A higher order PUF complex is central to regulation of C. elegans germline stem cells.

PUF RNA-binding proteins are broadly conserved stem cell regulators. Nematode PUF proteins maintain germline stem cells (GSCs) and, with key partner proteins, repress differentiation mRNAs, including gld-1. Here we report that PUF protein FBF-2 and its partner LST-1 form a ternary complex that represses gld-1 via a pair of adjacent FBF-2 binding elements (FBEs) in its 3ÚTR. One LST-1 molecule links two FBF-2 molecules via motifs in the LST-1 intrinsically-disordered region; the gld-1 FBE pair includes a well-established 'canonical' FBE and a newly-identified noncanonical FBE. Remarkably, this FBE pair drives both full RNA repression in GSCs and full RNA activation upon differentiation. Discovery of the LST-1-FBF-2 ternary complex, the gld-1 adjacent FBEs, and their in vivo significance predicts an expanded regulatory repertoire of different assemblies of PUF-partner complexes in nematode germline stem cells. It also suggests analogous PUF controls may await discovery in other biological contexts and organisms.

Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.

Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-ß1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.

Recommendations for patient-centered emergency care.

INTRODUCTION: Patient-centred care is more than just an aspiration, it represents a fundamental shift in the way healthcare must be delivered. Patient-centred emergency care is important for improving the patient and clinician experience and is essential for optimizing health outcomes. Creating a patient-centred emergency department emphasizes the importance of the patient's experience, preferences, and values. METHODS: To formulate recommendations for patient-centred care, we synthesized a literature review, stakeholder interviews, consensus from an expert panel of diverse healthcare professionals and a patient advocate, and reviewed our recommendations for feedback with a presentation at the Canadian Association of Emergency Physicians (CAEP) 2023 Annual Conference Academic Symposium. RESULTS: This paper gives practical recommendations for areas and strategies to improve patient-centredness in Emergency Medicine. It delves into the various dimensions of this approach, including the role of the physical environment, communications and interpersonal interactions, systems of care, and measurement, all of which are essential in providing optimal care to match the patients' needs. CONCLUSION: We seek to inspire a renewed commitment of placing the patient at the heart of emergency care, recognizing that patient-centredness is not merely an option but a fundamental aspect of delivering high quality, compassionate and effective healthcare in the emergency setting. In an era marked by technological advancements and evolving healthcare paradigms, the essence of medicine as a deeply human endeavour is becoming in some ways more possible, if we seize the opportunities.

RéSUMé: INTRODUCTION: Les soins axés sur le patient sont plus qu'une simple aspiration, ils représentent un changement fondamental dans la façon dont les soins de santé doivent être dispensés. Les soins d'urgence axés sur les patients sont importants pour améliorer l'expérience des patients et des cliniciens et sont essentiels pour optimiser les résultats pour la santé. La création d'un service d'urgence axé sur le patient souligne l'importance de l'expérience, des préférences et des valeurs du patient. MéTHODES: Afin de formuler des recommandations pour les soins axés sur les patients, nous avons synthétisé une analyse documentaire, des entrevues avec les intervenants, le consensus d'un comité d'experts composé de divers professionnels de la santé et d'un défenseur des patients. et nous avons examiné nos recommandations en matière de rétroaction lors d'une présentation au colloque universitaire annuel 2023 de l'Association canadienne des médecins d'urgence (ACMU). RéSULTATS: Ce document donne des recommandations pratiques sur les domaines et les stratégies pour améliorer l'orientation des patients en médecine d'urgence. Il examine les diverses dimensions de cette approche, y compris le rôle de l'environnement physique, les communications et les interactions interpersonnelles, les systèmes de soins et la mesure, qui sont tous essentiels pour fournir des soins optimaux afin de répondre aux besoins des patients. CONCLUSION: Nous cherchons à inspirer un engagement renouvelé à placer le patient au cœur des soins d'urgence, reconnaissant que l'orientation du patient n'est pas seulement une option, mais un aspect fondamental de la prestation de soins de santé de haute qualité, compatissants et efficaces en milieu d'urgence. À une époque marquée par les progrès technologiques et l'évolution des paradigmes de la santé, l'essence de la médecine en tant qu'entreprise profondément humaine devient à certains égards plus possible, si nous saisissons les opportunités.

Comparison of the precursor, amino acid oxidation, and end-product methods for the evaluation of protein turnover in senior dogs.

Stable isotope methods have been used to study protein metabolism in humans; however, there application in dogs has not been frequently explored. The present study compared the methods of precursor (13C-Leucine), end-products (15N-Glycine), and amino acid oxidation (13C-Phenylalanine) to determine the whole-body protein turnover rate in senior dogs. Six dogs (12.7 ± 2.6 years age, 13.6 ± 0.6 kg bodyweight) received a dry food diet for maintenance and were subjected to all the above-mentioned methods in succession. To establish 13C and 15N kinetics, according to different methodologies blood plasma, urine, and expired air were collected using a specifically designed mask. The volume of CO2 was determined using respirometry. The study included four methods viz. 13C-Leucine, 13C-Phenylalanine evaluated with expired air, 13C-Phenylalanine evaluated with urine, and 15N-Glycine, with six dogs (repetitions) per method. Data was subjected to variance analysis and means were compared using the Tukey test (P<0.05). In addition, the agreement between the methods was evaluated using Pearson correlation and Bland-Altman statistics. Protein synthesis (3.39 ± 0.33 g.kg-0,75. d-1), breakdown (3.26 ± 0.18 g.kg-0.75.d-1), and flux estimations were similar among the four methods of study (P>0.05). However, only 13C-Leucine and 13C-Phenylalanine (expired air) presented an elevated Pearson correlation and concordance. This suggested that caution should be applied while comparing the results with the other methodologies.

Spatial and temporal distribution of perfluoroalkyl substances (PFAS) detected after an aqueous film forming foam (AFFF) spill.

In 2015, > 460,000 L of aqueous film-forming foam (AFFF) and fire suppressors containing per- and polyfluoroalkyl substances (PFAS) were used to combat a fire at a petrochemical fuel storage terminal in the Port of Santos (Brazil). Sediments from seven sites were sampled repeatedly from 2 weeks to 1 year after the fire (n = 30). Æ©15PFAS concentrations ranged from 115 to 15,931 pg g-1 dry weight (dw). Perfluorooctane sulfonic acid (PFOS) was the most frequently detected compound with concentrations ranging from 363 to 4517 (average = 1603) pg g-1dw to <47.1 to 642 (average = 401) pg g-1 dw, followed by perfluorohexanoic acid (PFHxA) (from 38.8 to 219 (average = 162) pg g-1 dw after 15 days and from <20.8 to 161 (average = 101) pg g-1 dw one year later). Together, the hydrodynamics and fire events documented in the region were important features explaining the spread of PFAS.

Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging.

Formaldehyde (FA) is a recognized environmental and metabolic toxin implicated in cancer development and aging. Inherited mutations in the FA-detoxifying enzymes ADH5 and ALDH2 genes lead to FA overload in the severe multisystem AMeD syndrome. FA accumulation causes genome damage including DNA-protein-, inter- and intra-strand crosslinks and oxidative lesions. However, the influence of distinct DNA repair systems on organismal FA resistance remains elusive. We have here investigated the consequence of a range of DNA repair mutants in a model of endogenous FA overload generated by downregulating the orthologs of human ADH5 and ALDH2 in C. elegans. We have focused on the distinct components of nucleotide excision repair (NER) during developmental growth, reproduction and aging. Our results reveal three distinct modes of repair of FA-induced DNA damage: Transcription-coupled repair (TCR) operating NER-independently during developmental growth or through NER during adulthood, and, in concert with global-genome (GG-) NER, in the germline and early embryonic development. Additionally, we show that the Cockayne syndrome B (CSB) factor is involved in the resolution of FA-induced DNA-protein crosslinks, and that the antioxidant and FA quencher N-acetyl-l-cysteine (NAC) reverses the sensitivity of detoxification and DNA repair defects during development, suggesting a therapeutic intervention to revert FA-pathogenic consequences.

A Review of Methods to Modify the PDMS Surface Wettability and Their Applications.

Polydimethylsiloxane (PDMS) has attracted great attention in various fields due to its excellent properties, but its inherent hydrophobicity presents challenges in many applications that require controlled wettability. The purpose of this review is to provide a comprehensive overview of some key strategies for modifying the wettability of PDMS surfaces by providing the main traditional methods for this modification and the results of altering the contact angle and other characteristics associated with this property. Four main technologies are discussed, namely, oxygen plasma treatment, surfactant addition, UV-ozone treatment, and the incorporation of nanomaterials, as these traditional methods are commonly selected due to the greater availability of information, their lower complexity compared to the new techniques, and the lower cost associated with them. Oxygen plasma treatment is a widely used method for improving the hydrophilicity of PDMS surfaces by introducing polar functional groups through oxidation reactions. The addition of surfactants provides a versatile method for altering the wettability of PDMS, where the selection and concentration of the surfactant play an important role in achieving the desired surface properties. UV-ozone treatment is an effective method for increasing the surface energy of PDMS, inducing oxidation, and generating hydrophilic functional groups. Furthermore, the incorporation of nanomaterials into PDMS matrices represents a promising route for modifying wettability, providing adjustable surface properties through controlled dispersion and interfacial interactions. The synergistic effect of nanomaterials, such as nanoparticles and nanotubes, helps to improve wetting behaviour and surface energy. The present review discusses recent advances of each technique and highlights their underlying mechanisms, advantages, and limitations. Additionally, promising trends and future prospects for surface modification of PDMS are discussed, and the importance of tailoring wettability for applications ranging from microfluidics to biomedical devices is highlighted. Traditional methods are often chosen to modify the wettability of the PDMS surface because they have more information available in the literature, are less complex than new techniques, and are also less expensive.

Combined Germline and Mosaic SDHA Mutation Is Associated With a Multicancer Syndrome Including Neuroblastoma, Renal Cancer, and Multifocal GI Tumor.

Highlighting here a patient case with neuroblastoma, renal cancer & GIST from germline SDHA.

Skin assessment in congenital untreated isolated GH deficiency.

PURPOSE: The separation between the inside and outside through the skin was fundamental for the evolution of prevertebrates, which grow through extrapituitary circuits, to vertebrates, which grow through the somatotrophic axis, namely pituitary growth hormone (GH). and circulating IGF1.Individuals with untreated isolated growth hormone (GH) deficiency (IGHD) due to a mutation in the GH-releasing hormone receptor (GHRH) gene, residing in Itabaianinha, Brazil, are vulnerable to skin cancer and have reduced sweating. However other aspects of their skin physiology are still unknown. Our objectives were to evaluate the number of skin cancers, skin aging, and functional aspects of the skin in this IGHD cohort. METHODS: Twenty-six IGHD individuals and 26 controls matched by age, sex, ethnicity, and occupation were submitted to a biochemical, dermatological and a functional skin assessment by the Multi Probe Adapter Cutometer® MPA 580. RESULTS: There was no difference in the number of skin cancers and in the degrees of photodamage between the groups. The melanin content in the forearm was similar between the groups but was lower in the buttocks (p = 0.005), as well as skin resistance (p < 0.0001) and elasticity (p = 0.003), lower in the IGHD. There was no difference in hydration and sebum content between the two groups. CONCLUSION: IGHD is apparently associated with a neutral profile in terms of skin cancer and photodamage, with similar melanin on the forearm and lower buttocks, lower skin resistance and elasticity, with hydration and sebum similar to controls.

SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase (IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.

Markov models for clinical decision-making in radiation oncology: A systematic review.

The intrinsic stochasticity of patients' response to treatment is a major consideration for clinical decision-making in radiation therapy. Markov models are powerful tools to capture this stochasticity and render effective treatment decisions. This paper provides an overview of the Markov models for clinical decision analysis in radiation oncology. A comprehensive literature search was conducted within MEDLINE using PubMed, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Only studies published from 2000 to 2023 were considered. Selected publications were summarized in two categories: (i) studies that compare two (or more) fixed treatment policies using Monte Carlo simulation and (ii) studies that seek an optimal treatment policy through Markov Decision Processes (MDPs). Relevant to the scope of this study, 61 publications were selected for detailed review. The majority of these publications (n = 56) focused on comparative analysis of two or more fixed treatment policies using Monte Carlo simulation. Classifications based on cancer site, utility measures and the type of sensitivity analysis are presented. Five publications considered MDPs with the aim of computing an optimal treatment policy; a detailed statement of the analysis and results is provided for each work. As an extension of Markov model-based simulation analysis, MDP offers a flexible framework to identify an optimal treatment policy among a possibly large set of treatment policies. However, the applications of MDPs to oncological decision-making have been understudied, and the full capacity of this framework to render complex optimal treatment decisions warrants further consideration.

Molecular and Physiological Effects of 17α-methyltestosterone on Sex Differentiation of Black Rockfish, Sebastes schlegelii.

It is widely known that all-female fish production holds economic value for aquaculture. Sebastes schlegelii, a preeminent economic species, exhibits a sex dimorphism, with females surpassing males in growth. In this regard, achieving all-female black rockfish production could significantly enhance breeding profitability. In this study, we utilized the widely used male sex-regulating hormone, 17α-methyltestosterone (MT) at three different concentrations (20, 40, and 60 ppm), to produce pseudomales of S. schlegelii for subsequent all-female offspring breeding. Long-term MT administration severely inhibits the growth of S. schlegelii, while short term had no significant impact. Histological analysis confirmed sex reversal at all MT concentrations; however, both medium and higher MT concentrations impaired testis development. MT also influenced sex steroid hormone levels in pseudomales, suppressing E2 while increasing T and 11-KT levels. In addition, a transcriptome analysis revealed that MT down-regulated ovarian-related genes (cyp19a1a and foxl2) while up-regulating male-related genes (amh) in pseudomales. Furthermore, MT modulated the TGF-ß signaling and steroid hormone biosynthesis pathways, indicating its crucial role in S. schlegelii sex differentiation. Therefore, the current study provides a method for achieving sexual reversal using MT in S. schlegelii and offers an initial insight into the underlying mechanism of sexual reversal in this species.

Data-driven stabilization of NimPdn-m nanoalloys: a study using density functional theory and data mining approaches.

Green hydrogen, generated through the electrolysis of water, is a viable alternative to fossil fuels, although its adoption is hindered by the high costs associated with the catalysts. Among a wide variety of potential materials, binary nickel-palladium (NiPd) systems have garnered significant attention, particularly at the nanoscale, for their efficacious roles in catalyzing hydrogen and oxygen evolution reactions. However, our atom-level understanding of the descriptors that drive their energetic stability at the nanoscale remains largely incomplete. Here, we investigate by density functional theory calculations the descriptors that drives the stability of the NimPdn-m clusters for different sizes (n = 13, 27, 41) and compositions. To achieve our goals, a large number of trial configurations were generated and selected using data mining algorithms (k-means, t-SNE) and genetic algorithms, while the most important physical-chemical descriptors were identified using Spearman correlation analysis. We have found that core-shell formation, with the smaller Ni atoms lying in the center of the particle, plays a major role in the stabilization of the nanoalloys, and this effect causes the alloys to assume a icosahedral-fragment configuration (as the unary nickel cluster) instead of a fcc fragment (as the unary palladium cluster). However, the core-shell formation in this alloy is unique in that Pd poor compositions exhibit scattered Pd atoms on the surface. As the palladium content increases, this gives rise to the complete Pd shell. This stabilization mechanism is quantitatively supported by the different correlations observed in the number of Ni-Ni and Pd-Pd bonds with energy, in which the latter tends to decrease alloy stability. Furthermore, a notable trend is the correlation between the coordination number of Ni atoms with alloy stabilization, while the coordination of Pd atoms shows an inverse correlation.

Leishmania Ribosomal Protein (RP) paralogous genes compensate each other's expression maintaining protein native levels.

In the protozoan parasite Leishmania, most genes encoding for ribosomal proteins (RPs) are present as two or more copies in the genome. However, their untranslated regions (UTRs) are predominantly divergent and might be associated with a distinct regulation of the expression of paralogous genes. Herein, we investigated the expression profiles of two RPs (S16 and L13a) encoded by duplicated genes in Leishmania major. The genes encoding for the S16 protein possess identical coding sequences (CDSs) and divergent UTRs, whereas the CDSs of L13a diverge by two amino acids and by their UTRs. Using CRISPR/Cas9 genome editing, we generated knockout (Δ) and endogenously tagged transfectants for each paralog of L13a and S16 genes. Combining tagged and Δ cell lines we found evidence of differential expression of both RPS16 and RPL13a isoforms throughout parasite development, with one isoform consistently more abundant than its respective copy. In addition, compensatory expression was observed for each paralog upon deletion of the corresponding isoform, suggesting functional conservation between these proteins. This differential expression pattern relates to post-translational processes, given compensation occurs at the level of the protein, with no alterations detected at transcript level. Ribosomal profiles for RPL13a indicate a standard behavior for these paralogues suggestive of interaction with heavy RNA-protein complexes, as already reported for other RPs in trypanosomatids. We identified paralog-specific bound to their 3'UTRs which may be influential in regulating paralog expression. In support, we identified conserved cis-elements within the 3'UTRs of RPS16 and RPL13a; cis-elements exclusive to the UTR of the more abundant paralog or to the less abundant ones were identified.

Holmium:yttrium-aluminium-garnet laser with MOSES technology is more efficient than thulium fibre laser in supine mini-percutaneous nephrolithotomy.

OBJECTIVES: To address the paucity of literature comparing outcomes achieved with utilisation of the high-power holmium:yttrium-aluminium-garnet (Ho:YAG) laser with MOSES technology vs those achieved with the thulium fibre laser (TFL) in mini-percutaneous nephrolithotomy (PCNL). METHODS: A retrospective review was performed of patients undergoing supine mini-PCNL between August 2021 and May 2023. Exclusion criteria were urinary diversion, simultaneous utilisation of >1 laser platform, use of any other form of fragmentation, and ureteric stones. The Ho:YAG platform (Lumenis Pulse P120H™ with MOSES technology, 120W; Boston Scientific®) and the TFL (Soltive SuperPulsed Thulium Fibre [SPTF], 60W; Olympus®) were compared. Data on stone-free rate (SFR) were determined by computed tomography performed on the first postoperative day and presented as absence of stone fragments, no fragments larger than 2 mm, or no fragments larger than 4 mm. RESULTS: A total of 100 patients met the inclusion criteria, 51 mini-PCNLs with the Ho:YAG laser and 49 with the SPTF laser. No significant differences in demographics or stone characteristics were detected between the two groups. The Ho:YAG laser utilised less energy and time, resulting in higher ablation efficiency (P < 0.05) and less total operating time (P < 0.05). Overall, there was no difference in SFR in any category between the Ho:YAG group and the SPTF group (no fragments: relative risk [RR] 0.81, 95% confidence interval [CI] 0.59-1.12, P = 0.21; fragments <2 mm: RR 0.86, 95% CI 0.67-1.10, P = 0.23; fragments <4 mm: RR 0.96, 95% CI 0.80-1.15, P = 0.67). CONCLUSIONS: Although we observed an equivalent postoperative SFR, this study supports a shorter operating time and greater intra-operative laser efficiency with the Ho:YAG laser over the SPTF laser in mini-PCNL.

Brain morphometry and estimation of aging brain in subjects with congenital untreated isolated GH deficiency.

PURPOSE: Individuals with isolated GH deficiency (IGHD) due to a mutation in the GHRH receptor gene have a normal life expectancy and above 50 years of age, similar total cognitive performance, with better attention and executive function than controls. Our objectives were to evaluate their brain morphometry and brain aging using MRI. METHODS: Thirteen IGHD and 14 controls matched by age, sex, and education, were enrolled. Quantitative volumetric data and cortical thickness were obtained by automatic segmentation using Freesurfer software. The volume of each brain region was normalized by the intracranial volume. The difference between the predicted brain age estimated by MRI using a trained neuronal network, and the chronological age, was obtained. p < 0.005 was considered significant and 0.005 < p < 0.05 as a suggestive evidence of difference. RESULTS: In IGHD, most absolute values of cortical thickness and regional brain volumes were similar to controls, but normalized volumes were greater in the white matter in the frontal pole and in the insula bilaterally, and in the gray matter, in the right insula and in left Caudate (p < 0.005 for all comparisons) We also noticed suggestive evidence of a larger volume in IGHD in left thalamus (p = 0.006), right thalamus (p = 0.025), right caudate (p = 0.046) and right putamen (p = 0.013). Predicted brain ages were similar between groups. CONCLUSION: IGHD is primarily associated with similar absolute brain measurements, and a set of larger normalized volumes, and does not appear to alter the process of brain aging.

A Compound That Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Nonspecific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small-molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell-cycle, metabolic, and enzymatic assays were used to demonstrate their mechanism of action. A human patient-derived xenograft model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small-molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

The spread of pESI-mediated extended-spectrum cephalosporin resistance in Salmonella serovars-Infantis, Senftenberg, and Alachua isolated from food animal sources in the United States.

The goal of this study is to investigate the origin, prevalence, and evolution of the pESI megaplasmid in Salmonella isolated from animals, foods, and humans. We queried 510,097 Salmonella genomes under the National Center for Biotechnology Information (NCBI) Pathogen Detection (PD) database for the presence of potential sequences containing the pESI plasmid in animal, food, and environmental sources. The presence of the pESI megaplasmid was confirmed by using seven plasmid-specific markers (rdA, pilL, SogS, TrbA, ipf, ipr2 and IncFIB(pN55391)). The plasmid and chromosome phylogeny of these isolates was inferred from single nucleotide polymorphisms (SNPs). Our search resolved six Salmonella clusters carrying the pESI plasmid. Four were emergent Salmonella Infantis clusters, and one each belonged to serovar Senftenberg and Alachua. The Infantis cluster with a pESI plasmid carrying blaCTX-M-65 gene was the biggest of the four emergent Infantis clusters, with over 10,000 isolates. This cluster was first detected in South America and has since spread widely in United States. Over time the composition of pESI in United States has changed with the average number of resistance genes showing a decrease from 9 in 2014 to 5 in 2022, resulting from changes in gene content in two integrons present in the plasmid. A recent and emerging cluster of Senftenberg, which carries the blaCTX-M-65 gene and is primarily associated with turkey sources, was the second largest in the United States. SNP analysis showed that this cluster likely originated in North Carolina with the recent acquisition of the pESI plasmid. A single Alachua isolate from turkey was also found to carry the pESI plasmid containing blaCTX-M-65 gene. The study of the pESI plasmid, its evolution and mechanism of spread can help us in developing appropriate strategies for the prevention and further spread of this multi-drug resistant plasmid in Salmonella in poultry and humans.