °C, according to Q10 values >1. SMOC metabolites were more persistent in WS-amended soils than in unamended ones, in agreement with the DT50 values recorded for the parent compound. The results indicate that the effect of the mulch applied to soils as an organic amendment was different depending on the herbicide and incubation temperature. The outcomes of this research can give key suggestions for reducing the effects of residual herbicides following sustainable agricultural practices by avoiding soil and groundwater contamination, which is one of the challenges involved in the application of chemical inputs.

Effects on Biochemical Parameters and Animal Welfare of Dusky Grouper (Epinephelus marginatus, Lowe 1834) by Feeding CTX Toxic Flesh.

Ciguatera is a foodborne disease caused by ciguatoxins (CTXs), produced by dinoflagellates (genera Gambierdiscus and Fukuyoa), which bioaccumulate in fish through the food web, causing poisoning in humans. Currently, the physiological mechanisms of the species with the highest amount of toxins in their adult stage of life that are capable of causing these poisonings are poorly understood. Dusky grouper (Epinephelus marginatus) is a relevant fishing species and is part of the CTX food chain in the Canary Islands. This study developed an experimental model of dietary exposure featuring adult dusky groupers with two diets of tissue naturally contaminated with CTXs (amberjack and moray eel flesh) with two different potential toxicities; both groups were studied at different stages of exposure (4, 6, 10, 12, and 18 weeks). The results showed that this species did not show changes in its behavior due to the provided feeding, but the changes were recorded in biochemical parameters (mainly lipid and hepatic metabolism) that may respond to liver damage and alterations in the homeostasis of the fish; more research is needed to understand histopathological and cytotoxic changes.

Predicted mechanistic impacts of human protein missense variants.

Genome sequencing efforts have led to the discovery of tens of millions of protein missense variants found in the human population with the majority of these having no annotated role and some likely contributing to trait variation and disease. Sequence-based artificial intelligence approaches have become highly accurate at predicting variants that are detrimental to the function of proteins but they do not inform on mechanisms of disruption. Here we combined sequence and structure-based methods to perform proteome-wide prediction of deleterious variants with information on their impact on protein stability, protein-protein interactions and small-molecule binding pockets. AlphaFold2 structures were used to predict approximately 100,000 small-molecule binding pockets and stability changes for over 200 million variants. To inform on protein-protein interfaces we used AlphaFold2 to predict structures for nearly 500,000 protein complexes. We illustrate the value of mechanism-aware variant effect predictions to study the relation between protein stability and abundance and the structural properties of interfaces underlying trans protein quantitative trait loci (pQTLs). We characterised the distribution of mechanistic impacts of protein variants found in patients and experimentally studied example disease linked variants in FGFR1.

Hyper-late major response after 5†years of nivolumab: role of treatment beyond progression in head and neck cancer.

Patients with recurrent/metastatic (R/M) platinum-refractory squamous cell carcinoma of the head and neck (SCCHN) have fewer treatment options and harbor an especially poor prognosis. Maintaining treatment with anti-PD1 agents beyond response evaluation criteria in solid tumors-defined disease progression (TBP) has been shown to be efficacious in several solid tumors, including head and neck cancer. We present the case of a platinum-refractory locally recurrent, PD-L1-negative hypopharyngeal carcinoma, that received second-line nivolumab which was then maintained beyond progression under the following criteria: no Eastern Cooperative Oncology Group performance status deterioration, no rapidly progressive disease, no severe toxicity, and evidence of overall treatment benefit. The patient achieved a partial response 8 months after starting second-line nivolumab, with progressive disease at 26 months, then followed by the first TBP with nivolumab lasting for 15 months due to a new tumor progression. A second TBP with nivolumab lasting for 7 months, was followed by a third TBP with nivolumab for 12 months and achieving a major tumor response. Treatment is still ongoing 60 months after starting nivolumab, with excellent tolerance to therapy. Maintaining anti-PD1 agents beyond progression is an efficacious treatment option for patients with R/M SCCHN, that may achieve very durable disease control and even late major responses.