Search

Background: Electrographic flow (EGF) mapping reconstructs atrial electrical wavefront propagation, potentially revealing sources of atrial fibrillation (AF). Electrographic flow consistency (EGFC) measures the concurrence of wavefront patterns and may provide insights into atrial substrate health. This study aimed to compare EGF patterns during atrial fibrillation (AF) with sinus rhythm (SR) and explore the correlation between EGFC and regional bipolar voltage., Methods: In this single-center, prospective study, AF patients underwent mapping of the atria using bipolar voltage and EGF mapping. Mapping was performed during both AF and SR using a 16-electrode grid catheter (bipolar mapping) and a 64-pole basket catheter (EGF mapping). EGFC was computed as the average modulus of individual EGF vectors, reflecting flow pattern consistency., Results: Ten patients were enrolled. EGF identified 11 sources with a mean source activity of 32 ± 9% during AF. Eight out of eleven sources in AF converted to passive "sinks" when mapped in SR. EGFC was significantly lower during AF compared to SR (0.74 ± 0.14 vs 1.0 ± 0.11 AUs, P < 0.01), consistent with EGFC quantifying the more chaotic wavefront propagation during arrhythmia. No spatial correlation between areas of high EGFC during AF and SR was observed. EGFC correlated with bipolar voltage across rhythms and atria (r = 0.647, P < 0.0001)., Conclusion: EGF patterns varied by rhythm with AF showing lower EGFC values. EGFC correlated with bipolar voltage across rhythms and atria, suggesting its potential as an atrial myopathy marker akin to high-density voltage mapping and offering insights into atrial substrate health. Trial registration ClinicalTrials.gov Identifier: NCT06260670., Competing Interests: Declarations. Ethics approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Heart and Diabetes Center NRW, Ruhr University Bochum. Approval No. 2022–889. Consent to participate: Informed consent was obtained from all individual participants included in the study. Competing interests: PS is a member of the advisory board for Abbott, Biosense Webster, Boston Scientific and Medtronic. NM has no competing interests to declare that are relevant to the content of this article. SC, MK, KA and MJ are employees of and own equity in Cortex, Inc. M.K. is additionally a patent holder of the technology., (© 2024. The Author(s).)

In searching for putative new therapeutic strategies to treat neurodegenerative diseases, the mitochondrial 18 kDa translocator protein (TSPO) and cerebral isoforms of carbonic anhydrase (CA) were exploited as potential targets. Based on the structures of a class of highly affine and selective TSPO ligands and a class of CA activators, both developed by us in recent years, a small library of 2-phenylindole-based dual TSPO/CA modulators was developed, able to bind TSPO and activate CA VII in the low micromolar/submicromolar range. The interaction with the two targets was corroborated by computational studies. Biological investigation on human microglia C20 cells identified derivative 3 as a promising lead compound worthy of future optimization due to its (i) lack of cytotoxicity, (ii) ability to stimulate TSPO steroidogenic function and activate CA VII, and (iii) ability to effectively upregulate gene expression of the brain-derived neurotrophic factor.

Study Question: Can genome-wide genotyping data be analysed using a hypothesis-driven approach to enhance the understanding of the genetic basis of severe spermatogenic failure (SPGF) in male infertility?, Summary Answer: Our findings revealed a significant association between SPGF and the SHOC1 gene and identified three novel genes ( PCSK4 , AP3B1 , and DLK1 ) along with 32 potentially pathogenic rare variants in 30 genes that contribute to this condition., What Is Known Already: SPGF is a major cause of male infertility, often with an unknown aetiology. SPGF can be due to either multifactorial causes, including both common genetic variants in multiple genes and environmental factors, or highly damaging rare variants. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of SPGF. Genome-wide association studies (GWASs) have become essential approaches for deciphering the intricate genetic landscape of complex diseases, offering a cost-effective and rapid means to genotype millions of genetic variants. Novel methods have demonstrated that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes. However, this approach has not been previously applied to characterize the genetic component of a whole case-control cohort., Study Design Size Duration: We employed a hypothesis-driven approach focusing on all genetic variation identified, using a GWAS platform and subsequent genotype imputation, encompassing over 20 million polymorphisms and a total of 1571 SPGF patients and 2431 controls. Both common (minor allele frequency, MAF > 0.01) and rare (MAF < 0.01) variants were investigated within a total of 1797 loci with a reported role in spermatogenesis. This gene panel was meticulously assembled through comprehensive searches in the literature and various databases focused on male infertility genetics., Participants/materials Setting Methods: This study involved a European cohort using previously and newly generated data. Our analysis consisted of three independent methods: (i) variant-wise association analyses using logistic regression models, (ii) gene-wise association analyses using combined multivariate and collapsing burden tests, and (iii) identification and characterisation of highly damaging rare coding variants showing homozygosity only in SPGF patients., Main Results and the Role of Chance: The variant-wise analyses revealed an association between SPGF and SHOC1 -rs12347237 ( P  =   4.15E-06, odds ratio = 2.66), which was likely explained by an altered binding affinity of key transcription factors in regulatory regions and the disruptive effect of coding variants within the gene. Three additional genes ( PCSK4 , AP3B1 , and DLK1 ) were identified as novel relevant players in human male infertility using the gene-wise burden test approach ( P  <   5.56E-04). Furthermore, we linked a total of 32 potentially pathogenic and recessive coding variants of the selected genes to 35 different cases., Large Scale Data: Publicly available via GWAS catalog (accession number: GCST90239721)., Limitations Reasons for Caution: The analysis of low-frequency variants presents challenges in achieving sufficient statistical power to detect genetic associations. Consequently, independent studies with larger sample sizes are essential to replicate our results. Additionally, the specific roles of the identified variants in the pathogenic mechanisms of SPGF should be assessed through functional experiments., Wider Implications of the Findings: Our findings highlight the benefit of using GWAS genotyping to screen for both common and rare variants potentially implicated in idiopathic cases of SPGF, whether due to complex or monogenic causes. The discovery of novel genetic risk factors for SPGF and the elucidation of the underlying genetic causes provide new perspectives for personalized medicine and reproductive counselling., Study Funding/competing Interests: This work was supported by the Spanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation (PID2020-120157RB-I00) and the Andalusian Government through the research projects of 'Plan Andaluz de Investigación, Desarrollo e Innovación (PAIDI 2020)' (ref. PY20&#95;00212) and 'Proyectos de Investigación aplicada FEDER-UGR 2023' (ref. C-CTS-273-UGR23). S.G.-M. was funded by the previously mentioned projects (ref. PY20&#95;00212 and PID2020-120157RB-I00). A.G.-J. was funded by MCIN/AEI/10.13039/501100011033 and FSE 'El FSE invierte en tu futuro' (grant ref. FPU20/02926). IPATIMUP integrates the i3S Research Unit, which is partially supported by the Portuguese Foundation for Science and Technology (FCT), financed by the European Social Funds (COMPETE-FEDER) and National Funds (projects PEstC/SAU/LA0003/2013 and POCI-01-0145-FEDER-007274). S.S. is supported by FCT funds (10.54499/DL57/2016/CP1363/CT0019), ToxOmics-Centre for Toxicogenomics and Human Health, Genetics, Oncology and Human Toxicology, and is also partially supported by the Portuguese Foundation for Science and Technology (UIDP/00009/2020 and UIDB/00009/2020). S. Larriba received support from Instituto de Salud Carlos III (grant: DTS18/00101), co-funded by FEDER funds/European Regional Development Fund (ERDF)-a way to build Europe) and from 'Generalitat de Catalunya' (grant 2021SGR052). S. Larriba is also sponsored by the 'Researchers Consolidation Program' from the SNS-Dpt. Salut Generalitat de Catalunya (Exp. CES09/020). All authors declare no conflict of interest related to this study., Competing Interests: The authors declare that the research was conducted without any conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Cancer's persistent growth often relies on its ability to maintain telomere length and tolerate the accumulation of DNA damage. This study explores a computational approach to identify compounds that can simultaneously target both G-quadruplex (G4) structures and poly(ADP-ribose) polymerase (PARP)1 enzyme, offering a potential multipronged attack on cancer cells. We employed a hybrid virtual screening (VS) protocol, combining the power of machine learning with traditional structure-based methods. PyRMD, our AI-powered tool, was first used to analyze vast chemical libraries and to identify potential PARP1 inhibitors based on known bioactivity data. Subsequently, a structure-based VS approach selected compounds from these identified inhibitors for their G4 stabilization potential. This two-step process yielded 50 promising candidates, which were then experimentally validated for their ability to inhibit PARP1 and stabilize G4 structures. Ultimately, four lead compounds emerged as promising candidates with the desired dual activity and demonstrated antiproliferative effects against specific cancer cell lines. This study highlights the potential of combining Artificial Intelligence and structure-based methods for the discovery of multitarget anticancer compounds, offering a valuable approach for future drug development efforts.

Goji berry is acknowledged for its notable medicinal attributes and elevated free radical scavenger properties. Nevertheless, its susceptibility to mechanical injuries and biological disorders reduces the commercial diffusion of the fruit. A hyperspectral imaging system (HSI) was employed to identify common defects in the Vis-NIR range (400-1000 nm). The sensorial evaluation of visual appearance was used to obtain the reference measurement of defects. A supervised classification model employing PLS-DA was developed using raw and pre-processed spectra, followed by applying a covariance selection algorithm (CovSel). The classification model demonstrated superior performance in two classifications distinguishing between sound and defective fruit, achieving an accuracy and sensitivity of 94.9% and 96.9%, respectively. However, when extended to a more complex task of classifying fruit into four categories, the model exhibited reliable results with an accuracy and sensitivity of 74.5% and 77.9%, respectively. These results indicate that a method based on hyperspectral visible-NIR can be implemented for rapid and reliable methods of online quality inspection securing high-quality goji berries.

Background: Since the Substrate and Trigger Ablation for Reduction of Atrial Fibrillation Trial Part II (STAR-AF II), there has been a trend toward pulmonary vein isolation (PVI)-only ablation strategies for persistent atrial fibrillation (PeAF). Electrographic flow (EGF) mapping can identify active sources of atrial fibrillation (AF) and estimate the electrographic flow consistency (EGFC) of wavefront propagation through substrate, revealing functional AF mechanisms., Objective: We sought to examine the success of a PVI-only ablation strategy for a redo PeAF/longstanding PeAF population., Methods: Electrographic Flow-Guided Ablation in Redo Patients With Persistent Atrial Fibrillation (FLOW-AF [NCT04473963]) prospectively enrolled patients with nonparoxysmal AF undergoing redo ablation at 4 centers. One-minute EGF recordings using 64-pole basket catheters were obtained both pre-PVI and post-PVI following a 20-minute wait and confirmation of electrical isolation of veins. Patients with EGF-identified sources were randomized 1:1 to EGF-guided source ablation vs PVI-only. Patients with no sources were not randomized and mostly received PVI only., Results: Study of 85 patients enrolled 24 with EGF-identified sources randomized to PVI only and 23 with no sources receiving PVI only. Of these 47 patients, those with sources (Group 2) had different clinical characteristics including older age and higher CHA 2 DS 2 -VASc scores compared with those with no sources (Group 1). After PVI only, Group 1 had 70% (16 of 23) freedom from recurrent AF (FFAF) within 1 year vs Group 2 with 35% (8 of 23), P = .018. In addition, patients with high electrographic flow consistency (EGFC) indicative of healthy or normal substrate had 67% (10 of 15) FFAF vs 45% (14 of 31) in those with low EGFC suggestive of abnormal substrate, P = .011., Conclusion: Success rates in no-sources patients receiving PVI only are better than in those with sources randomized to PVI only. For the clinically heterogenous population of patients with PeAF, the presence of EGF-identified sources matters clinically, and PVI only will not be enough for all patients., Competing Interests: Disclosures Dr Verma is consultant and owns equity in Cortex, Inc; is consultant for Adagio Medical and Mediumics; has received research grants from Bayer Inc, Biosense Webster, Medtronic, and Boston Scientific. Dr Castellano is an employee of Cortex, Inc, with equity interest. Dr Kong is a former employee of Cortex, Inc, with equity interest and relevant patent holdings. Dr Neuzil has received support from a Scientific Grant by Ministry of Health, Czech Republic, DRO (NNH, IG 180504) and travel grants from Cortex, Inc. Dr Szili-Torok has served as consultant for Biotronik and has received institutional grants from Biotronik, Abbott NL, Biosense Webster, Acutus Medical Inc, Stereotaxis, and Catheter Precision. Dr Spitzer has received honoraria for lectures from Amgen, AstraZeneca, Biotronik, Daiichi Sankyo, and Edwards Medtronic and has participated in clinical trials for Boston Scientific, LifeTech, and Vanguard. Dr Rillig has served as consultant for Medtronic, KODEX-EPD, Biosense Webster, and Boston Scientific and has received travel grants and lecture fees from Cortex, Inc, Medtronic, CardioFocus, Biosense Webster, Abbott, Boehringer Ingelheim, Philips KODEX-EPD, Bayer Inc, Novartis, LifeTech, and Boston Scientific. Dr Reddy has served as consultant and owns equity in Cortex, Inc, Acutus Medical, Affera-Medtronic, Anumana, Apama Medical-Boston Scientific, APN Health, Aquaheart, Atacor, Autonomix, Axon Therapies, Backbeat, BioSig, CardiaCare, CardioNXT/AFTx, Circa Scientific, CoRISMA, Corvia Medical, Dinova-Hangzhou DiNovA EP Technology, East End Medical, EPD-Philips, EP Frontiers, Epix Therapeutics-Medtronic, EpiEP, Eximo, Farapulse-Boston Scientific, Field Medical, Focused Therapeutics, HRT, Intershunt, Javelin, Kardium, Keystone Heart, Laminar, LuxMed, Medlumics, Middlepeak, NuVera-Biosense Webster, Oracle Health, Restore Medical, Sirona Medical, SoundCath, and Valcare; has served as consultant for Abbott, AtriAN, Biosense Webster, BioTel Heart, Biotronik, Boston Scientific, Cairdac, Cardiofocus, Cardionomic, CoreMap, Fire1, Gore & Associates, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Philips, and Pulse Biosciences; and owns equity in DRS Vascular, Manual Surgical Sciences, Newpace, Nyra Medical, Surecor, and VizaraMed., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The management of Non-Obstructive (NOA) Azoospermia or Obstructive Azoospermia (OA) patients relies on testicular sperm extraction (TESE) followed by intracytoplasmic sperm injection (ICSI). In NOA patients the sperm recovery is successful in only 50% of cases and therefore the ability to predict those patients with a high probability of achieving a successful sperm retrieval would be a great value in counselling the patient and his partner. Several studies tried to suggest predictors of a positive TESE (e.g. FSH concentration), but most concluded that diagnostic testicular biopsy (histology) is best., Methods: This is a retrospective analysis of 526 TESE patients. After the extraction of the testis, the resulting sample was immediately given to the embryologist, who examined the tubules for sperm cryopreservation. During the same procedure, a different specimen was destined to the histological analysis. The comparison between the two methodological approaches was carried out through a score., Results: Concordance between TESE and testicular histology outcomes was found in 70,7% of patients; discordance was found in 29,3% of patients. Among the discordance outcomes, in approximately 95% we found at least 1 sperm in the TESE retrieval, while the histology report did not find any spermatozoa or found not enough compared to our evaluation; in only 5% of cases we did not find any spermatozoa or found not enough compared to what was detected in the testicular histology., Conclusion: Based on our experience, to increase diagnostic accuracy, a larger biopsy should be sent to the histopathology laboratory; another option may be to use TESE cell suspension (the same embryologists employ for cryopreservation) for cytological evaluation of spermatogenesis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Castellano, Tondo, Bulbul, Aprea, Monti, Carnesi, Levi Setti and Albani.)

Background: Metagenomics is a powerful approach for the detection of unknown and novel pathogens. Workflows based on Illumina short-read sequencing are becoming established in diagnostic laboratories. However, high sequencing depth requirements, long turnaround times, and limited sensitivity hinder broader adoption. We investigated whether we could overcome these limitations using protocols based on untargeted sequencing with Oxford Nanopore Technologies (ONT), which offers real-time data acquisition and analysis, or a targeted panel approach, which allows the selective sequencing of known pathogens and could improve sensitivity., Methods: We evaluated detection of viruses with readily available untargeted metagenomic workflows using Illumina and ONT, and an Illumina-based enrichment approach using the Twist Bioscience Comprehensive Viral Research Panel (CVRP), which targets 3153 viruses. We tested samples consisting of a dilution series of a six-virus mock community in a human DNA/RNA background, designed to resemble clinical specimens with low microbial abundance and high host content. Protocols were designed to retain the host transcriptome, since this could help confirm the absence of infectious agents. We further compared the performance of commonly used taxonomic classifiers., Results: Capture with the Twist CVRP increased sensitivity by at least 10-100-fold over untargeted sequencing, making it suitable for the detection of low viral loads (60 genome copies per ml (gc/ml)), but additional methods may be needed in a diagnostic setting to detect untargeted organisms. While untargeted ONT had good sensitivity at high viral loads (60,000 gc/ml), at lower viral loads (600-6000 gc/ml), longer and more costly sequencing runs would be required to achieve sensitivities comparable to the untargeted Illumina protocol. Untargeted ONT provided better specificity than untargeted Illumina sequencing. However, the application of robust thresholds standardized results between taxonomic classifiers. Host gene expression analysis is optimal with untargeted Illumina sequencing but possible with both the CVRP and ONT., Conclusions: Metagenomics has the potential to become standard-of-care in diagnostics and is a powerful tool for the discovery of emerging pathogens. Untargeted Illumina and ONT metagenomics and capture with the Twist CVRP have different advantages with respect to sensitivity, specificity, turnaround time and cost, and the optimal method will depend on the clinical context., (© 2024. The Author(s).)

The translocator protein (TSPO) is predominately localized on the outer mitochondrial membrane in steroidogenic cells. In the brain, TSPO expression, low under normal conditions, results upregulated in response to glial cell activation, that occurs in neuroinflammation. As a consequence, TSPO has been extensively studied as a biomarker of such conditions by means of TSPO-targeted radiotracers. Although [ 11 C]-PK11195, the prototypical TSPO radioligand, is still widely used for in vivo studies, it is endowed with severe limitations, mainly low sensitivity and poor amenability to quantification. Consequently, several efforts have been focused on the design of new radiotracers for the in vivo imaging of TSPO. The present review will provide an outlook on the latest advances in TSPO radioligands for neuroinflammation imaging. The final goal is to pave the way for (radio)chemists in the future design and development of novel effective and sensitive radiopharmaceuticals targeting TSPO.

Acetylation of histone proteins by histone acetyltransferases (HATs), and the resultant change in gene expression, is a well-established mechanism necessary for long-term memory (LTM) consolidation, which is not required for short-term memory (STM). However, we previously demonstrated that the HAT p300/CBP-associated factor (PCAF) also influences hippocampus (HPC)-dependent STM in male rats. In addition to their epigenetic activity, HATs acetylate nonhistone proteins involved in nongenomic cellular processes, such as estrogen receptors (ERs). Given that ERs have rapid, nongenomic effects on HPC-dependent STM, we investigated the potential interaction between ERs and PCAF for STM mediated by the dorsal hippocampus (dHPC). Using a series of pharmacological agents administered directly into the dHPC, we reveal a functional interaction between PCAF and ERα in the facilitation of short-term object-in-place memory in male but not female rats. This interaction was specific to ERα, while ERβ agonism did not enhance STM. It was further specific to dHPC STM, as the effect was not present in the dHPC for LTM or in the perirhinal cortex. Further, while STM required local (i.e., dHPC) estrogen synthesis, the facilitatory interaction effect appeared independent of estrogens. Finally, western blot analyses demonstrated that PCAF activation in the dHPC rapidly (5 min) activated downstream estrogen-related cell signaling kinases (c-Jun N-terminal kinase and extracellular signal-related kinase). Collectively, these findings indicate that PCAF, which is typically implicated in LTM through epigenetic processes, also influences STM in the dHPC, possibly via nongenomic ER activity. Critically, this novel PCAF-ER interaction might exist as a male-specific mechanism supporting STM., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as an emerging target class in oncology and other diseases. A successful strategy to identify PRMT substrate-competitive inhibitors has been to exploit chemical scaffolds able to mimic the arginine substrate. (S)-Alanine amide moiety is a valuable arginine mimic for the development of potent and selective PRMT4 inhibitors; however, its high hydrophilicity led to derivatives with poor cellular outcomes. Here, we describe the development of PRMT4 inhibitors featuring a central pyrrole core and an alanine amide moiety. Rounds of optimization, aimed to increase lipophilicity and simultaneously preserve the inhibitory activity, produced derivatives that, despite good potency and physicochemical properties, did not achieve on-target effects in cells. On the other hand, masking the amino group with a NAD(P)H:quinone oxidoreductase 1 (NQO1)-responsive trigger group, led to prodrugs able to reduce arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155). These results indicate that prodrug strategies can be successfully applied to alanine-amide containing PRMT4 inhibitors and provide an option to enable such compounds to achieve sufficiently high exposures in vivo., (© 2024 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Background: Patients undergoing antipsychotic treatment for psychiatric disorders may experience challenges in functioning, either stemming from the severity of the illness or from the tolerability issues of prescribed medications., Objectives: The aims of this cross-sectional study are to investigate the impact of adverse effects of antipsychotic drugs on patients' daily life functioning, comparing oral and long-acting injectable (LAI) antipsychotics, and further dividing antipsychotics by receptor-binding profiles based on recently defined data-driven taxonomy., Methods: This study involved patients with schizophrenia and bipolar spectrum disorders taking oral or LAI antipsychotics. Disability and functioning levels were assessed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS), and the adverse effects of medications were evaluated using the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale and its subscales., Results: The total sample consisted of 126 participants with a diagnosis of schizophrenia-spectrum or bipolar disorder, and included 54 males and 72 females ranging from 18 to 78 years of age (mean 45.1, standard deviation 14); 78 patients were taking oral antipsychotics and 48 were taking LAI antipsychotics, with subcategories of muscarinic (31), adrenergic/low dopamine (25), serotonergic/dopaminergic (23), dopaminergic (1), LAI muscarinic (15), LAI adrenergic (6), and LAI serotonergic/dopaminergic (25). The UKU total score for adverse effects showed significant correlations with WHODAS total score (ρ = 0.475; p < 0.001). Compared with oral antipsychotics, LAIs showed significantly lower scores in psychological (p = 0.014), autonomic (p = 0.008), other (p = 0.004), and sexual adverse effects (p = 0.008), as well as the UKU total score (p = 0.002). The Kruskal-Wallis test showed a significant difference in adverse effects between LAI and oral muscarinic subgroups, with LAIs having lower scores compared with antipsychotics binding to muscarinic receptors (p = 0.043)., Conclusion: These findings indicate clinically relevant differences in adverse effects among formulations, warranting further investigation for future observational studies., (© 2024. The Author(s).)

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP., (© 2024. The Author(s).)

Introduction: Bromodomain and ExtraTerminal (BET) domain proteins are transcriptional cofactors that, recognizing acetylated lysines of histone and non-histone proteins, can modulate gene expression. The BET family consists of four members, each of which contains two bromodomains (BD1 and BD2) able to recognize the acetylated mark. Pan-BET inhibitors (BETi) have shown a promising anticancer potential in many clinical trials; however, their further development has been in part hampered by the side effects due to their lack of selectivity. Mounting evidence suggests that BD1 is primarily involved in cancer and that its selective inhibition can phenocopy the anticancer effects of pan-BETi with increased tolerability. Therefore, the development of BD1 selective inhibitors is highly pursed in both academia and industry., Areas Covered: This review aims at giving an overview of the patent literature of BD1-selective BETi between 2014 and 2023. WIPO, USPTO, EPO, and SciFinder® databases were used for the search of patents., Expert Opinion: The development of BD1-selective BETi, despite challenging, is highly desirable as it could have a great impact on the development of new safer anticancer therapeutics. Several strategies could be applied to discover potent and selective compounds with limited side effects.

Introduction: Acute ischemic stroke is one of the leading global causes of morbidity and mortality. Mechanical thrombectomy has improved the functional prognosis of this condition; however, hemorrhagic transformation is a common complication. Spectral computed tomography (CT) imaging, as a neuroimaging control test, distinguishes contrast extravasation from hemorrhagic transformation due to the differential behavior of materials at dual energy levels. This distinction is valuable in its clinical therapeutic management., Material and Methods: A single-center, observational, retrospective study was conducted in which the presence of various clinical, radiological, and therapeutic variables in patients with acute ischemic stroke treated with mechanical thrombectomy at our hospital between July 2022 and March 2023 was investigated using access to a dissociated database and medical records., Results: Out of 155 included patients, spectral cranial CT was performed in 63, and conventional cranial CT in 75. In the spectral CT group, 21 hyperdense images were detected, compared to 28 in the conventional CT group. In 42.8% of cases where hyperdensity was detected in the conventional CT group, it was not possible to distinguish between contrast extravasation and hemorrhagic transformation, in contrast to the 4.8% in the spectral CT group (p < 0.001)., Conclusions: Spectral CT provides high diagnostic confidence to the radiologist in identifying the type of detected hyperdensity, thereby offering significant therapeutic confidence to the neurologist in early resuming anticoagulation therapy.

Current drugs for Alzheimer's Disease (AD), such as cholinesterase inhibitors (ChEIs), exert only symptomatic activity. Different psychometric tools are needed to assess cognitive and non-cognitive dimensions during pharmacological treatment. In this pilot study, we monitored 33 mild-AD patients treated with ChEIs. Specifically, we evaluated the effects of 6 months (Group 1 = 17 patients) and 9 months (Group 2 = 16 patients) of ChEIs administration on cognition with the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), and the Frontal Assessment Battery (FAB), while depressive symptoms were measured with the Hamilton Depression Rating Scale (HDRS). After 6 months (Group 1), a significant decrease in MoCA performance was detected. After 9 months (Group 2), a significant decrease in MMSE, MoCA, and FAB performance was observed. ChEIs did not modify depressive symptoms. Overall, our data suggest MoCA is a potentially useful tool for evaluating the effectiveness of ChEIs., (© 2024. The Author(s).)

The COVID-19 pandemic caused critical mental health issues and lifestyle disruptions. The aim of this study was to explore, during the lockdown of second-wave contagions in Italy, how stress was affected by dispositional (personality factors and intolerance to uncertainty) and behavioral (coping strategies) dimensions, how these variables differed among sex, age, educational, professional, and health groups, and how the various changes in work and daily routine intervened in the psychological impact of the emergency. Our results highlight that women, the youngs, students/trainees, those with chronic diseases, those who stopped their jobs due to restrictions, and those who left home less than twice a week were more stressed, while health professionals showed lower levels of the same construct. Those with higher levels of stress used more coping strategies based on avoidance, which positively correlated with age, agreeableness, conscientiousness, and intolerance to uncertainty, and negatively with openness. Stress levels also positively correlated with agreeableness, conscientiousness, intolerance to uncertainty, and seeking of social support, and negatively with openness, a positive attitude, and a transcendent orientation. Finally, stress was predicted mainly by behavioral dimensions. Our results are discussed and framed within the literature, as important insights for targeted intervention strategies to promote health even in emergencies.

Selenocysteine, the 21st amino acid specified by the genetic code, is a rare selenium-containing residue found in the catalytic site of selenoprotein oxidoreductases. Selenocysteine is analogous to the common cysteine amino acid, but its selenium atom offers physical-chemical properties not provided by the corresponding sulfur atom in cysteine. Catalytic sites with selenocysteine in selenoproteins of vertebrates are under strong purifying selection, but one enzyme, glutathione peroxidase 6 (GPX6), independently exchanged selenocysteine for cysteine <100 million years ago in several mammalian lineages. We reconstructed and assayed these ancient enzymes before and after selenocysteine was lost and up to today and found them to have lost their classic ability to reduce hydroperoxides using glutathione. This loss of function, however, was accompanied by additional amino acid changes in the catalytic domain, with protein sites concertedly changing under positive selection across distant lineages abandoning selenocysteine in glutathione peroxidase 6. This demonstrates a narrow evolutionary range in maintaining fitness when sulfur in cysteine impairs the catalytic activity of this protein, with pleiotropy and epistasis likely driving the observed convergent evolution. We propose that the mutations shared across distinct lineages may trigger enzymatic properties beyond those in classic glutathione peroxidases, rather than simply recovering catalytic rate. These findings are an unusual example of adaptive convergence across mammalian selenoproteins, with the evolutionary signatures possibly representing the evolution of novel oxidoreductase functions., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Sleep disorders have become increasingly prevalent, with many adults worldwide reporting sleep dissatisfaction. Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are common conditions associated with disrupted sleep patterns such as insomnia and hypersomnolence. These sleep disorders significantly affect the progression, severity, treatment, and outcome of unipolar and bipolar depression. While there is evidence of a connection between sleep disorders and depression, it remains unclear if sleep features differ between MDD and BD. In light of this, this narrative review aims to: (1) summarize findings on common sleep disorders like insomnia and hypersomnolence, strongly linked to MDD and BD; (2) propose a novel psychometric approach to assess sleep in individuals with depressive disorders. Despite insomnia seems to be more influent in unipolar depression, while hypersomnolence in bipolar one, there is no common agreement. So, it is essential adopting a comprehensive psychometric protocol for try to fill this gap. Understanding the relationship between sleep and MDD and BD disorders are crucial for effective management and better quality of life for those affected., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Immunotherapy has emerged as a game-changing approach for cancer treatment. Although monoclonal antibodies (mAbs) targeting the programmed cell death protein 1/programmed cell death protein 1 ligand 1 (PD-1/PD-L1) axis have entered the market revolutionizing the treatment landscape of many cancer types, small molecules, although presenting several advantages including the possibility of oral administration and/or reduced costs, struggled to enter in clinical trials, suffering of water insolubility and/or inadequate potency compared with mAbs. Thus, the search for novel scaffolds for both the design of effective small molecules and possible synergistic strategies is an ongoing field of interest. In an attempt to find novel chemotypes, a virtual screening approach was employed, resulting in the identification of new chemical entities with a certain binding capability, the most versatile of which was the benzimidazole-containing compound 10. Through rational design, a small library of its derivatives was synthesized and evaluated. The homogeneous time-resolved fluorescence (HTRF) assay revealed that compound 17 shows the most potent inhibitory activity (IC 50 ) in the submicromolar range and notably, differently from the major part of PD-L1 inhibitors, exhibits satisfactory water solubility properties. These findings highlight the potential of benzimidazole-based compounds as novel promising candidates for PD-L1 inhibition., (© 2023 The Authors. Archiv der Pharmazie published by Wiley-VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)

Albino plants display partial or complete loss of photosynthetic pigments and defective thylakoid membrane development, consequently impairing plastid function and development. These distinctive attributes render albino plants excellent models for investigating chloroplast biogenesis. Despite their potential, limited exploration has been conducted regarding the molecular alterations underlying these phenotypes, extending beyond photosynthetic metabolism. In this study, we present a novel de novo transcriptome assembly of an albino somaclonal variant of Agave angustifolia Haw., which spontaneously emerged during the micropropagation of green plantlets. Additionally, RT-qPCR analysis was employed to validate the expression of genes associated with chloroplast biogenesis, and plastome copy numbers were quantified. This research aims to gain insight into the molecular disruptions affecting chloroplast development and ascertain whether the expression of critical genes involved in plastid development and differentiation is compromised in albino tissues of A. angustifolia. Our transcriptomic findings suggest that albino Agave plastids exhibit high proliferation, activation of the protein import machinery, altered transcription directed by PEP and NEP, dysregulation of plastome expression genes, reduced expression of photosynthesis-associated nuclear genes, disruption in the tetrapyrrole and carotenoid biosynthesis pathway, alterations in the plastid ribosome, and an increased number of plastome copies, among other alterations., (© 2024 Scandinavian Plant Physiology Society.)

The majority of human diseases attributed to seafood are caused by Vibrio spp., and the most commonly reported species are Vibrio parahaemolyticus , Vibrio vulnificus , and Vibrio cholerae . The conventional methods for the detection of Vibrio species involve the use of selective media, which are inexpensive and simple but time-consuming. The present work aimed to develop a rapid method based on the use of multiplex real-time polymerase chain reaction (PCR) to detect V. parahaemolyticus , V. vulnificus , and V. cholerae in bivalve mollusks. 30 aliquots of bivalve mollusks ( Mytilus galloprovincialis ) were experimentally inoculated with two levels of V. parahaemolyticus , V. vulnificus , and V. cholerae . ISO 21872-1:2017 was used in parallel for qualitative analysis. The limit of detection of 50% was 7.67 CFU/g for V. cholerae , 0.024 CFU/g for V. vulnificus , and 1.36 CFU/g for V. parahaemolyticus . For V. vulnificus and V. cholerae , the real-time PCR protocol was demonstrated to amplify the pathogens in samples seeded with the lowest and highest levels. The molecular method evaluated showed a concordance rate of 100% with the reference microbiological method. V. parahaemolyticus was never detected in samples contaminated with the lowest level, and it was detected in 14 samples (93.33%) seeded with the highest concentration. In conclusion, the developed multiplex real-time PCR proved to be reliable for V. vulnificus and V. cholerae. Results for V. parahaemolyticus are promising, but further analysis is needed. The proposed method could represent a quick monitoring tool and, if used, would allow the implementation of food safety., Competing Interests: Conflict of interest: the authors declare no potential conflict of interest., (Copyright © 2024, the Author(s).)

Being the standard solvent for preparing stock solutions of compounds for drug discovery, DMSO is always present in assay buffers in concentrations ranging from 0.1 % to 5 % (v/v). Even at the lowest concentrations, DMSO-containing solutions can have significant effects on individual proteins and possible pitfalls cannot be eliminated. Herein, we used two protein systems, the lysine methyltransferases G9a/KMT1 C and SETD8/KMT5 A, to study the effects of DMSO on protein stability and on the binding of the corresponding inhibitors, using different biophysical methods such as nano Differential Scanning Fluorimetry (nanoDSF), Differential Scanning Fluorimetry (DSF), microscale thermophoresis (MST), and surface plasmon resonance (SPR), all widely used in drug discovery screening campaigns. We demonstrated that the effects of DMSO are protein- and technique-dependent and cannot be predicted or extrapolated on the basis of previous studies using different proteins and/or different assays. Moreover, we showed that the application of orthogonal biophysical methods can lead to different binding affinity data, thus confirming the importance of using at least two different orthogonal assays in screening campaigns. This variability should be taken into account in the selection and characterization of hit compounds, in order to avoid data misinterpretation., (© 2024 Wiley-VCH GmbH.)

The prevalence of sleep disorders, characterized by issues with quality, timing, and sleep duration is increasing globally. Among modifiable risk factors, diet quality has been suggested to influence sleep features. The Mediterranean diet is considered a landmark dietary pattern in terms of quality and effects on human health. However, dietary habits characterized by this cultural heritage should also be considered in the context of overall lifestyle behaviors, including sleep habits. This study aimed to systematically revise the literature relating to adherence to the Mediterranean diet and sleep features in observational studies. The systematic review comprised 23 reports describing the relation between adherence to the Mediterranean diet and different sleep features, including sleep quality, sleep duration, daytime sleepiness, and insomnia symptoms. The majority of the included studies were conducted in the Mediterranean basin and reported a significant association between a higher adherence to the Mediterranean diet and a lower likelihood of having poor sleep quality, inadequate sleep duration, excessive daytime sleepiness or symptoms of insomnia. Interestingly, additional studies conducted outside the Mediterranean basin showed a relationship between the adoption of a Mediterranean-type diet and sleep quality, suggesting that biological mechanisms sustaining such an association may exist. In conclusion, current evidence suggests a relationship between adhering to the Mediterranean diet and overall sleep quality and different sleep parameters. The plausible bidirectional association should be further investigated to understand whether the promotion of a healthy diet could be used as a tool to improve sleep quality.

Plant cell suspension cultures (PCSCs) are in vitro-cultured cells that can divide indefinitely in a sterile growth medium. These PCSCs can be derived from various plant tissues, such as the root, stem, leaves, or seeds, and are maintained in a suitable culture medium containing nutrients, vitamins, hormones, and other essential components necessary for their growth. PCSCs have extensive applications in biotechnology, particularly in producing pharmaceutical and chemical compounds. This chapter presents a protocol for generating cell lines from Arabidopsis thaliana root callus under different light conditions, which can be used to investigate the effects of light on plant cell growth and development. The protocol described in this chapter is a valuable tool for researchers interested in utilizing PCSCs in their studies., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Chloroplast isolation protocols have been extensively developed for various species of plants, particularly model organisms with easily manipulable physical characteristics. However, succulent plants, such as Agave angustifolia Haw., which possess adaptations for arid environments like the Crassulacean acid metabolism (CAM) and a thicker cuticle, have received less attention, resulting in a potential knowledge gap. This chapter presents a specialized protocol focusing on isolating chloroplast from A. angustifolia, a species exhibiting adaptations to arid conditions and holding ecological and economic significance due to its role in producing bacanora and mezcal beverages. By successfully isolating chloroplast from A. angustifolia plant growth in ex vitro and in vitro conditions, this protocol enables comprehensive future analyses to elucidate metabolic processes and explore potential applications in related species. Consequently, this research aims to bridge this knowledge gap in chloroplast isolation for succulent plants, providing new insights for future investigations in the field., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Different studies have been conducted to understand how patients with unipolar and bipolar depression differ in terms of cognitive and affective symptoms as well as in psychosocial function. Furthermore, the impact of antidepressants, second-generation antipsychotics, and mood stabilizers on these dimensions needs to be characterized, as well as the best psychometric approach to measure changes after pharmacological treatment., Objectives: This study aims to analyze the impact of psychotropic drugs on cognitive, affective, and psychosocial functioning in MDD and BD patients; to test the sensitivity of psychometric tools for measuring those changes; also, to understand how psychosocial abilities are associated with affective and cognitive dimensions in patients with MDD and BD., Methods: A total of 22 patients with MDD and 21 patients with BD in the depressive phase were recruited. Several psychometric tests were administered to assess affective, cognitive, and psychosocial symptoms before and after 12 weeks of drug treatment (T0 and T1) with different psychotropic drugs including second-generation antidepressants, second-generation antipsychotics and mood stabilizers (lamotrigine)., Results: MDD patients showed significant improvement in MoCA, Delayed Recall of Rey's 15 Words and HDRS, while a significant worsening was detected on Digit Span Backwards and on FAST scores. Instead, patients with BD showed significant improvements in the MoCA as the MDD patients, but only a trend of improvement (non-statistically significant) on the BDI-II. A positive correlation was detected in both groups between FAST and HDRS and BDI-II scores, especially in BD patients., Conclusion: Our results demonstrate that drug treatment with psychotropic drugs can improve cognitive and affective symptoms, but not all psychometric tools may be equally sensitive to detect those changes in MDD vs. BD patients. Moreover, we found that affective and cognitive dimensions can be considered as different psychopathological dimensions both in unipolar and bipolar depression., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Scope: This study aims to systematically review observational studies investigating the relation between dietary (poly)phenol consumption and various cognitive outcomes., Methods and Results: Embase and PubMed databases are searched from inception to April 2023 for observational studies investigating the relation between dietary (poly)phenol intake and cognitive outcomes. For quantitative analyses, random effects models, subgroup analyses, and dose-response analyses are performed. A total of 37 studies are included in the systematic review. Among (poly)phenols, a higher intake of flavonoids is associated with better cognitive function and lower odds of cognitive decline (although with some exceptions). A quantitative meta-analysis shows an overall inverse association with cognitive impairment and reduced association with the incidence of dementia or related disorders for total flavonoids (relative risk (RR) = 0.83, 95% confidence interval (CI): 0.76, 0.89), anthocyanins (RR = 0.73, 95% CI: 0.60, 0.89), flavones (RR = 0.77, 95% CI: 0.63, 0.94), flavan-3-ols (RR = 0.86, 95% CI: 0.82, 0.91), and flavonols (RR = 0.88, 95% CI: 0.80, 0.96). Data on other (poly)phenolic compounds (i.e., phenolic acids) are promising but too preliminary., Conclusion: Habitual inclusion of flavonoids in the diet may play a preventive role against cognitive disorders., (© 2023 The Authors. Molecular Nutrition & Food Research published by Wiley-VCH GmbH.)