Nat Commun. 2025 Jan 7;16(1):441. doi: 10.1038/s41467-024-55593-0.

ABSTRACT

New and more transmissible variants of SARS-CoV-2 have arisen multiple times over the course of the pandemic. Rapidly identifying mutations that affect transmission could improve our understanding of viral biology and highlight new variants that warrant further study. Here we develop a generic, analytical epidemiological model to infer the transmission effects of mutations from genomic surveillance data. Applying our model to SARS-CoV-2 data across many regions, we find multiple mutations that substantially affect the transmission rate, both within and outside the Spike protein. The mutations that we infer to have the largest effects on transmission are strongly supported by experimental evidence from prior studies. Importantly, our model detects lineages with increased transmission even at low frequencies. As an example, we infer significant transmission advantages for the Alpha, Delta, and Omicron variants shortly after their appearances in regional data, when they comprised only around 1-2% of sample sequences. Our model thus facilitates the rapid identification of variants and mutations that affect transmission from genomic surveillance data.

PMID:39774959 | DOI:10.1038/s41467-024-55593-0

Nat Commun. 2025 Jan 7;16(1):461. doi: 10.1038/s41467-025-55872-4.

ABSTRACT

The dual challenges of global population explosion and environmental deterioration represent major hurdles for 21st Century agriculture culminating in an unprecedented demand for food security. In this Review, we revisit historical concepts of plasticity and canalization before integrating them with contemporary studies of genotype-environment interactions (G×E) that are currently being carried out at the genome-wide level. In doing so we address both fundamental questions regarding G×E and potential strategies to best secure yields in both current and future climate scenarios.

PMID:39774717 | DOI:10.1038/s41467-025-55872-4

J Exp Bot. 2025 Jan 8:eraf005. doi: 10.1093/jxb/eraf005. Online ahead of print.

ABSTRACT

The complex gene regulatory landscape underlying early flower development in Arabidopsis has been extensively studied through transcriptome profiling, and gene networks controlling floral organ development have been derived from the analyses of genome wide binding of key transcription factors. In contrast, the dynamic nature of the proteome during the flower development process is much less understood. In this study, we characterized the floral proteome at different stages during early flower development and correlated it with unbiased transcript expression data. Shotgun proteomics and transcript profiling were conducted using an APETALA1-based floral induction system. A specific analysis pipeline to process the time-course proteomics data was developed. In total, 8,924 proteins and 23,069 transcripts were identified. Co-expression analysis revealed that RNA-protein pairs clustered in various expression pattern modules. An overall positive correlation between RNA and protein level changes was observed, but subgroups of RNA/protein pairs with anticorrelated gene expression changes were also identified and found to be enriched in hormone responsive pathways. In addition, the RNA-seq dataset reported here further expanded the identification of genes whose expression changes during early flower development, and its combination with previously published AP1 ChIP-seq datasets allowed the identification of additional AP1 direct and high-confidence targets.

PMID:39774695 | DOI:10.1093/jxb/eraf005

Anesth Analg. 2024 Nov 19. doi: 10.1213/ANE.0000000000007293. Online ahead of print.

ABSTRACT

BACKGROUND: Delirium after cardiac surgery is common, morbid, and costly, but may be prevented with risk stratification and targeted intervention. In this study, we aimed to identify protein biomarkers and develop a predictive model for postoperative delirium in older patients undergoing cardiac surgery.

METHODS: SomaScan analysis of 1305 proteins in the plasma from 57 older adults undergoing cardiac surgery requiring cardiopulmonary bypass was conducted to define delirium-specific protein signatures at baseline (preoperative baseline timepoint [PREOP]) and postoperative day 2 (POD2). Selected proteins were validated in 115 patients using the Enzyme-Linked Lectin Assay (ELLA) multiplex immunoassay platform. Proteins were combined with clinical and demographic variables to build multivariable models that estimate the risk of postoperative delirium and bring light to the underlying pathophysiology.

RESULTS: Of the 115 patients, 21 (18.3%) developed delirium after surgery. The SomaScan proteome screening evidenced differential expression of 115 and 85 proteins in delirious patients compared to nondelirious preoperatively and at POD2, respectively (P < .05). Following biological and methodological criteria, 12 biomarker candidates (Tukey's fold change [|tFC|] >1.4, Benjamini-Hochberg [BH]-P < .01) were selected for ELLA multiplex validation. Statistical analyses of model fit resulted in the combination of age, sex, and 3 proteins (angiopoietin-2; C-C motif chemokine 5; and metalloproteinase inhibitor 1; area under the curve [AUC] = 0.829) as the best performing predictive model for delirium. Analyses of pathways showed that delirium-associated proteins are involved in inflammation, glial dysfunction, vascularization, and hemostasis.

CONCLUSIONS: Our results support the identification of patients at higher risk of developing delirium after cardiac surgery using a multivariable model that combines demographic and physiological features, also bringing light to the role of immune and vascular dysregulation as underlying mechanisms.

PMID:39774401 | DOI:10.1213/ANE.0000000000007293

PLoS Comput Biol. 2025 Jan 7;21(1):e1012736. doi: 10.1371/journal.pcbi.1012736. Online ahead of print.

ABSTRACT

The denitrifying bacterium Thauera sp. MZ1T, a common member of microbial communities in wastewater treatment facilities, can produce different compounds from a range of carbon (C) and nitrogen (N) sources under aerobic and anaerobic conditions. In these different conditions, Thauera modifies its metabolism to produce different compounds that influence the microbial community. In particular, Thauera sp. MZ1T produces different exopolysaccharides with floc-forming properties, impacting the physical disposition of wastewater consortia and the efficiency of nutrient assimilation by the microbial community. Under N-limiting conditions, Thauera sp. MZ1T decreases its growth rate and accelerates the accumulation of polyhydroxyalkanoate-related (PHA) compounds including polyhydroxybutyrate (PHB), which plays a fundamental role as C and energy storage in this β-proteobacterium. However, the metabolic mechanisms employed by Thauera sp. MZ1T to assimilate and catabolize many of the different C and N sources under aerobic and anaerobic conditions remain unknown. Systems biology approaches such as genome-scale metabolic modeling have been successfully used to unveil complex metabolic mechanisms for various microorganisms. Here, we developed a comprehensive metabolic model (M-model) for Thauera sp. MZ1T (iThauera861), consisting of 1,744 metabolites, 2,384 reactions, and 861 genes. We validated the model experimentally using over 70 different C and N sources under both aerobic and anaerobic conditions. iThauera861 achieved a prediction accuracy of 95% for growth on various C and N sources and close to 85% for assimilation of aromatic compounds under denitrifying conditions. The M-model was subsequently deployed to determine the effects of substrates, oxygen presence, and the C:N ratio on the production of PHB and exopolysaccharides (EPS), showing the highest polymer yields are achieved with nucleotides and amino acids under aerobic conditions. This comprehensive M-model will help reveal the metabolic processes by which this ubiquitous species influences communities in wastewater treatment systems and natural environments.

PMID:39774301 | DOI:10.1371/journal.pcbi.1012736

J Clin Sleep Med. 2025 Jan 7. doi: 10.5664/jcsm.11524. Online ahead of print.

ABSTRACT

STUDY OBJECTIVES: Onera Health has developed the first wireless, patch-based, type-II PSG system, the Onera Sleep Test System (STS), to allow studies to be performed unattended at the patient's home or in any bed at a medical facility. The goal of this multicenter study was to validate data collected from the patch-based PSG to a traditional PSG for sleep staging and AHI.

METHODS: Simultaneous traditional PSG and patch-based PSG study data were obtained in a sleep laboratory from 206 participants with a suspected sleep disorder recruited from 7 clinical sites. Blinded, randomized scoring of the traditional PSG and patch-based PSG recordings was completed according to The AASM Manual for the Scoring of Sleep and Associated Events, version 2.6 criteria by three independent scorers.

RESULTS: Concordance correlation coefficients were high between the patch-based device and traditional PSG across essential sleep and respiratory variables - TST (0.87); Wake (0.84); NREM (0.80); N1 (0.72); N2 (0.71); N3 (0.64); REM (0.80) and AHI (0.94). There was substantial agreement between epoch sleep staging scored on the patch-based device and traditional PSG (average Cohen's kappa of 0.62 ± 0.13 across all scorers).

CONCLUSIONS: The patch-based type-II PSG had a similar performance on sleep staging and respiratory variables when compared to Traditional PSG, thus making it possible to use the patch-based PSG for a routine PSG study. These results open the possibility of performing unattended PSG studies efficiently and accurately outside the sleep laboratory improving access to high quality sleep assessments for patients with sleep disorders.

CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Identifier: NCT05310708.

PMID:39773950 | DOI:10.5664/jcsm.11524

BMC Bioinformatics. 2025 Jan 7;26(1):4. doi: 10.1186/s12859-024-06027-7.

ABSTRACT

In cell line perturbation experiments, a collection of cells is perturbed with external agents and responses such as protein expression measured. Due to cost constraints, only a small fraction of all possible perturbations can be tested in vitro. This has led to the development of computational models that can predict cellular responses to perturbations in silico. A central challenge for these models is to predict the effect of new, previously untested perturbations that were not used in the training data. Here we propose causal structural equations for modeling how perturbations effect cells. From this model, we derive two estimators for predicting responses: a Linear Regression (LR) estimator and a causal structure learning estimator that we term Causal Structure Regression (CSR). The CSR estimator requires more assumptions than LR, but can predict the effects of drugs that were not applied in the training data. Next we present Cellbox, a recently proposed system of ordinary differential equations (ODEs) based model that obtained the best prediction performance on a Melanoma cell line perturbation data set (Yuan et al. in Cell Syst 12:128-140, 2021). We derive analytic results that show a close connection between CSR and Cellbox, providing a new causal interpretation for the Cellbox model. We compare LR and CSR/Cellbox in simulations, highlighting the strengths and weaknesses of the two approaches. Finally we compare the performance of LR and CSR/Cellbox on the benchmark Melanoma data set. We find that the LR model has comparable or slightly better performance than Cellbox.

PMID:39773352 | DOI:10.1186/s12859-024-06027-7

Sci Transl Med. 2025 Jan 8;17(780):eadl2103. doi: 10.1126/scitranslmed.adl2103. Epub 2025 Jan 8.

ABSTRACT

Several antibiotic candidates are in development against Gram-positive bacterial pathogens, but their long-term utility is unclear. To investigate this issue, we studied the laboratory evolution of resistance to antibiotics that have not yet reached the market. We found that, with the exception of compound SCH79797, antibiotic resistance generally readily evolves in Staphylococcus aureus. Cross-resistance was detected between such candidates and antibiotics currently in clinical use, including vancomycin, daptomycin, and the promising antibiotic candidate teixobactin. These patterns were driven by overlapping molecular mechanisms through mutations in regulatory systems. In particular, teixobactin-resistant bacteria displayed clinically relevant multidrug resistance and retained their virulence in an invertebrate infection model, raising concerns. More generally, we demonstrate that putative resistance mutations against candidate antibiotics are already present in natural bacterial populations. Therefore, antibiotic resistance in nature may evolve readily from the selection of preexisting genetic variants. Our work highlights the importance of predicting future evolution of resistance to antibiotic candidates at an early stage of drug development.

PMID:39772773 | DOI:10.1126/scitranslmed.adl2103

J Proteome Res. 2025 Jan 7. doi: 10.1021/acs.jproteome.4c00160. Online ahead of print.

ABSTRACT

Immunoprecipitation coupled to tandem mass spectrometry (IP-MS/MS) methods is often used to identify protein-protein interactions (PPIs). While these approaches are prone to false positive identifications through contamination and antibody nonspecific binding, their results can be filtered using negative controls and computational modeling. However, such filtering does not effectively detect false-positive interactions when IP-MS/MS is performed on human plasma samples. Therein, proteins cannot be overexpressed or inhibited, and existing modeling algorithms are not adapted for execution without such controls. Hence, we introduce MAGPIE, a novel machine learning-based approach for identifying PPIs in human plasma using IP-MS/MS, which leverages negative controls that include antibodies targeting proteins not expected to be present in human plasma. A set of negative controls used for false positive interaction modeling is first constructed. MAGPIE then assesses the reliability of PPIs detected in IP-MS/MS experiments using antibodies that target known plasma proteins. When applied to five IP-MS/MS experiments as a proof of concept, our algorithm identified 68 PPIs with an FDR of 20.77%. MAGPIE significantly outperformed a state-of-the-art PPI discovery tool and identified known and predicted PPIs. Our approach provides an unprecedented ability to detect human plasma PPIs, which enables a better understanding of biological processes in plasma.

PMID:39772751 | DOI:10.1021/acs.jproteome.4c00160

ACS Appl Mater Interfaces. 2025 Jan 7. doi: 10.1021/acsami.4c17482. Online ahead of print.

ABSTRACT

Enveloped viruses, such as flaviviruses and coronaviruses, are pathogens of significant medical concern that cause severe infections in humans. Some photosensitizers are known to possess virucidal activity against enveloped viruses, targeting their lipid bilayer. Here we report a series of halogenated difluoroboron-dipyrromethene (BODIPYs) photosensitizers with strong virus-inactivating activity. Our structure-activity relationship analysis revealed that BODIPY scaffolds with a heavy halogen atom demonstrate significant efficacy against both tick-borne encephalitis virus (TBEV; Flaviviridae family) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; Coronaviridae family) along with high singlet oxygen quantum yields. Moreover, select compounds also inactivated other enveloped viruses, such as herpes simplex virus type 1 and monkeypox virus. The nature and length of the alkyl side chain notably influenced the virus-inactivating activity of BODIPY molecules. Furthermore, molecular dynamics studies highlighted the critical importance of the positioning of the chromophore moiety within the lipid bilayer. As membrane-targeting photosensitizers, BODIPYs interact directly with virus particles, causing damage to the viral envelope membranes. Thus, TBEV pretreated with BODIPY was completely noninfective for lab mice. Consequently, BODIPY-based photosensitizers hold potential either as broad-spectrum virus-inactivating antivirals against a variety of phylogenetically unrelated enveloped viruses or as potent inactivators of viruses for the development of vaccines for preventing life-threatening emerging viral diseases.

PMID:39772406 | DOI:10.1021/acsami.4c17482

STAR Protoc. 2025 Jan 7;6(1):103517. doi: 10.1016/j.xpro.2024.103517. Online ahead of print.

ABSTRACT

Recently, studies have emerged exploring the potential application of fecal microbiota transplantation (FMT) in pre-clinical settings. Here, we present a protocol for FMT for mice housed in a specific pathogen-free (SPF) facility. We describe steps for sample collection, microaerophilic processing of freshly collected fecal pellets, and administration through oral gavage. We then detail procedures for the engraftment of the bacterial community. This protocol focuses on age- and gender-matched, healthy donor mice using a mobile and cost-effective alternative to an anoxic cabinet.

PMID:39772388 | DOI:10.1016/j.xpro.2024.103517

Theranostics. 2025 Jan 1;15(3):1122-1134. doi: 10.7150/thno.101358. eCollection 2025.

ABSTRACT

Rationale: Acute liver failure (ALF) is characterized by rapid hepatic dysfunction, primarily caused by drug-induced hepatotoxicity. Due to the lack of satisfactory treatment options, ALF remains a fatal clinical disease, representing a grand challenge in global health. Methods: For the drug repositioning to ALF of mesalamine, which is clinically approved for the treatment of inflammatory bowel disease (IBD), we propose a supramolecular prodrug nanoassembly (SPNs). Mesalamine is modified with a functional peptide of the FRRG sequence. The resulting mesalamine prodrugs form nanoassemblies solely through intermolecular interactions, ensuring high drug loading capacity and reducing the potential toxicity associated with the carrier materials of conventional nanoparticle systems. Results: In acetaminophen (APAP)-induced ALF mouse models, the SPNs predominantly accumulate in injured target tissues owing to the nanoparticles' propensity to target the liver. Subsequently, cathepsin B overexpressed in hepatocytes by drug-induced inflammation triggers the release of mesalamine from the nanoassemblies via enzymatic cleavage, resulting in remarkable therapeutic efficacy. Meanwhile, nonspecific drug release in healthy cells is inhibited due to their relatively lower cathepsin B expression, which helps prevent the exacerbation of the ALF by minimizing adverse events related to drug exposure. Conclusions: This study provides valuable insights into designing rational nanomedicine for repurposing mesalamine in ALF treatment, potentially inspiring further research to discover effective and safe therapeutic options for patients.

PMID:39776792 | PMC:PMC11700871 | DOI:10.7150/thno.101358

Sci Rep. 2025 Jan 7;15(1):1141. doi: 10.1038/s41598-024-79723-2.

ABSTRACT

Sodium aescinate (SA), a natural plant extract with various bioactivities, is widely used to treat oedema and inflammation in clinics. However, adverse events, including liver injury, kidney injury, and phlebitis, have been reported in patients with SA in recent years. In this study, we used BALB/c mice and L02 cells to evaluate the role of ferroptosis in SA-induced liver injury. SA significantly increased AST, ALT, MDA and Fe2+, decreased GSH levels, and induced pathological changes in the liver in vivo. SA also reduced the viability of L02 cells and induced LDH release, intracellular cysteine reduction, GSH depletion, iron accumulation, ROS production, and lipid peroxidation, indicating that SA causes ferroptosis. In addition, SA inhibited transcriptional activity of activating transcription factor 4 (ATF4) and subsequently reduced the expression of the downstream genes xCT (solute carrier family 7a member 11, SLC7A11) and Cystathionine gamma-lyase (CTH) which play vital roles in GSH biosynthesis. Interestingly, the cytotoxic effects of SA were effectively attenuated by ATF4 overexpression, while they were significantly aggravated by ATF4 silencing. These results revealed that SA triggers hepatocyte ferroptosis by inhibiting the activity of ATF4, which causes an oxidative imbalance.

PMID:39774712 | DOI:10.1038/s41598-024-79723-2

PLoS One. 2025 Jan 8;20(1):e0313338. doi: 10.1371/journal.pone.0313338. eCollection 2025.

ABSTRACT

BICSTaR (BICtegravir Single Tablet Regimen) is an ongoing, observational cohort study assessing the virologic effectiveness and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in treatment-experienced (TE) and treatment-naïve (TN) people with HIV across 14 countries over 24 months. We present 12-month outcomes from participants in the BICSTaR Japan cohort. Retrospective and prospective data were pooled from people with HIV aged ≥20 years receiving B/F/TAF within routine clinical care in Japan. Outcomes included virologic effectiveness (primary endpoint; HIV-1 RNA <50 copies/mL), CD4 count, CD4/CD8 ratio, drug-related adverse events (DRAEs), persistence, and patient-reported outcomes (prospective TN cohort only). Overall, 200 participants were enrolled and included in the 12-month analysis population (150 retrospective, 50 prospective; 116 TN and 84 TE). Most participants were male at birth (99%); median age was 34 years in TN and 45 years in TE participants. At 12 months, virologic effectiveness was high: 92% (90/98) of TN and 95% (72/76) of TE participants had HIV-1 RNA <50 copies/mL (missing = excluded analysis). Median (quartile [Q]1, Q3) CD4 cell count increased by +202.0 (126.0, 311.0) cells/μL in TN (p<0.001) and +11.0 (-60.0, 87.0) cells/μL in TE (p = 0.380) participants. Through 12 months, DRAEs were reported by 13% (25/200) of all participants (16% [18/116] TN, 8% [7/84] TE); diarrhea, weight gain, and headache were the most common. Most DRAEs were mild in severity and no severe DRAEs were reported. One TN participant (<1%; 1/116) and two TE participants (2%; 2/84) discontinued B/F/TAF due to DRAEs (macrocytic anemia, vertigo, diarrhea, and headache). Treatment persistence at 12 months exceeded 98% in both TN and TE participants. In prospective TN participants, improvements in bothersome symptom count and quality-of-life measures were observed. B/F/TAF demonstrated high levels of virologic effectiveness and tolerability in people with HIV treated as part of routine clinical care in Japan.

PMID:39774438 | DOI:10.1371/journal.pone.0313338

Sci Rep. 2025 Jan 7;15(1):1220. doi: 10.1038/s41598-024-84679-4.

ABSTRACT

Macular degeneration is a leading cause of irreversible vision loss, significantly impacting quality of life. To enhance clinical practice and reduce the risk of drug-related macular degeneration, we analyzed drug-related trends using real-world data. Disproportionality analysis of adverse event reports from the FDA Adverse Event Reporting System (FAERS, 2004-2023) identified 67,683 cases involving 1402 drugs. Among these, 42 drugs were linked to significant risks, including treatments for breast cancer (tamoxifen, raloxifene, anastrozole, letrozole) and diabetes (insulin lispro, insulin human). The BCPNN algorithm revealed that 45.2% (19/42) of these drugs had the strongest associations with macular degeneration, with pentosan polysulfate sodium, travoprost, and tolterodine being the highest-risk drugs. Lifitegrast, nicotine, and travoprost were associated with the shortest onset times for ocular adverse events. Among drug classes, glucocorticosteroids were linked to the most rapid onset of ocular side effects (P < 0.001), typically occurring within two months compared to other drugs. Drug-related macular degeneration was more common in women (70.4%) and predominantly affected those aged 60-80. The incidence of drug-related macular degeneration has steadily increased in recent years. This study offers valuable pharmacovigilance insights, highlighting drugs and demographic factors linked to macular degeneration.

PMID:39774257 | DOI:10.1038/s41598-024-84679-4

Int J STD AIDS. 2025 Jan 8:9564624241308372. doi: 10.1177/09564624241308372. Online ahead of print.

ABSTRACT

BACKGROUND: BICSTaR is a multi-national, observational cohort evaluating the effectiveness, safety, and patient-reported outcomes (PROs) in treatment-naïve (TN) and -experienced (TE) people with HIV-1 receiving bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in routine clinical care. We present the 12-month (M12) outcomes of the Italian BICSTaR cohort.

METHODS: Participants initiating B/F/TAF in routine care were prospectively followed. Outcomes included virological and immunologic effectiveness, drug-related adverse events (DRAEs), treatment persistence, and PROs using the HIV Symptom Index (HIV-SI) and the HIV Treatment Satisfaction Questionnaires (HIVTSQ).

RESULTS: N = 201 were included (29 TN, 172 TE), 83% male, median age 38 years in TN, 48 years in TE. At baseline, 94% of TE had an HIV-1 RNA <50 cp/mL, 92% switched to B/F/TAF for simplification. Overall, 69% reported comorbidities (TN: 59%, TE: 70%). At M12, 88% (23/26) of TN and 96% (152/159) of TE had an HIV-1 RNA <50 cp/mL in the discontinuation = failure analysis (without emergence of resistance to B/F/TAF). Median CD4 count changes were +296 cells/µL (interquartile range [IQR], 118, 383) in TN, and +23 cells/µl (-137, 114) in TE. DRAEs were reported for 5% and led to discontinuation in 1%. M12 persistence on B/F/TAF was 97%. TN had a median HIV-SI bothersome symptom count decrease of -1.5 (IQR, -5.0, 0.0). Median treatment satisfaction change score was +29.0 (21, 30) in TE indicating an improvement.

CONCLUSIONS: In this real-world Italian cohort of mostly treatment-experienced people switching for simplification, B/F/TAF demonstrated high effectiveness and persistence over 12 months and confirmed the favourable safety profile shown in clinical trials.

TRIAL REGISTRATION: European cohort: EUPAS22185.

PMID:39772928 | DOI:10.1177/09564624241308372

Postepy Biochem. 2024 Dec 2;70(4):438-446. doi: 10.18388/pb.2021_577.

ABSTRACT

Prostaglandyny są hormonami występującymi niemal we wszystkich ssaczych tkankach. Jako cząsteczki sygnałowe odgrywają one kluczową rolę w regulacji wielu procesów fizjologicznych, m. in. cyklu wzrostu włosa. W artykule opisano historię odkrycia prostaglandyn, w tym prace profesora Ryszarda Gryglewskiego - odkrywcy prostacykliny. Szczególną uwagę zwrócono na syntetyczny analog prostaglandyny F2α - latanoprost. Jest to lek wskazany w leczeniu jaskry, którego działaniem ubocznym jest nadmierny wzrost rzęs. Jako prolek, latanoprost ulega przekształceniu do aktywnego metabolitu - kwasu latanoprostowego. Dzięki ostatnim badaniom wiadomo, że kwas latanoprostowy ma szanse stać się skuteczną alternatywą dla minoksydylu i finasterydu - jedynych leków zarejestrowanych obecnie do leczenia łysienia androgenowego. Wprowadzenie na rynek leków przeciwko łysieniu zawierających pochodne prostaglandyn, w tym kwas latanoprostowy będzie procesem znacznie szybszym w porównaniu do tradycyjnej ścieżki rozwoju produktu, opartego o nowy związek chemiczny.

PMID:39772319 | DOI:10.18388/pb.2021_577

Postepy Biochem. 2024 Dec 2;70(4):462-473. doi: 10.18388/pb.2021_568.

ABSTRACT

Farmakogenomika to dziedzina z pogranicza farmacji i genomiki. Zajmuje się ona badaniem wpływu występujących u pacjenta wariantów genów związanych z metabolizmem leków na jego reakcję na konkretny lek. Rolą testów farmakogenomicznych jest określenie tempa metabolizmu leków i wykorzystanie tej informacji w praktyce klinicznej. Takie podejście otwiera nowe możliwości w optymalizacji terapii, poprzez dobranie właściwego leku i dostosowanie dawki tak, aby zminimalizować działania niepożądane, jednocześnie maksymalizując skuteczność podawanego preparatu. Dzięki temu zwiększona jest szansa na przypisanie pacjentowi odpowiedniego leku, co przyspiesza wprowadzenie skutecznej terapii. Perspektywy zastosowania farmakogenomiki w psychiatrii są obiecujące, choć podobnie jak w przypadku schorzeń innych układów, stworzenie jednolitych rekomendacji jest utrudnione przez złożoność wielu zaburzeń psychicznych oraz wpływ innych czynników, takich jak interakcje pomiędzy przyjmowanymi lekami. Z tego powodu rekomendacje tworzone przez różne instytucje różnią się między sobą. Celem niniejszego artykułu jest omówienie aktualnych możliwości zastosowania farmakogenomiki w psychiatrii oraz trudności jej wprowadzenia jako standardu leczenia psychiatrycznego.

PMID:39772325 | DOI:10.18388/pb.2021_568

Int J Mol Sci. 2024 Dec 20;25(24):13631. doi: 10.3390/ijms252413631.

ABSTRACT

The notochord is an axial structure required for the development of all chordate embryos, from sea squirts to humans. Over the course of more than half a billion years of chordate evolution, in addition to its structural function, the notochord has acquired increasingly relevant patterning roles for its surrounding tissues. This process has involved the co-option of signaling pathways and the acquisition of novel molecular mechanisms responsible for the precise timing and modalities of their deployment. To reconstruct this evolutionary route, we surveyed the expression of signaling molecules in the notochord of the tunicate Ciona, an experimentally amenable and informative chordate. We found that several genes encoding for candidate components of diverse signaling pathways are expressed during notochord development, and in some instances, display distinctive regionalized and/or lineage-specific patterns. We identified and deconstructed notochord enhancers associated with TGF-β and Ctgf, two evolutionarily conserved signaling genes that are expressed dishomogeneously in the Ciona notochord, and shed light on the cis-regulatory origins of their peculiar expression patterns.

PMID:39769393 | DOI:10.3390/ijms252413631

Pharmaceutics. 2024 Dec 17;16(12):1607. doi: 10.3390/pharmaceutics16121607.

ABSTRACT

Background/Objectives: Glucagon-like peptide-1 (GLP-1) receptor is currently one of the most explored targets exploited for the management of diabetes and obesity, with many aspects of its mechanisms behind cardiovascular protection yet to be fully elucidated. Research dedicated towards the development of oral GLP-1 therapy and non-peptide ligands with broader clinical applications is crucial towards unveiling the full therapeutic capacity of this potent class of medicines. Methods: This study describes the virtual screening of a natural product database consisting of 695,133 compounds for positive GLP-1 allosteric modulation. The database, obtained from the Coconut website, was filtered according to a set of physicochemical descriptors, then was shape screened against the crystal ligand conformation. This filtered database consisting of 26,325 compounds was used for virtual screening against the GLP-1 allosteric site. Results: The results identified ten best hits with the XP score ranging from -9.6 to -7.6 and MM-GBSA scores ranging from -50.8 to -32.4 and another 58 hits from docked pose filter and a second round of XP docking and MM-GBSA calculation followed by molecular dynamics. The analysis of results identified hits from various natural products (NPs) classes, to whom attributed antidiabetic and anti-obesity effects have been previously reported. The results also pointed to β-lactam antibiotics that may be evaluated in drug repurposing studies for off-target effects. The calculated ADMET properties for those hits revealed suitable profiles for further development in terms of bioavailability and toxicity. Conclusions: The current study identified several NPs as potential GLP-1 positive allosteric modulators and revealed common structural scaffolds including peptidomimetics, lactams, coumarins, and sulfonamides with peptidomimetics being the most prominent especially in indole and coumarin cores.

PMID:39771585 | DOI:10.3390/pharmaceutics16121607