The SASP factor IL-6 sustains cell-autonomous senescent cells via a cGAS-STING-NFκB intracrine senescent noncanonical pathway.

Senescent cells produce a Senescence-Associated Secretory Phenotype (SASP) that involves factors with diverse and sometimes contradictory activities. One key SASP factor, interleukin-6 (IL-6), has the potential to amplify cellular senescence in the SASP-producing cells in an autocrine action, while simultaneously inducing proliferation in the neighboring cells. The underlying mechanisms for the contrasting actions remain unclear. We found that the senescence action does not involve IL-6 secretion nor the interaction with the receptor expressed in the membrane but is amplified through an intracrine mechanism. IL-6 sustains intracrine senescence interacting with the intracellular IL-6 receptor located in anterograde traffic specialized structures, with cytosolic DNA, cGAS-STING, and NFκB activation. This pathway triggered by intracellular IL-6 significantly contributes to cell-autonomous induction of senescence and impacts in tumor growth control. Inactivation of IL-6 in somatotrophic senescent cells transforms them into strongly tumorigenic in NOD/SCID mice, while re-expression of IL-6 restores senescence control of tumor growth. The intracrine senescent IL-6 pathway is further evidenced in three human cellular models of therapy-induced senescence. The compartmentalization of the intracellular signaling, in contrast to the paracrine tumorigenic action, provides a pathway for IL-6 to sustain cell-autonomous senescent cells, driving the SASP, and opens new avenues for clinical consideration to senescence-based therapies.

Thrifty tissues prefer recycled purines over new-cleotides.

In two recent studies appearing in Cell1 and Cell Metabolism,2 Tran et al. and Wu et al. describe underappreciated nuance in organismal and cellular purine nucleotide salvage pathways and identify purine salvage as a metabolic limitation for tumor growth.

Ultradense Array of On-Chip Sensors for High-Throughput Electrochemical Analyses.

High-throughput sensors are valuable tools for enabling massive, fast, and accurate diagnostics. To yield this type of electrochemical device in a simple and low-cost way, high-density arrays of vertical gold thin-film microelectrode-based sensors are demonstrated, leading to the rapid and serial interrogation of dozens of samples (10 µL droplets). Based on 16 working ultramicroelectrodes (UMEs) and 3 quasi-reference electrodes (QREs), a total of 48 sensors were engineered in a 3D crossbar arrangement that devised a low number of conductive lines. By exploiting this design, a compact chip (75 × 35 mm) can enable performing 16 sequential analyses without intersensor interferences by dropping one sample per UME finger. In practice, the electrical connection to the sensors was achieved by simply switching the contact among WE adjacent fingers. Importantly, a short analysis time was ensured by interrogating the UMEs with chronoamperometry or square wave voltammetry using a low-cost and hand-held one-channel potentiostat. As a proof of concept, the detection of Staphylococcus aureus in 15 samples was performed within 14 min (20 min incubation and 225 s reading). Additionally, the implementation of peptide-tethered immunosensors in these chips allowed the screening of COVID-19 from patient serum samples with 100% accuracy. Our experiments also revealed that dispensing additional droplets on the array (in certain patterns) results in the overestimation of the faradaic current signals, a phenomenon referred to as crosstalk. To address this interference, a set of analyses was conducted to design a corrective strategy that boosted the testing capacity by allowing using all on-chip sensors to address subsequent analyses (i.e., 48 samples simultaneously dispensed on the chip). This strategy only required grounding the unused rows of QRE and can be broadly adopted to develop high-throughput UME-based sensors. In practice, we could analyze 48 droplets (with [Fe(CN)6]4-) within ∼8 min using amperometry.

Chitosan Coating as a Strategy to Increase Postemergent Herbicidal Efficiency and Alter the Interaction of Nanoatrazine with Bidens pilosa Plants.

The atrazine nanodelivery system, composed of poly(ε-caprolactone) (PCL+ATZ) nanocapsules (NCs), has demonstrated efficient delivery of the active ingredient to target plants in previous studies, leading to greater herbicide effectiveness than conventional formulations. Established nanosystems can be enhanced or modified to generate new biological activity patterns. Therefore, this study aimed to evaluate the effect of chitosan coating of PCL+ATZ NCs on herbicidal activity and interaction mechanisms with Bidens pilosa plants. Chitosan-coated NCs (PCL/CS+ATZ) were synthesized and characterized for size, zeta potential, polydispersity, and encapsulation efficiency. Herbicidal efficiency was assessed in postemergence greenhouse trials, comparing the effects of PCL/CS+ATZ NCs (coated), PCL+ATZ NCs (uncoated), and conventional atrazine (ATZ) on photosystem II (PSII) activity and weed control. Using a hydroponic system, we evaluated the root absorption and shoot translocation of fluorescently labeled NCs. PCL/CS+ATZ presented a positive zeta potential (25 mV), a size of 200 nm, and an efficiency of atrazine encapsulation higher than 90%. The postemergent herbicidal activity assay showed an efficiency gain of PSII activity inhibition of up to 58% compared to ATZ and PCL+ATZ at 96 h postapplication. The evaluation of weed control 14 days after application ratified the positive effect of chitosan coating on herbicidal activity, as the application of PCL/CS+ATZ at 1000 g of a.i. ha-1 resulted in better control than ATZ at 2000 g of a.i. ha-1 and PCL+ATZ at 1000 g of a.i. ha-1. In the hydroponic experiment, chitosan-coated NCs labeled with a fluorescent probe accumulated in the root cortex, with a small quantity reaching the vascular cylinder and leaves up to 72 h after exposure. This behavior resulted in lower leaf atrazine levels and PSII inhibition than ATZ. In summary, chitosan coating of nanoatrazine improved the herbicidal activity against B. pilosa plants when applied to the leaves but negatively affected the root-to-shoot translocation of the herbicide. This study opens avenues for further investigations to improve and modify established nanosystems, paving the way for developing novel biological activity patterns.

In vitro conjugation of IncB/O-plasmid: Minimum inhibitory concentration of ß-lactams increases 16-fold in Salmonella enterica compared with Escherichia coli.

The use of antimicrobials in poultry leaves residues in the litter, favoring the emergence of antimicrobial-resistant pathogens and making it a source of contamination. An in vitro 4 × 4 factorial trial was performed to investigate the influence of four treatments, consisting of antimicrobial sub-concentrations, on the transference of IncB/O-plasmid through conjugation in four groups. Each group was composed of one plasmid donor bacterium (Escherichia coli H2332) and a recipient bacterium (Escherichia coli J62 or Salmonella enterica serovars, Enteritidis, Typhimurium, or Heidelberg). Our results showed a little decrease in the conjugation frequency in almost all treatments between the two bacterial species, which varied according to each strain. The MIC test revealed an increase of up to 4096-fold in resistance to beta-lactams in Salmonella serovars after plasmid acquisition. This finding suggests that some genetic apparatus may be involved in increased antimicrobial resistance in Salmonella serovars after the acquisition of primary resistance determinants.

Intrarenal pressure and flow rate profile using LithoVue™ elite: impact of different irrigation systems and working channel instruments.

PURPOSE: To report real-time IRP and FR while performing flexible ureteroscopy in porcine kidney model utilizing LithoVue™ Elite (Boston Scientific®) with different irrigation systems, including automated pumps. METHODS: Using an ex-vivo model of porcine kidney, IRPs were measured with LithoVue Elite. Ureteroscopic settings (US) were tested with all permutations of irrigation methods (IM), working channel occupant (WCO), and ureteral access sheaths (UAS). IMs included: Single Action Pumping System (SAPS™, Boston Scientific), Thermedx FluidSmart™ (Stryker®), and ENDOMAT™ (Karl Storz®). Pumps were tested at 50, 100, and 150 mmHg. WCOs included a 1.9Fr zero-tip basket, 200 µm, and 365 µm laser fibers. UASs utilized 11/13Fr and 12/14Fr 36 cm. RESULTS: 84 different US were tested (252 experiments). ENDOMAT had higher IRP but the same FR as Thermedx at the same US for 50 and 100 mmHg (p < 0.01). SAPS had higher IRP and FR than pumps in all US studies (p < 0.01). There was positive correlation between pressure set by the pump and both IRP and FR (rho > 0.9). As the diameter of the WCO increased, lower IRP and FR were observed with the pumps (p < 0.01). With SAPS, IRP was similar regardless of WCO, but FR was decreased with the increased diameter of WCO (p = 0.81 and p < 0.01, respectively). There was significantly higher IRP when using 11/13Fr UAS than 12/14Fr (p < 0.01). CONCLUSION: IRP was higher with SAPS than automated pumps. ENDOMAT showed higher IRP than Thermedx when under 150 mmHg. IRP and FR increase with higher pump pressure and decrease with larger diameter WCO. Likewise, a larger UAS significantly reduced IRP.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.