Autosomal dominant acute porphyrias are rare inherited disorders of haem biosynthesis characterised by accumulation of potentially neurotoxic porphyrin precursors and attacks of severe abdominal pain with autonomic and neuropsychiatric features. Disease severity ranges from asymptomatic individuals to those with recurrent, life-threatening attacks. The International Porphyria Network invited 34 acute porphyria specialists from 17 countries to form an expert panel. The invited group included clinicians from diverse specialities (ie, internal medicine, haematology, endocrinology, gastroenterology, hepatology, neurology, and biochemistry), together with laboratory scientists and patient representatives. The panel met online (in 2023-25) to develop 15 evidence-based recommendations with the use of the Grading of Recommendations, Assessment, Development, and Evaluations framework addressing attack prevention, management of sporadic and recurrent attacks, long-term follow-up, surveillance for primary liver cancer, and family screening. The guidelines support safe, consistent clinical care and improved outcomes, recognising global variation in resources and access to high-cost drugs, and highlighting priorities for future research.
Monitoring biochemical parameters is an essential component of pharmacological safety and routine clinical practice. Abnormalities in hepatic and renal function observed during hospitalization may reflect pharmacological exposure, underlying disease processes, or their interaction. However, real-world data describing the frequency and distribution of such laboratory abnormalities in hospital settings remain limited. This study aimed to evaluate the prevalence of biochemical abnormalities of hepatic and renal function among patients receiving pharmacological therapy and to assess the frequency of laboratory alterations associated with commonly prescribed drug groups. A retrospective observational study was conducted using laboratory data from the Department of Clinical Biochemistry. The analysis included 3,500 adult patients who underwent biochemical testing while receiving pharmacological therapy between January 2023 and December 2025. The evaluated parameters included alanine aminotransferase, aspartate aminotransferase, serum creatinine, urea, sodium, and potassium. Patients were categorized according to the main pharmacological therapy received, including antibiotics, non-steroidal anti-inflammatory drugs, and antihypertensive medications. Abnormal values were defined according to institutional laboratory reference ranges. Among the 3,500 patients included in the analysis, 52.3% were male and 47.7% were female, with a mean age of 56.8±15.4 years. Antibiotics were prescribed to 41.6% of patients, non-steroidal anti-inflammatory drugs to 33.2%, and antihypertensive medications to 25.2%. Elevated alanine aminotransferase levels were observed in 18.9% of patients, while increased aspartate aminotransferase levels were detected in 15.4%. Hepatic enzyme abnormalities were more frequently observed among patients receiving antibiotics and non-steroidal anti-inflammatory drugs, with statistically significant differences between therapy groups (p<0.05). Renal function abnormalities were identified in 14.7% of patients for creatinine and 12.9% for urea, particularly among patients treated with non-steroidal anti-inflammatory drugs. Electrolyte disturbances were less frequent, with hyponatremia observed in 6.1% and hyperkalemia in 4.3% of cases. Overall, 27.6% of patients exhibited at least one clinically relevant biochemical abnormality during hospitalization while receiving pharmacological therapy. A considerable proportion of hospitalized patients receiving pharmacological therapy present with clinically significant biochemical abnormalities affecting hepatic, renal, or electrolyte parameters. Although causality cannot be established in this retrospective design, these findings underscore the importance of systematic laboratory monitoring as part of hospital-based pharmacovigilance and patient safety strategies.
Modern biochemistry is producing vast amounts of chemical knowledge. Ontologies, such as the Chemical Entities of Biological Interest (ChEBI) ontology, can help organising this knowledge. With manual classification alone however, ontologies cannot keep up with the growth of their domain. In this work, we propose a novel taxonomy of 67 classes related to peptides, a large branch in ChEBI with nearly 15,000 compounds. The existing natural language definitions in ChEBI have been expanded and specified more precisely. These natural language definitions are accompanied by a logical axiomatisation in monadic second-order logic (MSOL). To use the axiomatisation for automated classification, a methodology has been developed that translates monadic second-order definitions first into partial first-order definitions and finally into an algorithmic classification. This connects three aspects important to ontological definitions: They reflect the opinions of experts, they are unambiguous, and they can be checked automatically. In our evaluation, we compare the results of our classification to the current taxonomy of ChEBI . This reveals potential inconsistencies in ChEBI as well as areas that might benefit from automated extensions. We also evaluate our natural-language definitions in an expert survey.Scientific contribution: This work provides precise natural-language definitions of 14 current ChEBI classes as well as 53 new peptide-related classes. These definitions are formalised in MSOL and come with an efficient implementation that allows for large-scale molecule classification, including a full classification of ChEBI and PubChem.
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Circadian clocks coordinate daily rhythms, shaping mating, host-seeking, and pathogen transmission in mosquitoes. In this review article, we discuss the current understanding of the molecular clockwork in key mosquito species, including Aedes aegypti and Anopheles gambiae, highlighting clade-specific features and diversified transcription-translation feedback loops relative to Drosophila's canonical clock model. We synthesize evidence and propose mechanistic hypotheses about the integration of environmental cues by central and peripheral clocks in an organ- and sex-specific manner, including a reanalysis of rhythmic RNA-sequencing data. Finally, we discuss how temporal synchrony among vector, host, and parasite determines transmission efficiency and how emerging single-cell and circuit-level tools will refine models of mosquito circadian organization. Overall, this review provides a framework for understanding mosquito daily and circadian rhythms.
Diagnostic pathology has long relied on the morphological interpretation of hematoxylin and eosin (H&E)-stained tissues to guide diagnosis and assess prognostic features. While pathologists intuitively recognize spatial patterns and architectural organization, these assessments remain largely qualitative and difficult to quantify systematically. Immunohistochemistry and immunofluorescence have introduced molecular specificity but are limited in multiplexing capacity, whereas bulk genomic and transcriptomic assays provide high molecular depth but lose spatial context by averaging signals across heterogeneous cell populations. Recent advances in spatial proteomics-including mass spectrometry-based imaging and cyclic immunofluorescence-now enable multiplexed, single-cell protein analysis within intact tissue architecture. These technologies have revealed complex immune and stromal microenvironments, spatially organized biomarkers predictive of therapeutic response, and molecular gradients underlying disease progression. By integrating histological and molecular information, spatial proteomics bridges traditional microscopy with high-dimensional omics, allowing quantitative, spatially resolved insights into tissue organization and disease mechanisms. This review summarizes recent developments in multiplexed spatial proteomics from both scientific and pathological perspectives, highlighting how these technologies extend beyond morphology to quantify histologic patterns, refine biomarker discovery, and facilitate clinical translation. The review also examines translational challenges and barriers to clinical implementation, including costs, standardization requirements, and workflow integration.
Insulin-like growth factor 2 (IGF2) engages multiple receptors of the insulin-hormone family, yet the structural determinants of its selectivity remain poorly defined. Vesiculin, a naturally occurring des[37-40]IGF2 isoform, represents a unique probe for dissecting these interactions. Here, we combine chemical synthesis, receptor-binding assays, phosphorylation studies, and molecular dynamics simulations to characterize vesiculin and compare it with wild-type IGF2. Vesiculin consistently displayed a reduced affinity for the majority of binding partners, with the most pronounced loss observed for IGF2R and its isolated domain 11 (D11). Computational analyses revealed that this reduction originates from the destabilization of the IGF2 C-domain, which in wild-type IGF2 forms cooperative contacts with IGF2R domains D6 and D8. Deletion of Arg37-Arg40 abolishes these interactions and enforces ineffective compensatory contacts. For the insulin receptor, the loss of these residues disrupts stabilizing electrostatic contacts with the α-CT and L2 domains. In contrast, IGF1R binding is only modestly affected, and vesiculin shows a markedly diminished affinity for IGFBP3, raising questions about its bioactivity. Together, these findings redefine the IGF2-IGF2R binding interface and highlight the IGF2 C-domain as a central determinant of receptor specificity across the insulin-IGF system, providing a framework for designing IGF2 analogs.
Fragile X messenger ribonucleoprotein 1 (FMRP) is a multidomain RNA-binding protein highly expressed in neurons. It comprises a structured N-terminal region (NTR) containing five RNA/protein interaction domains and a large intrinsically disordered C-terminal region. A limited number of fragile X syndrome (FXS)-associated point mutations have been identified in the NTR, leading to the expression of mutated protein variants. Here, we show that the destabilizing effects of these mutations on the NTR region are less severe than those previously observed in the isolated domains, suggesting the presence of inter-domain interactions that stabilize the overall NTR architecture. Moreover, we demonstrate that the NTR structured region has an intrinsic propensity to undergo liquid-liquid phase separation (LLPS) and amyloid fibril formation in vitro, depending on protein concentration, and we characterize how three FXS-associated mutations (R138Q, G266E, and I304N) affect these processes. We show that the mutations either destabilize the entire NTR (G266E/I304N), markedly affect the kinetics of LLPS and suppress the droplet liquid nature (R138Q/G266E), or promote solid or gel-like non-amyloid aggregation (G266E), thus providing mechanistic insights into how they may alter protein function, contributing to the pathogenic mechanism. These findings suggest that the interplay between protein stability, LLPS, and fibrillization is finely regulated and may be critical for understanding FMRP function and its dysfunction in disease.
Renal Fanconi syndrome (RFS) refers to a generalized dysfunction of the proximal tubule, including impaired 1-α hydroxylation of vitamin D. Consequently, rickets is a typical complication. Clinical observations in children with severe nutritional vitamin D deficiency sometimes include proximal tubular dysfunction, raising the possibility that lack of vitamin D could not only be a consequence of RFS but also a cause of it, although this has never been confirmed. Observations in Mendelian disorders with their genetically defined pathophysiology can provide clearer insights. We performed a retrospective review of 2 cases with vitamin D deficiency due to loss-of-function variants in CYP27B1. Additionally, we performed an in silico search for vitamin D-responsive elements (VDRE) in the promoter region of genes encoding proximal tubular transporters. Both cases presented with clinical rickets that had been resistant to supplementation with cholecalciferol. Biochemistries at presentation showed a non-anion gap metabolic acidosis, generalized aminoaciduria and urinary phosphate wasting consistent with proximal tubular dysfunction. Symptoms resolved upon treatment with active vitamin D. VDRE motifs were identified in the promoters of SLC34A1 and SLC34A3. Our observations support the notion of vitamin D deficiency as a cause of RFS and suggest that unresolved cases of RFS should be actively investigated for it.
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Aggression is a complex social behaviour observed in many animal species, including dogs, and remains a major global concern due to its serious implications for public safety and animal welfare. This study focuses on Pit Bull dogs, a breed frequently associated with severe aggression episodes in many countries, making them an appropriate model for investigating the neuroanatomical factors underlying canine aggression. To better understand its underlying mechanisms, this study investigated neuroanatomical and biochemical factors associated with aggression in Pit bulls. 14 dogs were selected for MRI analysis based on their aggression scores obtained through a aggression assesment survey derived from Canine Behavioral Assessment and Research Questionnaire. The dogs underwent MRI scans and blood and urine sampling and were divided into control and aggressive groups. MRI analyses focused on the prefrontal cortex, amygdala, and hippocampus. Biochemical analyses included serum or plasma levels of serotonin, dopamine, vasopressin, adrenaline, noradrenaline, testosterone, cortisol, and adrenocorticotropic hormone, along with urinary concentrations of their metabolites; metanephrine, vanillylmandelic acid, homovanillic acid, and 5-hydroxyindoleacetic acid. Results showed significantly decreased prefrontal cortex volumes and increased amygdala volumes in aggressive dogs compared to controls. Testosterone and dopamine levels were also significantly higher in the aggressive group. These findings suggest that structural alterations in key brain regions, combined with hormonal and neurotransmitter imbalances, may contribute to a maladaptive neurocognitive profile. Reduced top-down control by the prefrontal cortex may fail to inhibit exaggerated threat perception and emotional reactivity mediated by the amygdala, leading to aggressive behaviour in Pit bulls.
Mechanotransduction, i.e., the conversion of mechanical cues into biochemical signals, is essential for bone development, remodeling, and adaptation. Although mechanical loading is known to regulate osteoblast function and bone homeostasis, dissecting the early and sustained mechanotransductive responses at the microscale remains challenging due to limitations of existing in vitro models. Here, we report the development and application of a mechanostimulation system comprising a polypyrrole (PPy)-based wire actuator that expands and contracts (4 μm in radius) upon electrical actuation and enables precise, localized micromechanical stimulation of a small number of cells within standard culture formats. Using this system, we applied short-term (30 min) cyclic (Cyc30) or static (Stat30), as well as prolonged (120 min) cyclic (Cyc120) stimulations to two osteoblast-like cells (MC3T3-E1 or KUSA-A1). Subsequent transcriptomic profiling and computational network analyses revealed that Cyc30 was not capable of inducing significant changes in mRNA expression, suggesting cellular adaptation to short-term cyclic loading. In contrast, Stat30 induced the upregulation of Fos, Btg2, Egr1, and Fosl1, all known genes associated with mechanotransduction, supporting the validity and reproducibility of our experimental mechanostimulation system. Notably, two long non-coding RNAs (B930036N10Rik and 5430431A17Rik) were identified for the first time as being upregulated in response to Stat30 stimuli. Among the differentially expressed genes (DEGs) upregulated by Cyc120 stimuli, Hmox1, a stress-inducible enzyme known for its roles in maintaining cellular homeostasis and promoting survival, was the only DEG repeatedly observed across the Cyc30/Cyc120 and Stat30/Cyc120 comparisons in both cell types, potentially emerging as a key stress-response gene under prolonged mechanical loading. Collectively, these results establish the PPy-based microactuator as a powerful tool for microscale mechanobiology, and provide molecular insight into immediate-early responsive transcriptional programs underlying osteoblastic mechanoadaptation conserved across different cell types.
Delirium is a common complication following coronary artery bypass graft (CABG) surgery, associated with longer hospital stays, increased morbidity, and higher healthcare costs. To evaluate the effectiveness of a multicomponent care bundle in preventing postoperative delirium among patients undergoing CABG surgery. This single-blind, non-randomised trial included 94 patients consecutively allocated by time period (47 per group). The primary outcome was delirium incidence at postoperative day 1 assessed by a blinded neurologist using DSM-5 criteria. Delirium subtypes were classified by RASS scores. The control group received standardised care; the study group received standardised care plus continuous family presence, patient-selected music, and earplug use. Cortisol, ACTH, glucose, sleep quality, pain, and anxiety were evaluated. Statistical significance was set at p < 0.05. At postoperative day 1, delirium incidence assessed by DSM-5 criteria was 14.9% in the study group vs. 38.3% in controls (p = 0.013; OR = 0.28, 95% CI: 0.10-0.76; ARR = 23.4%). Hyperactive delirium was markedly lower (2.1% vs. 14.9%). At postoperative days 1 and 2, cortisol, ACTH, glucose, pain, and anxiety levels were lower, and sleep quality was higher in the study group. Adherence to all bundle components exceeded 90%. The multicomponent care bundle was associated with significant reduction in postoperative delirium (NNT = 4.3), particularly hyperactive delirium, and improvements in stress biomarkers and psychological well-being. High adherence supports feasibility of this low-cost, nurse-led intervention. Randomised trials are needed to confirm causality.
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Agricultural systems require sustainable alternatives to chemical pesticides for controlling crop pathogens. This study evaluated biochar derived from grape pomace, a major winery byproduct, as an antimicrobial agent against tomato root pathogens (Fusarium oxysporum f. sp. lycopersici, Phytophthora infestans, Verticillium dahliae and Rhizoctonia solani). Under in vitro conditions, pathogens were exposed to biochar, washed biochar, and aqueous extracts in solid and liquid media. Biochar significantly inhibited fungal growth, whereas aqueous extracts showed no antifungal activity. Similar effects of washed and unwashed biochar indicate that inhibition is associated with the solid biochar structure rather than soluble compounds, and pH alone did not explain the effect. F. oxysporum and R. solani were most sensitive at lower concentrations. Metabolomic analysis identified 59 differential metabolites linked to stress responses. These findings highlight grape pomace-derived biochar as a promising sustainable strategy for managing tomato root pathogens.
Choline is an essential nutrient required for the synthesis of key molecules, such as phosphatidylcholine, sphingomyelin, acetylcholine, and S-adenosylmethionine. Choline metabolism encompasses two phases, namely the postprandial and postabsorptive states. The former enables the digestion, absorption, distribution, and storage of choline derivatives after a meal, while the latter allows the cellular utilization of choline and the mobilization of stored choline-containing molecules during fasting. Understanding choline metabolism is fundamental to the study of lipid disorders such as steatohepatitis or atherosclerosis, as well as neurodegenerative diseases, including Alzheimer's disease, and inflammatory signaling pathways. Members of the alkaline phosphatase (AP) superfamily are prominent contributors to extracellular choline metabolism. Within this family, several APs and ectonucleotide pyrophosphatases/phosphodiesterases (ENPP) members are required for physiological choline metabolism. While intestinal alkaline phosphatase (IAP) and alkaline sphingomyelinase/ENPP7 both participate in the digestion of choline-containing derivatives in the gut during the postprandial phase, circulating ENPP2, ENPP6, and tissue-nonspecific alkaline phosphatase (TNAP) act during the postabsorptive phase to generate choline. In this review we first provide a comprehensive overview of choline metabolism and then describe how APs and ENPPs have functionally and structurally co-evolved to catalyze sequential reactions within this metabolic pathway.
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KRAS mutations are commonly found in 90% of pancreatic ductal adenocarcinoma (PDAC) cases, making it one of the deadliest cancers. Key oncogenic signaling networks, such as KRAS, TP53-MDM2, EGFR, and PI3K/AKT/mTOR, are frequently altered in this invasive disease. These networks function within a dense desmoplastic tumor environment that inhibits drug delivery and fosters therapeutic resistance. Although KRAS mutations are a primary oncogenic driver and occur in approximately 90% of patients with PDAC, variant-specific biology (e.g., G12D, G12R, G12V, and G12C) affects downstream signaling dependency and treatment response. Although specific KRASG12C inhibitors have been developed, their use in PDAC remains limited because of compensatory pathway activation and mutation prevalence. Similarly, whereas EGFR amplification and adaptive signaling bypass pathways decrease the durability of EGFR-targeted therapies, TP53 inactivation and MDM2 axis dysregulation contribute to genomic instability and treatment resistance. Although resistance to chemotherapy and targeted therapies, survival signaling, and metabolic reprogramming are all significantly affected by the PI3K/AKT/mTOR system, the therapeutic results with pathway inhibitors have been mixed. Significantly, these signaling pathways function within a coordinated, interdependent network, wherein single-agent approaches are compromised by crosstalk and feedback activation. This review synthesizes these main signaling axes, emphasizing molecular pathology, including mutation-specific biology, diagnostic techniques such as liquid biopsy and NGS, the role of natural compounds, the tumor microenvironment (TME) in pancreatic cancer (PC), and the limitations noted in therapeutic trials. Novel therapeutic approaches include KRAS-directed degradation techniques, pathway co-inhibition, rational combination methods, and therapy paradigms driven by the TME. To discover new molecules with long-lasting therapeutic effects, a system-level understanding of pathway interactions within the PDAC microenvironment is necessary.
Reptiles often inhabit environments that are in close proximity to humans and livestock, creating opportunities for parasite transmission. They are common in areas where they find shelter, food and warmth. The Bengal monitor lizard (Varanus bengalensis), a member of the family Varanidae, represents one of the largest groups of extant poikilothermic predators. Monitor lizards are known to harbor several tick species that serve as vectors for a variety of pathogens. No prior information is available in the literature regarding ticks infesting V. bengalensis in Pakistan as well as regarding the occurrence of Toxoplasma gondii in these ticks. Therefore, we aimed to determine the molecular prevalence of T. gondii in Amblyomma gervaisi ticks (n = 93) collected from 24 V. bengalensis in Buner District, Khyber Pakhtunkhwa Province, Pakistan, between May and September 2023. Polymerase chain reaction (PCR) amplified a 300 bp fragment specific for the ITS-1 region of T. gondii in 10 of the 93 (11%) A. gervaisi ticks. DNA sequencing and BLAST analysis confirmed the presence of T. gondii. Phylogenetic analysis showed that these sequences clustered with the ITS-1 sequences of T. gondii detected in reptiles and mammals from Pakistan, Brazil, China, Tunisia and Portugal. The prevalence of T. gondii in A. gervaisi was not limited to a specific tick sex, feeding stage or month of sampling. However, among the tick developmental stages, nymphs had the highest rate of T. gondii infection. In conclusion, for the very first time from Pakistan, we are reporting the presence of T. gondii in A. gervaisi that were infesting monitor lizards. We recommend that similar and large scale studies should be conducted in all those areas of Pakistan that are unexplored for the presence of T. gondii in A. gervaisi ticks. Prevalence of this parasite should also be screened in all the animals harboring these as well as other tick species. This will help in better understanding of T. gondii transmission to new hosts that will lead toward its effective control.
The purpose of this study was to examine whether Ki67-scores have a predictive significance for pathological complete response (pCR) and invasive disease-free survival (IDFS) in HER2-positive breast cancer. This retrospective, bi-centric cohort study focused on HER2-positive early breast cancer patients undergoing neoadjuvant chemotherapy from 2015 to 2023. Multivariable logistic regression was used to find independent association between various clinical parameters, including Ki67, and pCR. Ki67-values were categorized into three groups (low ≤ 15%, intermediate 15-35%, high > 35%). Kaplan-Meier estimator calculated differences in IDFS. The study included 244 patients with known Ki67-expression. 147 patients (60.3%) achieved pCR. When categorized, 18 (7.4%) were Ki67 low, 114 (46.7%) Ki67 intermediate and 112 (45.9%) Ki67 high. No correlation between Ki67-score as continuous variable and pCR was observed (p = 0.25). HER2 immunohistochemistry (IHC) score 3 + significantly increased pCR compared to IHC score 2 + (63.2% vs. 45%, p = 0.031). Hormone receptor (HR)-positive tumors had a lower pCR rate (53.1% vs. 74.4%, p = 0.001) compared to HR-negative tumors. 5-year IDFS showed no difference between low Ki67 (88.9%; 95% CI 75.5-100%), intermediate Ki67 (82.0%; 95% CI 72.6-92.7%), and high Ki67 (80.9%, 95% CI 70.1-92.3%) subgroups (p = 0.7). In HER2-positive breast cancer, the Ki67-score showed no association with either pCR or IDFS, thereby questioning its clinical utility. Conversely the HER2 IHC-score and HR-status were predictive indicators for achieving pCR. Clinical decisions in patients with early HER2-positive breast cancer should not be influenced by Ki67-scores, especially not by using cut-offs.